Neurodegeneration with Brain Iron Accumulation (NBIA) and PKAN

A group of hereditary neurodegenerative diseases with abnormal iron accumulation in the basal ganglia, centred on pantothenate kinase-associated neurodegeneration (PKAN, PANK2 gene), with the remaining group entities — PLAN, MPAN, BPAN, aceruloplasminaemia, neuroferritinopathies, Kufor-Rakeb syndrome, FAHN, Woodhouse-Sakati syndrome and CoPAN — addressed in dedicated subsections.

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

Neurodegeneration with brain iron accumulation (NBIA) is a clinical and radiological group rather than a single disease. The following tables bring together the identifiers for each entity and essential clinical data; prevalence figures are presented with the nature of the estimate, discussed in section 9. The group overview GeneReviews (NBK121988, updated on 6 March 2025) was endorsed by the European Reference Network for Rare Neurological Diseases (ERN-RND) as best clinical practice for all NBIAs, in an update published on 29 January 2026 [1, 2].

Table 0.1 — Identifiers of the entities covered in the article

Sources: [1, 3–22]. For PKAN, classification codes are ICD-10 G23.0 and ICD-11 5C64.10 [11].

Table 0.2 — Essential clinical data

Sources: [1, 4, 7, 10–12, 14, 15, 17, 18, 23–27].

The relevant European reference network is ERN-RND, through the “Dystonia, Paroxysmal Disorders and NBIA” disease group [2]. In France, the PNDS (French National Diagnosis and Care Protocol) of the Haute Autorité de Santé (HAS) for NBIA, dated April 2022, was drawn up by the reference centre for rare neurogenetic diseases (CRMR Neurogénétique) of the BRAIN-TEAM health network (filière), as a joint project with the G2M and DéfiScience filières; the French organisation is described in section 9.4 [28]. No newborn screening exists for any of the entities in the sources consulted.

1. Introduction

1.1. Definition of the group

NBIA denotes a set of hereditary neurological diseases in which magnetic resonance imaging (MRI) or neuropathological examination shows abnormal iron accumulation in the basal ganglia, most frequently the globus pallidus and substantia nigra, often accompanied by cerebral and cerebellar atrophy [1]. Cardinal manifestations vary with subtype and include progressive dystonia, dysarthria, spasticity, parkinsonism, neuropsychiatric changes, optic atrophy or retinal degeneration and, in some types, cognitive decline. Onset ranges from childhood to adulthood and progression may be rapid or slow, with long periods of stability; early-onset forms generally progress faster [1]. Iron is not the primary cause in most entities: of the ten diseases in which Saudubray recognises brain iron accumulation, only aceruloplasminaemia and neuroferritinopathy are directly related to iron homeostasis, whereas in the others deposition is variable, poorly understood and only partly responsible for symptoms [29]. MRI-detectable iron accumulation also occurs with ageing and other chronic neurodegenerative diseases, so the radiological sign must be interpreted alongside clinical findings [29].

1.2. From Hallervorden-Spatz syndrome to PKAN

The historical designation “Hallervorden-Spatz syndrome” is no longer recommended because of the unethical activities of the two German neuropathologists before and during the Second World War, as documented by Shevell in 2003 and recognised by GeneReviews [3]. The molecular turning point came in 2001, when Zhou and colleagues, through mapping in families with the syndrome, identified variants in a new pantothenate kinase gene, PANK2, and proposed an oxidative stress mechanism [30]. In 2003, Hayflick and colleagues studied 123 patients from 98 families with a clinical diagnosis of Hallervorden-Spatz syndrome, classified them into classic (early onset, rapid progression) and atypical (late onset, slow progression) forms, and found that all classic patients and one-third of atypical patients had PANK2 variants; all patients with variants had a T2-weighted MRI pattern of central hyperintensity within a hypointense globus pallidus, termed the “eye-of-the-tiger” sign, absent in all patients without variants [31]. That study established the PKAN designation. HARP syndrome (hypoprebetalipoproteinaemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration), described as a separate entity, proved allelic, and the two published families belong to the PKAN spectrum [3, 32].

1.3. Discovery of the remaining genes

Aceruloplasminaemia was the first NBIA with a known molecular basis. Miyajima and colleagues described “familial apocaeruloplasmin deficiency” in 1987 [7] and, in 1995, Harris and colleagues identified a 5-base-pair insertion in CP exon 7 in a patient with complete absence of serum caeruloplasmin, late-onset retinal and basal ganglia degeneration and excess hepatic iron, establishing the disease as a recessive iron metabolism disorder and suggesting CP testing in patients with movement disorders and “non-classical Wilson” presentations [33]. In 2001, in the same Nature Genetics issue as the PANK2 discovery, Curtis and colleagues described an adult-onset dominantly inherited basal ganglia disease, phenotypically resembling Huntington disease or parkinsonism, caused by an adenine insertion in FTL, found in five apparently unrelated individuals from north-east England and Cumbria [26].

Infantile neuroaxonal dystrophy was described by Franz Seitelberger in 1952, and Karak syndrome was published as the presentation of two siblings with early cerebellar ataxia, dystonia, spasticity and intellectual decline, with cerebellar atrophy and iron in the globus pallidus and substantia nigra [4]. In 2006, Morgan and colleagues showed that variants in PLA2G6, encoding calcium-independent group VI phospholipase A2, caused INAD, NBIA and Karak syndrome [34]. That same year, Ramirez and colleagues associated loss-of-function variants in ATP13A2, a lysosomal type 5P ATPase, with recessive early-onset parkinsonism with pyramidal degeneration and dementia described in a Jordanian family (Kufor-Rakeb syndrome) [35]; inclusion in NBIA followed later, based on brain iron observed in a family described in 1994 [1]. In 2008, Alazami and colleagues identified a founder 1-base-pair deletion in C2orf37 (now DCAF17) in eight Saudi families with Woodhouse-Sakati syndrome, a condition described in 1983 [36, 37]. In 2010, Kruer and colleagues described FAHN through autozygosity mapping in two families with FA2H variants, linking white matter degeneration to NBIA and demonstrating allelism with SPG35 and a progressive familial leukodystrophy [38]. In 2011, Hartig and colleagues found a homozygous 11-base-pair deletion in the orphan gene C19orf12 and, screening 23 idiopathic NBIA index cases, identified two pathogenic alleles in 18, defining MPAN [39]. In 2012, Haack and colleagues identified de novo variants in X-chromosomal WDR45 through exome sequencing and proposed BPAN [40]. CoPAN was described in 2014 through exome sequencing in two patients with COASY variants [1, 21], and FTH1 neuroferritinopathy was defined in 2023 in a series of five children [11].

1.4. Nomenclature and number of genes

The number of entities varies with inclusion criteria. The 2025 overview GeneReviews recognises 11 genes with iron accumulation confirmed at autopsy (ATP13A2, C19orf12, COASY, CP, DCAF17, FA2H, FTH1, FTL, PANK2, PLA2G6 and WDR45) [1]; the 2022 Saudubray refers to at least 15 genes [41]; a 2021 review counted 15 monogenic entities [42]; and the July 2026 review by Cascone and colleagues lists 18 genes, adding SCP2, CRAT, SLC27A3, MECR, AP4M1, REPS1 and GTPBP2 [22]. The 2022 French PNDS adopts an intermediate list of 15 genes — the ten of the classic forms (PANK2, PLA2G6, C19orf12, WDR45, FA2H, COASY, ATP13A2, DCAF17, FTL and CP) and five recently described ones (SCP2, GTPBP2, AP4M1, REPS1 and CRAT) — without FTH1 [28]. A 2025 review covers ten NBIAs, listing the same entities as this article except the FTH1 form [43]. The difference mainly reflects the inclusion of radiological phenocopies. The four most frequent forms are PKAN, PLAN, MPAN and BPAN, and known genes account for approximately 85% of patients diagnosed with NBIA [44]. The PNDS presents the same issue from another angle: among patients with clinical and imaging features of NBIA, the proportion without a pathogenic variant in one of the 15 genes ranges from 20% to just over 50% depending on the study, mainly because laboratories apply more or less strict criteria for accepting test requests; the two figures are not comparable, because one has as its denominator the patients of a reference registry and the other series with heterogeneous entry criteria [28, 44]. Proposed nomenclature for PLA2G6 diseases encompasses the entire spectrum under PLAN, with infantile PLAN (formerly INAD), juvenile PLAN (formerly atypical NAD and Karak syndrome) and adult PLAN (formerly PLA2G6-related dystonia-parkinsonism or PARK14); in Movement Disorder Society nomenclature for genetic movement disorders, this corresponds to NBIA/DYT/PARK-PLA2G6 [4]. SENDA (static encephalopathy of childhood with neurodegeneration in adulthood) has been replaced by BPAN [6]. FAHN is also classified as a leukodystrophy or SPG35, depending on perspective [9].

1.5. Definition of the entities within scope

PKAN is an autosomal recessive disease due to biallelic PANK2 variants, with a classic form beginning in the first decade, progressive dystonia and frequent retinopathy, and a later-onset atypical form dominated by speech and psychiatric changes with slow progression [3]. PLAN is the recessive disease due to PLA2G6 variants, now understood as an age-related continuum rather than discrete phenotypes [4]. MPAN results from C19orf12 variants, with recessive or, less frequently, dominant inheritance [5]. BPAN is the X-linked dominant disease due to WDR45 variants, almost always de novo, with a biphasic course [6, 24]. Aceruloplasminaemia is systemic iron overload due to absent caeruloplasmin ferroxidase activity [7]. Neuroferritinopathies are dominant diseases due to FTL (adult) or FTH1 (childhood) variants [8, 11]. Kufor-Rakeb syndrome is recessive juvenile parkinsonism due to ATP13A2; FAHN is recessive FA2H neurodegeneration; Woodhouse-Sakati syndrome combines endocrinopathy, alopecia and extrapyramidal disease due to DCAF17; and CoPAN is the recessive COASY form, allelic with pontocerebellar hypoplasia type 12 [1, 11, 29].

2. Molecular Genetics and Pathophysiology

2.1. Brain iron and mechanistic classification

The body requires more than 20 mg of iron daily, but absorbs only 1–2 mg in the duodenum through the DMT1 transporter (SLC11A2); the remainder is recycled by macrophage haem oxygenase. Ferroportin (SLC40A1) exports iron, which is oxidised from Fe2+ to Fe3+ by hephaestin in enterocytes and, in other cell types, by membrane caeruloplasmin, before transferrin transport; ferritin is the storage form and hepcidin inhibits ferroportin under regulation by HFE, haemojuvelin and TFR2. Iron cannot be actively excreted [29]. In this context, the review by Cascone and colleagues organised the 18 NBIA genes by mechanism, showing that only three (CP, FTL and FTH1) act directly in iron homeostasis [22].

Table 2.1 — Mechanistic classification of NBIA genes

Source: [22], Table 1.

2.2. PANK2 and the coenzyme A pathway

PANK2 is located at 20p13 and encodes pantothenate kinase 2, the only human pantothenate kinase isoform (PANK1α, PANK1β, PANK2, PANK3 and PANK4) targeted to mitochondria, where it occupies the intermembrane space [11, 22]. The enzyme phosphorylates pantothenate (vitamin B5) to 4'-phosphopantothenate, the first and rate-limiting step in coenzyme A (CoA) biosynthesis; the pathway continues through phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), which generates 4'-phosphopantetheine, and ends with bifunctional CoA synthase (COASY), responsible for the final two steps [22]. PANK2 also phosphorylates N-pantothenoylcysteine and pantetheine, undergoes feedback inhibition by acetyl-CoA in eukaryotes and is activated by palmitoylcarnitine, linking CoA synthesis to mitochondrial fatty acid entry [3, 22]. The predicted protein is 50.5 kDa [3].

PKAN results from deficient or absent PANK2 activity. Two complementary hypotheses have been proposed: accumulation of N-pantothenoylcysteine and pantetheine, toxic directly or through free-radical damage as iron chelators, and CoA depletion with defective membrane biosynthesis in tissues where PANK2 is the main pantothenate kinase or CoA demand is greater [3]. The retina is an example: rods continually renew their membrane discs, potentially explaining retinopathy [3]. Saudubray interprets the dysfunction as impaired fatty acid β-oxidation with oxidative stress at the most vulnerable sites [29]. Animal models (yeast, fly, zebrafish and mouse) do not reproduce the full phenotype: Pank2 knockout mice have defective spermatogenesis and late retinal degeneration without motor impairment, but a ketogenic diet triggers PKAN-like motor dysfunction; GABAergic medium spiny neurones and astrocytes derived from patients' induced pluripotent stem cells show iron overload, ferroptosis and altered endosomal trafficking; plasma metabolomics revealed altered lipid and cholesterol synthesis, with elevated plasma lactate and pantothenate [22]. Zhang and colleagues showed that the most frequent variant, historical p.Gly521Arg, produces a misfolded, inactive protein, whereas nine other pathogenic variants produce proteins with normal catalytic activity and regulation, suggesting additional PANK2 functions [3].

Neuropathologically, most lesions lie in the globus pallidus and, variably, adjacent structures. In the index case studied by Kruer, the eye-of-the-tiger sign corresponded to an area of rarefaction in the centre of the internal globus pallidus, depleted of viable neurones, with iron in coarse perivascular haemosiderin deposits. Axonal spheroids occur in the pallidonigral system and cerebral white and grey matter, not restricted to iron-containing areas, and ubiquitinated apolipoprotein E-enriched aggregates in the globus pallidus resemble infarct lesions, suggesting a tissue hypoxic-ischaemic component in pathogenesis [3]. In the series by Giuliano and colleagues, central hyperintensity was interpreted as tissue rarefaction with microglial activation and hypointensity as iron, which obliterates the central signal in advanced disease [45].

2.3. PANK2 variants, nomenclature and genotype–phenotype correlations

The PANK2 MANE Select transcript is NM_001386393.1 (ENST00000610179.7; protein NP_001373322.1). Historical literature, GeneReviews and most clinical reports use NM_153638 (NP_705902.2), encoding the longer isoform, a preprotein; the difference between the two numbering systems is fixed at 330 nucleotides and 110 amino acids and was confirmed using VariantValidator for the variants in Table 2.2 [3, 46]. The classical literature variant p.Gly521Arg thus corresponds to p.Gly411Arg on the MANE transcript; ClinVar classifies NM_001386393.1(PANK2):c.1231G>A (p.Gly411Arg) as pathogenic/likely pathogenic, with criteria provided by multiple submitters without conflicts (last evaluated on 1 February 2026), and also records G521R, G230R and G85R names from other transcripts [47]. The “historical” nomenclature given in parentheses by GeneReviews (1231G>A, Gly411Arg; 1253C>T, Thr418Met; 1021C>T, Arg341Ter) coincides with MANE transcript numbering, so the same allele appears under two names in the literature and only specifying the transcript enables reports to be compared [3].

Table 2.2 — Selected PANK2 variants in both numbering systems

Sources: [3, 45, 46, 48]. Allele frequencies refer to patient alleles, not the general population [3].

Sources differ on the variant attributed to the original HARP patient. GeneReviews states that c.1413-1G>T (IVS4-1G>T) was originally identified in an individual diagnosed with HARP syndrome (Ching and colleagues, 2002) [3]; GeneGuidance, citing the same paper, describes the original HARP patient as homozygous for p.Arg371Ter [11]. The sources consulted cannot resolve these descriptions or determine whether p.Arg371Ter uses another numbering system, so both are recorded here. Other variants of population relevance are recurrent p.Arg440Pro in Korea, described using the original paper's numbering, and a founder 3-base-pair deletion in the Netherlands [3].

There is no complete genotype–phenotype correlation. Two null alleles consistently produce the classic form, as does p.Gly521Arg homozygosity; other combinations (null with missense, homozygous missense or compound heterozygous missense) may produce classic or atypical disease without a predictable pattern [3]. Two-thirds of patients are compound heterozygotes [3]. In the 2003 series, truncating variants predominated in the classic form and missense variants in the atypical form, and predicted protein levels correlated with severity [31]; interallelic complementation was proposed in compound heterozygotes with missense variants in subunit interaction domains [3]. Intrafamilial phenotype is reasonably consistent, with greater variation in atypical families [3], but the Dominican cohort shows that the same homozygous c.680A>G variant is distributed equally between classic and atypical forms, pointing to modifiers [48]. No phenotypes beyond the PKAN/HARP spectrum are known to be associated with PANK2 [3]. In gene–disease curation, GenCC records definitive validity (G2P), and Genomics England PanelApp and Labcorp classify the association as strong; ClinGen has no validity, dosage or actionability curation for PANK2 [11].

2.4. PLA2G6 (PLAN)

PLA2G6, at 22q13.1, encodes calcium-independent group VIA phospholipase A2 (iPLA2-β, also called PNPLA9), an 85/88 kDa protein hydrolysing glycerophospholipids at the sn-2 position, releasing a free fatty acid, usually arachidonic or docosahexaenoic acid (DHA), and a lysophospholipid [4, 49]. It participates in phospholipid remodelling, eicosanoid synthesis, apoptosis, membrane homeostasis and repair of oxidised mitochondrial phospholipids [4, 11]. The defect alters membrane lipid composition and leads to axonal pathology with spheroids, the neuropathological hallmark of the infantile form [4, 29]. The mechanism is loss of function; infantile and atypical form variants abolish fatty acid release, whereas dystonia-parkinsonism variants may retain catalytic activity while altering substrate preference or regulation [49]. Genotype–phenotype correlation is limited to the observation that loss-of-function variants and missense variants predicted to be more deleterious in silico are associated predominantly with the infantile form [4]; in Altuame's series of 28 patients, truncating variants differed from missense or in-frame variants in timing of first clinical concern and initial language loss [50]. The founder variant NM_003560.4:c.2070_2072del p.(Val691del) (MANE; NM_003560.2 in GeneReviews, with the same designation) occurs in a North African cohort (Tunisia) and in Israeli Bedouins [4]. As an allelic disease, Saudubray describes infantile pontocerebellar hypoplasia with anterior horn degeneration in two homozygous siblings, and GeneReviews considers the association with Schindler disease type 1 speculative [4, 49].

2.5. C19orf12 (MPAN)

C19orf12, at 19q12, encodes a small mitochondrial protein, with 141- and 152-amino-acid isoforms, associated with the membrane and coregulated with fatty acid biogenesis and branched-chain amino acid degradation proteins; a role in lipid homeostasis is suspected [5]. The recessive form results from loss of function; the dominant form results from heterozygous variants in the last exon (exon 3) that escape nonsense-mediated decay and produce a protein truncated after amino acid 79, with a proposed dominant-negative effect [5]. Angelini and colleagues described eight patients from four French families with dominant MPAN, including two mosaic carriers with an atypical late-onset phenotype, and fibroblasts with iron storage and autophagy abnormalities more severe than in the recessive form [51]. Neuropathology shows widespread Lewy bodies in the neocortex, deep grey matter and midbrain, more prominent than in PLAN, alongside spheroids and tau pathology [5, 39].

Table 2.3 — Clinically relevant C19orf12 variants (NM_001031726.3, transcript used by GeneReviews)

Source: [1, 5]. SPG43 has been proposed as an allelic disease, but early MPAN spastic paraparesis may lead to a provisional hereditary spastic paraplegia diagnosis until the full phenotype becomes apparent [5].

2.6. WDR45 (BPAN)

WDR45, at Xp11.23, has 12 exons, the first two non-coding; the longest transcript is NM_007075.3 and variant NM_001029896.1 has an alternative 5'UTR and one fewer amino acid [6]. It encodes WIPI4, a protein with WD40 repeats arranged in a seven-bladed beta-propeller, the origin of the disease name, which binds phosphatidylinositol-3-phosphate, acts downstream of WIPI2 in controlling autophagosome size and, with WIPI1, promotes ATG2A- and ATG2B-mediated lipid transfer [6, 11]. Patient lymphoblasts and brain show dysregulated autophagic flux; neurones are particularly vulnerable because of the extent of axonal and dendritic cytoplasm relative to perinuclear lysosomes [6]. Iron metabolism is altered in patient fibroblasts but, as in other NBIAs, iron accumulation is probably secondary, questioning its removal as a therapeutic goal [24]. Variants occur in exons 3–12 and include all types (missense, nonsense, splice variants, small insertions and deletions); most predict loss of function and are de novo and private; a de novo 19.9 kb deletion spanning WDR45 exons 3–12 and adjacent genes (PRAF2 and part of CCDC120) was described in a man [6]. Neuropathology predominantly affects the substantia nigra rather than globus pallidus, with axonal spheroids and numerous tau-positive neurofibrillary tangles, without β-amyloid plaques, Lewy bodies or α-synuclein pathology, unlike MPAN and PLAN [6].

The sex distribution is atypical for an X-linked disease. Far fewer males are affected, and the phenotype is similar in both sexes. Females are functional mosaics through X-inactivation, and most surviving males have somatic mosaicism; five males from three families with germline variants (two missense and one 3-base-pair in-frame deletion) have been described, generally more severely affected than their sisters [6]. The 2021 consensus summarises phenotype determinants as timing and tissue distribution of the somatic variant, presence of a second X chromosome and X-inactivation pattern; mosaic males tend to have mild to classic phenotypes, and non-mosaic males tend to be more severe than typical females [24]. Germline nonsense variants would be incompatible with male survival [11]. Analysis of 160 published cases showed no clear genotype–phenotype correlation [25]. No allelic diseases are known [6]. Saudubray classifies BPAN among cellular trafficking and autophagy disorders alongside Kufor-Rakeb syndrome, and notes that TRAPPC11 recruits the ATG2B-WIPI4 complex to pre-autophagosomal membranes [52].

2.7. CP (aceruloplasminaemia)

CP has 19 exons and encodes caeruloplasmin, a blue copper oxidase carrying more than 95% of plasma copper with ferroxidase activity crucial to tissue iron mobilisation: it oxidises Fe2+ to Fe3+ without releasing oxygen radicals, allowing apotransferrin loading [7, 11]. There is a secreted 1,040-amino-acid form produced predominantly by hepatocytes, and a glycosylphosphatidylinositol-anchored 1,065-amino-acid form generated by alternative splicing downstream of exon 18, expressed in astrocytes and viscera and essential for iron export from brain, retinal, hepatic and pancreatic cells [7, 29]. More than 70 pathogenic variants have been described in over 60 families, without hotspots, more than half loss-of-function; abnormal products are degraded, retained in the endoplasmic reticulum or prevented from incorporating copper in the Golgi apparatus [7]. GeneReviews Table 5 (NM_000096.3) lists c.2962G>A p.(Gly988Ser), also called Gly969Ser in mature-peptide numbering, and c.2991T>G p.(His997Gln), also called His978Gln [7]. Pathology shows visceral iron with heavier loading in liver than brain, without cirrhosis; iron in islet of Langerhans beta cells; and, in the brain, iron in the globus pallidus, putamen, cerebral and cerebellar cortex, more in astrocytes than neurones, with astrocytic deformity, characteristic globular structures and marked Purkinje cell loss [7]. There is no clear genotype–phenotype correlation [7].

2.8. FTL and FTH1 (neuroferritinopathies)

Ferritin comprises heavy (FTH) and light (FTL) subunits and each molecule stores up to 4,500 iron atoms [8]. FTL, at 19q13.33, has four exons; variant c.460dupA p.(Arg154LysfsTer27) (NM_000146.3) accounts for approximately 80% of alleles, alters the 22 carboxy-terminal residues (helix D, DE loop and helix E) and extends the protein by four amino acids, altering storage capacity and allowing excessive neuronal iron release through a dominant-negative effect; mitochondrial respiratory chain dysfunction has also been documented [8]. The mechanism is gain of function, so large deletions or duplications are not expected as a cause [8]. The only described missense variant, c.286G>A p.(Ala96Thr), was published by a Portuguese group (Maciel and colleagues, 2005) in early-onset bilateral pallidal involvement, according to the GeneReviews attribution [8]. Histopathology shows spherical iron and ferritin inclusions in microglia, oligodendrocytes and neurones, and neuroaxonal spheroids [8].

FTL has two allelic diseases without neurodegeneration, whose distinction has therapeutic consequences. Heterozygous nonsense variants cause L-ferritin deficiency (OMIM 615604), with low serum ferritin without iron-deficiency anaemia or neurological dysfunction [8]. Variants in the 5'UTR iron-responsive element cause hereditary hyperferritinaemia-cataract syndrome (OMIM 600886), with high ferritin, bilateral cataracts and no brain iron; transferrin saturation is normal in this syndrome and phlebotomy and iron depletion are inappropriate and potentially harmful [8, 11].

FTH1 neuroferritinopathy (NBIA9, OMIM 620669) was defined by Shieh and colleagues in 2023 in five unrelated children with heterozygous de novo nonsense variants, four with recurrent p.Phe171Ter; neuropathology shows widespread ferritin inclusions, and the proposed mechanism is toxic gain of function of the truncated subunit [11]. ClinGen classified gene–disease validity as moderate for NBIA9 (23 September 2025) and limited for haemochromatosis type 5, described in a Japanese family [11].

2.9. ATP13A2, FA2H, COASY and DCAF17

ATP13A2 encodes a lysosomal P5-type ATPase transporting polyamines and divalent metal cations, necessary for intracellular manganese homeostasis and neuroprotective during oxidative stress, metal exposure and α-synuclein toxicity; deficiency causes lysosomal and mitochondrial dysfunction through disrupted autophagy [1, 29, 53]. Truncating variants are retained in the endoplasmic reticulum and degraded by the proteasome [35]. The same recessive variants produce three allelic phenotypes: Kufor-Rakeb syndrome, spastic paraplegia SPG78 (OMIM 617225) and CLN12 neuronal ceroid lipofuscinosis, as well as a juvenile amyotrophic lateral sclerosis-like phenotype [11, 29, 53]. ClinGen classifies the Kufor-Rakeb association as definitive [11].

FA2H, at 16q23.1, has seven exons (NM_024306.4) and encodes fatty acid 2-hydroxylase, a 43 kDa, 372-amino-acid endoplasmic reticulum protein requiring iron as a cofactor and α-hydroxylating long- and very-long-chain fatty acids destined for myelin galactosylceramides and sulphatides [9, 27]. Loss of function reduces 2-hydroxysphingomyelin and 2-hydroxygalactosylceramide, causing abnormal white matter, increased membrane fluidity and autophagy effects; in the peripheral nervous system, a second enzyme may compensate, unlike in the central nervous system [9, 27]. Variants are mostly private, deletions and duplications are rare, and there is no genotype–phenotype correlation or allelic disease beyond the SPG35/leukodystrophy spectrum [9]. Four patients from non-consanguineous families with maternal or paternal chromosome 16 uniparental disomy have been described [9].

COASY, at 17q21.2, encodes bifunctional CoA synthase (PPAT and DPCK activities), catalysing the final two CoA synthesis steps [22, 29]. Complete biallelic loss causes pontocerebellar hypoplasia type 12 (OMIM 618266), with prenatal onset, microcephaly, arthrogryposis and death in infancy; variants retaining residual activity cause CoPAN; Cavestro and colleagues proposed a single CoPAN–PCH12 spectrum in 2024 [11, 22]. Riboflavin-responsive lipid storage myopathy was described in 2026 [11]. PPCS deficiency, affecting the second pathway enzyme, is associated with severe dilated cardiomyopathy without neurodegeneration or brain iron [29].

DCAF17, at 2q31.1, has a long 14-exon transcript (NM_025000.4) encoding the 520-amino-acid α isoform, a nucleolar protein of unknown function expressed in brain, skin and liver, linked to ubiquitination [10, 22]. Variants are small deletions, nonsense and splice variants and small insertions-deletions, with no pathogenic missense variants described; the mechanism is loss of function [10]. Of 33 molecularly confirmed families in GeneReviews, only one was compound heterozygous [10]. The founder variant NM_025000.4:c.436del p.(Ala147HisfsTer9) (published designation c.436delC), with the same designation on NM_001164821.1, explains Saudi and Qatari cases and has also been found in Tunisia, Kuwait and Bahrain; in the systematic review by Kohil and colleagues (2023), involving 185 patients from 97 families in 12 countries, there was no clear genotype–phenotype correlation for the 13 variants described [10, 11].

2.10. Recent genes and NBIA without an identified cause

In October 2025, Travaglini and colleagues proposed SLC27A3 as a new NBIA gene based on a single 19-year-old patient homozygous for c.1138C>T p.(Arg380Ter), with progressive ataxia, neuropathy, optic atrophy, cognitive deterioration, mood disorder and brain iron, whose fibroblasts lacked the protein and showed severely impaired mitochondrial respiration [54]. Evidence rests on one patient. A substantial proportion of patients with clinical, radiological and sometimes neuropathological evidence of NBIA still have no identified variant in known genes and do not cluster into clear phenotypes [1].

2.11. Inheritance patterns

Most NBIAs are autosomal recessive (PKAN, PLAN, recessive MPAN, aceruloplasminaemia, Kufor-Rakeb, FAHN, Woodhouse-Sakati and CoPAN). FTL neuroferritinopathy, FTH1 neuroferritinopathy and some MPAN are autosomal dominant, and BPAN is X-linked dominant [1]. FTL neuroferritinopathy penetrance is 100%, with variable onset age and progression [8]; reduced penetrance has been suggested in two individuals with dominant MPAN [5]. Somatic and germline mosaicism have practical importance in BPAN and dominant MPAN, and uniparental disomy is described in FAHN (chromosome 16) and PLAN (paternal chromosome 22 isodisomy) [4, 6, 9, 51].

3. Clinical Spectrum and Manifestations by System

The following descriptions predominantly represent natural history because no NBIA has disease-modifying treatment; where data reflect treated patients (for example, receiving levodopa or deep brain stimulation), this is indicated.

3.1. Classic PKAN

The classic clinical presentation is homogeneous. In the 2017 consensus, onset occurred before 6 years in 90% of patients (range 6 months to 12 years; mean 3 years and 4 months) [23]. The most common presentation is gait disturbance due to lower-limb dystonia and spasticity, with clumsiness and frequent falls; a history of developmental delay, particularly motor, attention deficit hyperactivity disorder (ADHD) or toe walking is frequent, and visual symptoms prompt the first consultation in some children [3, 23]. Signs are predominantly extrapyramidal. Dystonia is invariably present and generally early, with prominent cranial and oromandibular involvement, dysarthria, rigidity, choreoathetosis and striatal toe; corticospinal involvement (spasticity, hyperreflexia, Babinski sign) is common, and seizures are rare [1, 3]. Action-induced jaw dystonia when eating or speaking should always prompt consideration of PKAN, and truncal opisthotonus is common in both forms and highly suggestive [23].

Cranial and limb dystonia causes recurrent tongue injury and, through extreme bone stress combined with osteopenia, atraumatic long-bone fractures; pain and distress may precipitate status dystonicus in a cycle difficult to break [3]. Severe dystonia and postural instability are the main causes of disability, and dystonia is also associated with stridor, extreme opisthotonus, dislocations, airway obstruction, orthopaedic deformities and infections [23]. Most patients lose safe independent walking by 10 years, and loss of all independent function typically occurs in the second decade; progression is stepwise, with declines over days or weeks followed by plateaux lasting weeks or months, without identified precipitants, and lost skills are rarely regained [3, 23]. GeneReviews places loss of ambulation at 10–15 years after onset in the classic form [3].

Cognition varies. In a study of 16 children and adults (Freeman, 2007), cognitive performance ranged from high average to well below average, with a strong inverse correlation between onset age and intellectual impairment; children with classic disease retain acquired cognitive abilities rather than losing them alongside motor loss [3, 23].

Pigmentary retinopathy occurs in two-thirds of patients with the classic form. It is early but often recognised only through electroretinography (ERG) and visual fields; it progresses from night blindness to progressive peripheral field loss and sometimes blindness, with fundus changes from a mottled retina to bone spicules, visible choroidal vasculature and annular “bull's-eye” maculopathy. Patients with a normal ophthalmological examination at diagnosis rarely develop subsequent retinopathy [3]. Abnormal eye movements (vertical saccade abnormalities and saccadic pursuit) are common; in Egan's study (2005), 8 of 10 patients had sectoral iris palsy compatible with bilateral Adie pupils; optic atrophy is rare [3]. Visual disability generally follows neurological disability, but poor low-light vision and constricted fields contribute to falls [23]. In an Iranian cross-sectional study of 74 eyes from confirmed NBIA patients and 80 control eyes, optical coherence tomography showed thinning of almost all retinal layers, ERG was abnormal in 45.9% and visual evoked potentials (VEP) in 32.4%; in PKAN, the outer nuclear layer was reduced and the PKAN-DRS severity scale correlated with disease duration and scotopic b-wave amplitude [55].

3.2. Atypical PKAN, late forms and HARP syndrome

Atypical PKAN is an inclusive term for non-classic phenotypes, forming a continuum with classic disease. Onset occurs from late childhood to adulthood (1–28 years; mean 13 years and 8 months) and progression is slower [23]. Presentation frequently involves speech, as an isolated feature or part of the syndrome, with palilalia, tachylalia and dysarthria, or neuropsychiatric disturbances, followed by dystonia or parkinsonism [3, 23]. The French PNDS adds that the extrapyramidal profile depends on age at onset — dystonia predominates with adolescent onset and parkinsonism with onset after 20 years — and describes a course with faster deterioration in the first years, followed by stabilisation [28]. Psychiatric symptoms affect most adolescents and adults, often before diagnosis: impulsivity with violent outbursts, obsessive-compulsive disorder (OCD), emotional lability, anxiety, depression, motor and vocal tics and, rarely, psychosis [3, 23]. Motor involvement is late, with patients described as clumsy in childhood and adolescence; spasticity and corticospinal signs eventually limit walking; freezing of gait, particularly when changing direction or surface, resembles Parkinson disease, and an essential tremor-like syndrome has been reported [3]. A 2026 Belgian report described upper-limb freezing with palilalia and cluttering [56]. Retinopathy is rare and optic atrophy is not associated with the atypical form [3].

With progression, parkinsonism contributes increasingly to disability: it is relatively symmetric, with marked postural instability, little tremor and variable bradykinesia and rigidity; dysarthria has a substantial impact [23]. Plateaux last months, years or decades, and static disease or minimal progression over 5–10 years is not rare; in a study of nine atypical patients, most symptoms emerged in the first 5 years, followed by a relatively stable phase [23]. Loss of ambulation may occur 15–40 years after onset [3]. Adults with atypical PKAN have completed higher education, served in the armed forces, married and had children [23]. The spectrum extends to very late-onset forms: Moradian and colleagues described a woman with onset at approximately 47 years of gait disturbance, retropulsive falls, micrographia and dysarthria, followed by dysphagia and incontinence, labelled progressive supranuclear palsy (PSP), without dopaminergic response, with globus pallidus and putamen hypointensity without a defined eye-of-the-tiger sign and pathogenic PANK2 variants [57].

HARP syndrome combines hypoprebetalipoproteinaemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration; acanthocytosis occurs in a subset of PKAN patients and the pre-beta-lipoprotein fraction may be low or absent [3, 11].

3.3. Diagnostic experience and disease burden in PKAN

In an interview study of 37 caregivers and 2 patients conducted to validate PKAN-ADL, mean age at onset, first MRI and genetic testing decreased with severity; mean disease duration ranged from 9.7 to 15.2 years by group; the first MRI led to diagnosis in 56.4% of cases; patients averaged 13.0 medical consultations and 55.2 therapy sessions over a period unspecified in the published abstract; 56.8% of caregivers changed employment, and the proportion of patients requiring full-time care ranged from 11.1% to 100% according to severity [58]. The study was funded by the company developing fosmetpantotenate.

3.4. PLAN

PLAN is an age-related continuum with intermediate phenotypes [4].

Infantile PLAN (INAD). Onset occurs between 6 months and 3 years, with psychomotor delay, plateau or regression; development may be normal until 6–18 months, and only approximately one-third learn to walk independently [4]. Early axial hypotonia progresses to weakness and symmetric spastic tetraparesis, causing discomfort, hindering orthoses and positioning and leading to contractures and scoliosis; lower-limb reflexes may disappear in a length-dependent manner with peripheral involvement. Strabismus and nystagmus are early and optic atrophy with visual loss develops in most; unexplained irritability is frequent before 5 years, sleep disturbances are common, and early dysautonomia causes constipation, cold extremities, breath-holding spells and, later, hypothermia or hyperthermia [4]. In an Iranian study, 5 of 18 children had hearing loss on brainstem auditory evoked potentials [4]. Seizures occur in a minority, late in the course, and non-epileptic movements may mimic seizures [4]; Saudubray states that seizures have not been described in the infantile form, a discrepancy resolved by more recent sources in favour of a minority with late seizures [4, 49]. In Altuame and colleagues' natural history series (28 molecularly diagnosed patients: 16 from Riyadh, 8 from the Americas and 4 from Europe), the first signs were speech disturbance and loss of gross motor milestones, followed by fine motor loss and bulbar dysfunction; nystagmus occurred in 60.7% and strabismus in 28.6%; cerebellar atrophy and elevated aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were consistent findings [50]. In a 5-year prospective study cited by GeneReviews, median age at death was 10 years and 8 months, and children continued vocalising, laughing and smiling until the latest stages [4]. The Oxford Desk Reference reports mean age at death of approximately 9 years [32]. In an Indian series of 10 children published in 2026, one patient had an eye-of-the-tiger sign and another the split globus pallidus sign typical of MPAN [59].

Juvenile PLAN (atypical NAD). Onset generally occurs in early childhood and may extend to early adolescence. In Menicucci's French cohort (14 individuals), all acquired language, independent walking and social skills, and loss of walking and speech regression occurred at a median age of 10 years (ranges 3–19 and 3–21 years) [4]. In a cohort of 62 individuals cited by GeneReviews as unpublished data, the most common presentation was gait difficulty and falls at a median age of 3 years, median walking-loss age was 6.5 years and median survival was 39 years [4]. Speech delay and autistic features may be the only evidence for at least a year, and the child may initially be diagnosed with autism spectrum disorder (ASD) or cerebral palsy; spastic tetraparesis, dystonia and dysarthria eventually predominate, and parkinsonism appears late [4]. Impulsivity, attention deficit, hyperactivity and emotional lability are common [4].

Adult PLAN (PARK14). Onset age ranges from 4 to 37 years, mostly in late adolescence and the third decade (median 20 years) [4]. Presentation is frequently neuropsychiatric (depression, personality changes, aggression, delusions, paranoia), with gait disturbance; dystonia follows, particularly of hands and feet, alongside parkinsonism with bradykinesia, resting tremor, rigidity and very marked postural instability, sometimes with rapid cognitive decline [4]. Initial levodopa response is dramatic but short-lived, followed by motor fluctuations and dyskinesias at doses lower than in idiopathic Parkinson disease [4]. Seizures and dysautonomia occur late, and in reported cases death generally occurred approximately 10 years after onset [4].

3.5. MPAN

MPAN typically begins between 3 and 16 years (juvenile) or 17 and 24 years (adult), with cases up to 55 years, and onset age is similar between siblings [5]. The most common presentation is gait disturbance followed by progressive spastic paresis; additional features are dystonia, limited to hands and feet or generalised, neuropsychiatric disturbances (emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, hyperactivity) and cognitive decline [5]. Lower motor neurone involvement, with distal-to-proximal reflex loss and motor axonopathy with denervation, is almost universal and mimicked juvenile amyotrophic lateral sclerosis in four families; initial isolated spastic paraparesis may lead to a hereditary spastic paraplegia diagnosis [5]. Optic atrophy is MPAN's most distinguishing feature: it was present in all 18 patients with two loss-of-function variants in the original series, even without symptoms [5, 39]. Parkinsonism, with REM sleep behaviour disorder, is more common in adult-onset and rapidly progressive cases [5]. Bladder incontinence may be early [5]. End-stage disease features severe dementia, spasticity, dystonia and parkinsonism, loss of walking and communication, weight loss and stereotyped hand or head movements; death results from complications such as aspiration pneumonia, and survival generally extends well into adulthood [5]. Fewer than 200 patients had been described in the 2021 GeneReviews, and recessive and dominant phenotypes are indistinguishable [5], although mosaic carriers may have atypical late-onset phenotypes [51]. Saudubray gives a mean presentation age of 11 years [29].

Table 3.1 — Frequency of manifestations over the course of MPAN

Source: [5], Table 2; the denominator comprises reported cases and the registry, without a specified number.

3.6. BPAN

BPAN has a biphasic course. In childhood, it presents with global developmental delay particularly affecting expressive language, abnormal gait, epilepsy, sleep disturbance and autistic features with hand stereotypies and repetitive behaviours; a round, coarse-featured face, mild telecanthus and diastema may occur, and awake bruxism and hyperpnoea episodes are common, as in Pitt-Hopkins and Rett syndromes [6, 24]. In an analysis of 160 published cases, median onset was 10 months and median diagnostic delay 6.2 years; mortality was low up to 39 years and females had milder disease [25]. Epilepsy occurs in approximately two-thirds of children; it involves multiple types (absences, tonic, atonic, tonic-clonic, myoclonic and focal impaired awareness seizures, epileptic spasms), may begin with febrile seizures and include West and Lennox-Gastaut syndromes, and tends to resolve or attenuate in late childhood or adolescence [6, 24]. Spasms may emerge early (at 3 months) or late (at 3 years), and stereotyped episodes on waking may prove epileptic [24]. Most children acquire only a few words; rare girls have near-normal language and mild learning difficulties, and asymptomatic carriers exist [6, 24]. Most eventually walk, often late, and by 3 years most walk and say at least one word, with an ataxic, broad-based or crouched gait [24]. Hyperphagia, premature adrenarche from 1–2 years and, in one case, menarche at 6 years have been described [1, 24]. In a Korean series of six girls, four had seizures, two central precocious puberty, all thinning of the corpus callosum, and only the two oldest had substantia nigra and globus pallidus iron; neuron-specific enolase was elevated in all tested [60]. The French PNDS describes the change in perspective brought by early molecular diagnosis: increasing numbers of patients are identified in childhood because of an apparently static developmental delay, with a Rett-like picture in girls and severe epileptic encephalopathy in boys, without abnormal movements or MRI changes in the foreground; in boys with WDR45 variants, identified mainly by exome sequencing, developmental and epileptic encephalopathies predominate, and brain iron is inconsistent and rare at the time of diagnosis [28].

The second phase, with relatively abrupt onset sometimes over months, occurs between late childhood and middle age, with parkinsonism (prominent bradykinesia, rigidity, freezing of gait, postural instability, little tremor), dystonia often starting in the upper limbs and dementia, preceded by subtle behavioural changes such as apathy or aggression [6, 24]. In the founding series of 23 patients (20 females), mean age was 25 years (15–37) [61]; in a review of 64 cases cited by the 2021 consensus, mean age at deterioration was 27 years and 2 months (13–39), with possible ascertainment bias towards later ages, and whether all patients regress is unknown [24]. An adult-onset case resembling early-onset Parkinson disease was published in 2025 [62]. Parkinsonism consistently responds to levodopa, but almost all patients develop early motor fluctuations progressing to disabling dyskinesias (treated patient data) [61]. In Gavazzi and colleagues' study (53 individuals, 43 female, Philadelphia), adaptive skills declined by a median −2.9 points yearly on the Vineland composite (VABS-3), and gross motor function measured by GMFM-88 had a median of 33.4% [63]. Sleep is disturbed at all ages, with difficulty falling asleep, abnormal REM sleep, hypersomnolence and hyposomnolence, and “dance-like” limb movements at sleep onset [6]. Ophthalmological findings include strabismus, amblyopia, astigmatism, high myopia, partial retinal colobomas, retinal detachment and loss of the pupillary ruff (7 of 23 patients in the founding series) [6, 24]. Dysphagia, weight loss and incontinence emerge in the degenerative phase, and reported deaths occurred between 30 and 50 years from parkinsonism complications and aspiration [24].

Table 3.2 — Age-related BPAN clinical progression (2021 consensus)

Source: [24], Table 2; progression varies between individuals.

3.7. Aceruloplasminaemia

Aceruloplasminaemia is an adult systemic disease. The triad comprises retinal degeneration, diabetes mellitus and neurological disease in individuals aged 30 to over 70 years; microcytic anaemia frequently precedes diabetes and neurological manifestations, and biochemical signs precede clinical signs by years or decades [7, 64]. Neurological manifestations correspond to iron deposition regions: blepharospasm, grimacing, facial and cervical dystonia, tremor, chorea, gait ataxia and dysarthria; more than half have cognitive dysfunction (apathy, forgetfulness) and psychiatric symptoms occur [7, 29]. Retinopathy differs from diabetic retinopathy, with early macular degeneration, preserved acuity and small yellowish opacities over pigment epithelial atrophy [7]. Iron also accumulates in liver, pancreas, heart and thyroid, with risks of heart failure and hypothyroidism [7]. A United Arab Emirates case published in 2026 had diabetes years before prominent psychiatric symptoms and neurological decline, with substantial diagnostic delay [65].

Table 3.3 — Manifestations in 71 Japanese patients with aceruloplasminaemia (Kono and Miyajima, 2015)

Source: [7], Table 2. Expression varies even within families.

3.8. Neuroferritinopathies

FTL neuroferritinopathy is an adult-onset movement disorder, with mean onset at 40 years (second to seventh decade) [8]; Saudubray places onset in early adulthood [29]. It starts with chorea or dystonia in one or two limbs, affects other limbs over 5–10 years and generalises over approximately 20 years, potentially leading to wheelchair dependence; initial asymmetry persists [8]. Most patients develop speech-specific action orofacial dystonia, with dysarthrophonia, frontalis overactivity and orolingual dyskinesia [8]. Cognitive deficits affect verbal fluency and learning and executive function, subtly but progressively and less prominently than in Huntington disease, with disinhibition, lability and aggression; adult acute psychosis episodes have been described [8, 41]. Two families had cerebellar signs and one patient late parkinsonism [8]. The French PNDS places onset between 30 and 60 years (around 50 years in its subtype table, above the GeneReviews mean of 40 years), reports an initial cerebellar presentation in a French family with the FTL insertion designated 498-499insTC in the original article, and notes that low serum ferritin is inconsistent [8, 28]. On MRI, the cortical iron rim (cortical pencil lining) is not specific: it also occurs in aceruloplasminaemia and, physiologically, after 50 years of age [28].

Table 3.4 — Manifestations in 40 patients with FTL c.460dupA (Chinnery, 2007)

Source: [8], Table 2.

FTH1 neuroferritinopathy begins in childhood with microcephaly, global delay, feeding difficulties, limited speech, intellectual disability, progressive spasticity, dystonia, dysphagia and epilepsy; 2026 reports extended the spectrum to an adult woman and two siblings [1, 11].

3.9. Kufor-Rakeb syndrome

Kufor-Rakeb syndrome has juvenile onset, generally in the second decade, with parkinsonism, spasticity and pyramidal signs, supranuclear gaze palsy and dementia; the original Jordanian family also had facial-faucial-finger minimyoclonus, visual hallucinations and oculogyric dystonic spasms [1, 11]. Heterogeneity is marked even within families, and only 11 independent families had been described by 2015 [11]. Levodopa response forms part of the original definition, but the therapeutic window narrowed with increasing peak-dose dyskinesias, spasticity and cognitive decline [11]. Brain iron may be absent, appear late or be associated with more severe variants, and GeneReviews cites a São Paulo group report (Chien and colleagues, 2011) of ATP13A2 neurodegeneration without iron accumulation [1]. In the Iranian retinal study, pachychoroid occurred exclusively in Kufor-Rakeb syndrome [55].

3.10. FAHN

FAHN begins in childhood or adolescence with subtle gait disturbance and increasing falls, due to focal dystonia or corticospinal involvement [9]. Spasticity ranges from paraparesis with preserved walking to tetraparesis requiring a wheelchair; dystonia, often initially focal, generalises but is milder than in PKAN, without status dystonicus; axial and appendicular ataxia, prominent dysarthria potentially progressing to anarthria and dysphagia occur [9]. Optic atrophy progresses from subtle acuity loss to functional blindness, with oculomotor abnormalities, strabismus, nystagmus and supranuclear gaze palsy in some patients; some have peripheral neuropathy [9]. Seizures are late, infrequent and respond well to antiseizure medicines, and intellectual impairment is progressive in most, with intermittent declines separated by relative stability [9]. Saudubray, counting approximately 70 patients with FA2H deficiency across ethnicities, describes an expanding spectrum with later onset and an akinetic-rigid syndrome over time [27]. Premature death frequently occurs in the third or fourth decade from nutrition-related immunodeficiency and respiratory compromise [9].

3.11. Woodhouse-Sakati syndrome

Virtually all patients have hypogonadism, apparent at puberty, and progressive hair thinning from childhood, often with total alopecia in adults [10]. Two clinical types may coexist within a family: type 1, with severe progressive neurological disability between 9 and 17 years, severe intellectual disability and dystonia; type 2, with absent or mild neurological involvement without impact on activities of daily living [10].

Females have primary amenorrhoea with very low oestradiol and elevated gonadotrophins (hypergonadotrophic hypogonadism), although less elevated than expected for the degree of ovarian failure, and streak ovaries without oocytes; males have moderately low testosterone with inappropriately low gonadotrophins, reduced spermatogenesis and possible azoospermia; approximately 30% have an unclassifiable hormonal profile and smell is normal [10]. Insulin-like growth factor 1 (IGF-1) is low in all, without short stature; type 2 diabetes affects 66% of patients and 96% of those older than 25 years; primary non-autoimmune hypothyroidism occurs in 30%, at approximately 20 years [10, 37]. Alopecia is frontotemporal from childhood, with sparse eyelashes and eyebrows, absent facial hair in males and wrinkled facial skin in advanced stages; a long triangular face, prominent nasal bridge, keratoconus in four patients and ST-segment and T-wave electrocardiographic changes in the original report occur [10].

Extrapyramidal disease emerges insidiously in childhood or early adolescence, with segmental craniocervical, oromandibular or single-limb dystonia, high-pitched dysarthric speech and dysphagia, and generalises and disables most patients; truncal dystonia causes severe scoliosis [10]. Dystonia was absent from the 1983 report, but up to 65% eventually develop some degree [10]. Moderate bilateral postlingual sensorineural hearing loss occurs in 62%, and intellectual disability, typically mild, in 58%; ten patients completed higher education [10]. In Agopiantz's review (72 patients from 29 families), intellectual impairment affected 87%, deafness 76% and cervicofacial dystonia with limb pain 42%, or 89% after 25 years [37]; differences between series reflect distinct denominators and criteria.

Table 3.5 — Frequency of manifestations in Woodhouse-Sakati syndrome (GeneReviews)

Source: [10].

3.12. CoPAN

CoPAN begins in childhood with motor difficulties progressing to dystonia, particularly oromandibular, spasticity, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment and neuropsychiatric changes, including obsessive-compulsive behaviour; progression is slow and patients stop walking in the third decade [1, 22]. A five-patient series published in 2024 extended the spectrum to deafness, language and autism spectrum disorders, cerebral atrophy and microcephaly, with epilepsy in all [11]. Clinically, CoPAN closely resembles PKAN [29].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In infants and young children, suspicion arises with developmental regression or plateau with axial hypotonia followed by spasticity, nystagmus, strabismus or optic atrophy (infantile PLAN), or global delay with minimal expressive language, diverse seizure types and Rett-like hand stereotypies in a girl (BPAN) [4, 6]. In BPAN, early imaging is non-specific, particularly without iron-sensitive sequences, and diagnosis is now made predominantly through panels or exome sequencing [6, 24]. In school-age children, gait disturbance combined with oromandibular dystonia, dysarthria, spasticity and pigmentary retinopathy suggests classic PKAN; the Oxford Desk Reference includes fundus examination (pigmentary retinopathy or optic atrophy), ERG and MRI in the assessment of all paediatric dystonia [3, 66]. Spastic paraparesis with optic atrophy and motor neuronopathy suggests MPAN, and spastic paraparesis with ataxia, optic atrophy and leukodystrophy suggests FAHN [5, 9]. A girl with progressive alopecia from childhood, absent puberty and dystonia in a consanguineous Middle Eastern family suggests Woodhouse-Sakati syndrome; alopecia may be the first sign [10, 11].

In adolescents and young adults, palilalia, tachylalia, dysarthria, psychiatric symptoms or tics followed by dystonia or parkinsonism suggest atypical PKAN; a tic or Tourette syndrome diagnosis may precede PKAN [3, 23]. Early-onset parkinsonism with a dramatic initial levodopa response and early dyskinesias, with psychiatric changes, suggests adult PLAN or BPAN; the 2021 consensus recommends considering BPAN in adults with intellectual disability developing parkinsonism, dystonia and early-onset dementia [4, 24]. Juvenile parkinsonism with supranuclear gaze palsy and dementia suggests Kufor-Rakeb syndrome [1]. In middle-aged adults, chorea or focal dystonia with speech-induced action orofacial dystonia and dominant inheritance suggest neuroferritinopathy; low serum ferritin is a clue [8, 41]. Iron-refractory microcytic anaemia, diabetes and retinal degeneration preceding neurological signs suggest aceruloplasminaemia; first contact is often with a haematologist or general practitioner [7, 11]. A PSP-like presentation without dopaminergic response and with pallidal hypointensity may represent late-onset PKAN [57].

The French PNDS organises suspicion according to entry points: delayed psychomotor development and, above all, regression in children; extrapyramidal syndrome at any age; cervicofacial dystonia, isolated or associated with an extrapyramidal syndrome; and, less often, cerebellar ataxia [28]. The history reconstructs the family history over at least three generations, the first symptom and the age at which it appeared, and any developmental delay, and the examination actively looks for retinitis pigmentosa, optic atrophy, peripheral neuropathy, epilepsy, cognitive impairment and endocrine abnormalities, some of which can only be demonstrated by targeted investigations [28]. In the summary intended for the attending physician, one or more of these signs warrant referral to paediatric neurology or neurology for brain MRI, which establishes the radiological diagnosis before genetic testing [28].

4.2. Entity-specific warning signs

Table 4.1 — Clinical clues pointing to a specific NBIA

4.3. Emergencies

Status dystonicus (dystonic storm) is common in PKAN, requires urgent attention and often admission, and most children and young adults with severe PKAN have at least one episode [23]. Any acute worsening of dystonia or unexplained distress should prompt systematic investigation for occult fractures (ribs, skull, long bones, often atraumatic), occult gastrointestinal bleeding, urinary or other infection, joint dislocation, faecal impaction, oral lacerations and pressure ulcers [1, 3, 23]. Inspiratory stridor from adductor laryngeal dystonia may compromise the airway [23]. Aspiration is the leading cause of death in advanced PKAN, PLAN, MPAN and BPAN [3–5, 24]. In infantile PLAN, sudden temperature rises and falls in late stages require monitoring [4].

4.4. Newborn screening and presymptomatic diagnosis

The sources consulted describe no newborn screening programmes for any NBIA. Presymptomatic diagnosis is limited to siblings of patients with known variants, with entity-specific indications (section 8): in aceruloplasminaemia and Woodhouse-Sakati syndrome, assessment of asymptomatic siblings is recommended in order to treat endocrine and haematological complications early, whereas the PKAN consensus recommends genetic testing only in symptomatic siblings [7, 10, 23]. The French PNDS restricts presymptomatic diagnosis to at-risk adults from families with a confirmed genetic diagnosis, in a multidisciplinary clinic declared to the Agence de la biomédecine, respecting autonomy, the right to know or not to know, confidentiality and informed consent; as no preventive or curative measure exists, French law (article R1131-5 of the Public Health Code) does not permit testing of asymptomatic minors [28]. This general rule diverges from the GeneReviews recommendations for aceruloplasminaemia and Woodhouse-Sakati syndrome, in which early assessment of siblings allows endocrine and haematological complications to be treated early (section 8.4) [7, 10].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and general principles

No NBIA has formal consensus diagnostic criteria; diagnosis relies on suggestive clinical findings, characteristic neuroimaging and molecular confirmation [1, 4, 6]. For PKAN, GeneReviews defines cardinal features: extrapyramidal dysfunction (at least one of dystonia, spasticity or choreoathetosis); onset in the first decade in classic disease and most frequently the second or third in atypical disease; loss of ambulation 10–15 years after onset in classic disease and 15–40 years in atypical disease; and an eye-of-the-tiger sign on T2 MRI at a field strength of at least 1.5 tesla [3]. Molecular diagnosis requires biallelic pathogenic or likely pathogenic PANK2 variants; two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis under American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [3]. Exclusionary findings include caeruloplasmin or copper metabolism abnormalities, evidence of neuronal ceroid lipofuscinosis, beta-hexosaminidase A or GM1-galactosidase deficiency and peripheral nervous system spheroids, suggesting PLAN or MPAN [3]. With only one identified variant, experts may establish the diagnosis using clinical findings and characteristic MRI, and without testing access, confidence is reasonable with typical clinical and imaging findings [23].

5.2. Magnetic resonance imaging

Iron-sensitive sequences — susceptibility-weighted imaging (SWI), gradient echo (GRE) and T2* — are the first-line investigation, and image quality (field strength, slice thickness) limits iron detection [1, 23]. The French PNDS recalls the physical basis: iron is isointense on T1 and hypointense on T2, as is calcium, and computed tomography (CT) distinguishes them, because calcium is hyperdense and iron isodense; metals (iron, copper) bound to neuromelanin form paramagnetic complexes that are hyperintense on T1; T2* mapping and QSM quantify the overload; and T1, T2 and FLAIR sequences retain their role in assessing atrophy, gliosis, cavitation and the white matter [28]. In almost all NBIAs, iron is relatively symmetrical in the globus pallidus, with variable involvement of the substantia nigra, red nucleus, dentate nucleus and striatum, and cerebellar, cerebral and corpus callosum atrophy and white matter changes worsen as the disease progresses [28]. In classic PKAN, abnormalities are generally apparent by 3–4 years with these sequences and may emerge much earlier; with clear neurological signs, MRI almost always shows abnormalities [23]. The eye-of-the-tiger sign — globus pallidus T2 hypointensity surrounding a central hyperintense region — is virtually pathognomonic of PKAN and was present in all variant-positive patients in the 2003 series [1, 31]. It nevertheless has limitations: it may be absent initially, iron may replace the central region producing uniform hypointensity, some Dominican patients lacked it, and some supposed eye-of-the-tiger signs proved to represent MPAN [3]. Giuliano's Sicilian series documented the complete sequence: initial pallidal hyperintensity mimicking mitochondrial disease, eye-of-the-tiger appearance approximately six years later and isolated hypointensity in advanced disease [45]. Computed tomography may show pallidal calcification in PKAN and BPAN, and diffusion tensor imaging links white matter changes to dystonia progression [3, 22]. Quantitative susceptibility mapping (QSM) at 3 tesla, at a Turkish centre analysing 16 patients, showed 2.5-fold greater pallidal iron in PKAN and MPAN, and a globus pallidus value above 0.1133 ppm increased the likelihood of PKAN 18-fold; this is an unvalidated candidate biomarker [67]. A 2025 imaging review confirms MRI as the modality of choice and distinguishes primary iron metabolism diseases (neuroferritinopathy, aceruloplasminaemia) from forms with secondary iron, linking the group to ferroptosis [68].

Table 5.1 — Entity-specific neuroimaging patterns

Sources: [1, 3–10, 22, 24].

In BPAN, normal MRI in a young child does not exclude diagnosis, and iron emergence neither coincides with nor predicts clinical deterioration [24]. Early absence of iron is frequent in PLAN, and cerebellar atrophy combined with elevated AST and LDH is often the most useful clue [4]. In MPAN, sisters homozygous for p.(Ala63Pro) had no MRI iron, and iron appeared only on subsequent scans in some cases [5]. In neuroferritinopathy, T2 iron is present from onset and T2* and fast spin echo sequences distinguish four NBIA subtypes (McNeill, 2008) [8]. In adults, Saudubray summarises that pallidal T2 hypointensity suggests NBIA, basal ganglia T2 hyperintensity suggests energy metabolism disease, and thalamic and brainstem hyperintensity suggests Wilson disease [69].

5.3. Laboratory biomarkers

Table 5.2 — Biomarkers with diagnostic value

Sources: [3, 4, 7, 8, 64, 70, 71].

When clinical and MRI findings are compatible, the French PNDS defines a minimum set of first-line investigations: full blood count with a search for acanthocytes, serum and urinary copper, caeruloplasmin, serum ferritin and iron, calcium-phosphate profile, fasting blood glucose and brain CT, to distinguish calcium from iron [28]. Depending on the clinical orientation, these are supplemented by electromyography, when neuropathy is suspected (PLAN, MPAN); a sleep study, looking for apnoeas or REM sleep behaviour disorder, which points to BPAN; EEG, in the presence of seizures (PLAN, FAHN, BPAN, Woodhouse-Sakati syndrome) or to look for fast rhythms in a regressing child (PLAN); and ophthalmological examination, looking for optic atrophy (PLAN, MPAN, FAHN) or retinopathy (PKAN) [28]. The search for acanthocytes, which the PNDS keeps as first-line and associates with PKAN in its subtype table, contrasts with the PKAN consensus, which does not consider it justified in most patients with a genetic diagnosis (section 5.9) [23, 28].

Low caeruloplasmin is a diagnostic pitfall because it occurs in Wilson disease and aceruloplasminaemia, opposite diseases: the former is copper overload and the latter iron overload, treated with an iron rather than copper chelator [11]. The BPAN consensus does not recommend routine AST, creatine kinase, LDH or neuron-specific enolase testing, whose reported abnormalities have uncertain significance [24]. Neurophysiology supports PLAN (electromyographic denervation, high-voltage fast electroencephalographic rhythms, delayed VEP and distal axonal sensorimotor neuropathy), MPAN (motor axonopathy) and Woodhouse-Sakati syndrome (prolonged VEP and somatosensory evoked potential latencies) [4, 5, 10]. On BPAN EEG, diffuse continuous fast beta activity may be an early non-specific finding, and hypsarrhythmia is common in children with spasms [24].

5.4. Genetic testing and algorithm

The overview GeneReviews recommends clinical history, examination and three-generation family history, followed by an NBIA multigene panel as the strategy most likely to identify the cause while limiting VUS; single-gene testing (sequencing followed by deletion and duplication analysis) is preferable when imaging or phenotype points to a type, such as the eye-of-the-tiger sign for PANK2 or the DCAF17 c.436del founder variant in Saudis and Qataris; exome or genome sequencing is the option when clinical findings and imaging did not suggest NBIA [1, 10]. The PKAN consensus considers sequencing and deletion and duplication analysis necessary for complete PANK2 analysis, and states that panels may be more efficient [23]. In PLAN, single-gene testing is rarely useful, and if exome identifies only one or no variant despite strong suspicion, genome or targeted enrichment sequencing should be considered [4]. In BPAN, single-gene testing or a panel with deletion and duplication analysis is recommended, discussing mosaicism detection capability with the laboratory, because exome and genome generally have insufficient read depth for low-level somatic mosaicism; parental testing is also recommended [6, 24]. In aceruloplasminaemia and FAHN, an exome array may be used after a non-diagnostic exome, and in FAHN apparent homozygosity without a large deletion should prompt parental testing or investigation for uniparental disomy [7, 9]. Without an identified genetic cause, patients should be referred for research, and the Oregon Health & Science University (OHSU) international registry welcomes contact for idiopathic NBIA and VUS review [1].

Practical algorithm. (1) Clinical suspicion → MRI with SWI/GRE/T2*. (2) Eye-of-the-tiger sign → PANK2 (sequencing and deletions/duplications). (3) Another NBIA pattern or an indeterminate pattern → NBIA panel with copy-number analysis. (4) Neurodevelopmental phenotype without an NBIA pattern → exome or genome. (5) Suspected aceruloplasminaemia → serum caeruloplasmin, copper, iron and ferritin before genetic testing. (6) Suspected neuroferritinopathy → serum ferritin and FTL sequencing. (7) Saudis or Qataris with a Woodhouse-Sakati phenotype → targeted c.436del testing. (8) Negative result or only one variant → reassess phenotype, consider genome, undetected deletions, mosaicism or disomy, and research [1, 7, 8, 10, 23].

French diagnostic pathway. The French PNDS starts from three elements of suspicion — suggestive clinical features and family history, and MRI with T2* or gradient echo showing iron in the basal ganglia — and a minimum work-up with ferritin, a search for acanthocytes, copper studies and a calcium-phosphate profile [28]. It recommends the NBIA panel as first line in all patients, whatever the family history, and only after a negative panel exome or genome sequencing, access to which requires validation of the indication at a multidisciplinary team meeting (RCP) according to the criteria of the France Genomic Medicine Plan 2025 (PFMG 2025), with the patient referred to a neurogenetics reference or competence centre [28]. In January 2022, the available panels were those of Bordeaux (9 genes: PANK2, PLA2G6, WDR45, FTL, C19orf12, FA2H, CP, DCAF17 and ATP13A2) and Lille (the same 9, plus COASY and SCP2), and movement disorder, intellectual disability or epilepsy panels included NBIA genes (8 in the Strasbourg movement disorder panel and 7 in the cerebellum–abnormal movements panel of the Trousseau Hospital, Paris) [28]. The PNDS decision tree (Appendix 3) separates two branches: a typical eye-of-the-tiger sign or extrapyramidal signs before 10 years, with a panel oriented mainly towards PANK2; and acanthocytes, hypoferritinaemia without another cause or hyperferritinaemia with collapsed caeruloplasmin, with a panel oriented towards PANK2, FTL and CP [28]. For exome or genome sequencing, in addition to the index case, a sample from another affected relative and/or from at least one healthy relative, preferably the parents, is required; analysis of the index case alone is accepted only exceptionally, with onset before 20 years or a strongly suggestive family context (more than two affected, consanguinity) [28]. Because of the low yield, the PNDS does not propose high-throughput sequencing when suspicion of NBIA begins after 50 years, unless there is a positive family history or proven consanguinity; the decision tree in the same document sets this limit at 60 years, an internal inconsistency that the text does not resolve [28]. The RCP may request phenotype-guided investigations — ophthalmology (retinopathy, optic neuropathy), audiometry, electromyography, blood glucose and hormonal assessment of hypogonadism — and brain CT if there is doubt about calcium deposits [28]. An increasingly frequent circumstance is the identification of variants in an NBIA gene in an exome or genome requested for developmental delay, intellectual disability, epileptic encephalopathy or abnormal movements, sometimes before iron is visible, as in BPAN; the causal attribution of the variant is then confirmed by agreement between molecular and clinical geneticists [28].

The PNDS strategy diverges from that of the overview GeneReviews, which prefers single-gene testing when the eye-of-the-tiger sign points to PANK2 and reserves the panel for the other patterns; in the PNDS, even the eye-of-the-tiger sign leads to the panel, with PANK2 as the main target [1, 28]. The requirement for family samples and the age limit for exome or genome sequencing are access rules of the French system and not clinical exclusion criteria.

5.5. Test performance and limitations

The percentages in Table 5.3 are proportions of variants detected by each method among molecularly diagnosed patients, rather than clinical sensitivities; a negative result does not exclude diagnosis.

Table 5.3 — Yield of molecular methods by gene

Sources: [3–10].

In PKAN, 23% of families have known or suspected consanguinity and 33% have homozygous variants [3]. Apparent homozygosity in any recessive disease may represent an undetected deletion on the other allele (false homozygosity) or uniparental isodisomy, clarified through parental testing [1]. Deep intronic and splice variants require functional investigation: in the Sicilian series, novel c.906-1G>A was confirmed by leucocyte RT-PCR, showing an aberrant 349-base-pair band due to exon 4 skipping [45]. Lack of validated functional biomarkers makes VUS classification difficult in PLAN; clinical findings, MRI, elevated AST or LDH, electromyographic abnormalities and fast EEG rhythms help, particularly in consanguineous individuals with a homozygous VUS [4].

5.6. Report content and segregation

The report should specify gene, transcript version (for PANK2, MANE NM_001386393.1, with NM_153638 numbering in parentheses when used in the literature), DNA and protein HGVS nomenclature, zygosity, ACMG/AMP classification and, for the X chromosome, hemizygosity or an allele fraction suggesting mosaicism [3, 6, 46]. Parental segregation analysis is recommended in all recessive forms to confirm trans phase, in BPAN to distinguish de novo from inherited variants, and in MPAN and neuroferritinopathy to assess dominant inheritance [1, 5, 8, 24]. DNA banking is recommended in probands without molecular confirmation [3].

5.7. Biopsy and neuropathology

Before genetics, neuropathology was the main PLAN diagnostic technique, with axonal spheroids visible in conjunctival, skin, rectal, muscle or sural nerve biopsies; electron microscopy shows membranotubular profiles, mitochondrial aggregates and increased axonal diameter [4, 49]. Spheroids accumulate with age and may be absent from some tissues, so biopsy may confirm but not exclude disease, and they have not been described in adult PLAN [4]. Peripheral spheroids, formerly considered exclusive to PLAN, also occur in MPAN [5]. Biopsy is now justified only when clinical findings strongly suggest PLAN and molecular tests are negative [4].

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing (PGT) are possible in all NBIAs after identification of familial pathogenic variants, with inheritance-specific nuances discussed in section 8 [1]. The first successful PKAN preimplantation genetic diagnosis, in Thailand, combined linkage analysis, minisequencing and next-generation sequencing aneuploidy screening, with amniocentesis confirmation [72]. In France, each request for prenatal or preimplantation diagnosis in NBIA is submitted for the opinion of a multidisciplinary prenatal diagnosis centre (CPDPN) [28].

5.9. Assessment after diagnosis

Table 5.4 — Recommended assessment after diagnosis

Sources: [1, 3–7, 10, 23, 24]. When genetic diagnosis precedes imaging, the PKAN consensus recommends MRI only if it will influence decisions, and does not justify investigating acanthocytes or spermatogenesis abnormalities in most patients [23]. In the BPAN consensus, MRI may support an uncertain genetic diagnosis, but should not be repeated merely to document progression [24].

6. Differential Diagnosis

6.1. Differential diagnosis within NBIA

Table 6.1 — Comparison of NBIAs

Sources: [1, 3–10].

MRI is the main distinguishing tool. In most non-PKAN NBIAs, the globus pallidus is uniformly T2 hypointense without the eye-of-the-tiger sign, which has never been observed without PANK2 variants [3, 31]. The MPAN hyperintense medial medullary lamina streak may simulate the eye-of-the-tiger sign, and red and dentate nuclear iron points to neuroferritinopathy or aceruloplasminaemia [3]. Absence of seizures favours PKAN because seizures are prominent in some other NBIAs, and frequent optic atrophy distinguishes MPAN [3, 5]. The PKAN GeneReviews illustrates this distinction with two T2 MRIs, one showing an eye-of-the-tiger sign and the other isolated pallidal hypointensity in non-PKAN NBIA [3].

6.2. Differential diagnosis of PKAN

In classic disease, consider X-linked intellectual disability with Dandy-Walker malformation, α-L-fucosidosis (FUCA1; coarse facies, visceromegaly, pallidal hyperintensity without an eye-of-the-tiger sign), Leigh syndrome (symmetric pallidal hyperintensity without an iron rim, with other basal ganglia lesions) and infantile PLAN (peripheral spheroids and cerebellar atrophy) [3]. The Brazilian genetic syndromes textbook includes iron or copper storage diseases, Wilson disease and PANK2 variants among conditions confusable with Leigh syndrome, alongside organic acidurias [73]. In atypical disease, the differential includes early-onset Parkinson disease (including juvenile PRKN disease) and PLA2G6 dystonia-parkinsonism; primary familial brain calcification (PDGFB, PDGFRB, SLC20A2), whose pallidal deposits may simulate an eye-of-the-tiger sign; aceruloplasminaemia; neuroferritinopathy, without PKAN's marked dysarthria; PSP, with mean onset age of 66 years and vertical gaze palsy; and primary psychiatric disease [3]. GeneReviews attributes PSP to MAPT with recessive inheritance, which does not reflect usual PSP, generally sporadic; the relevant clinical point is that T2 MRI distinguishes through presence of the eye-of-the-tiger sign [3]. Moradian's case illustrates the converse risk: PKAN beginning at 47 years labelled PSP, with pallidal hypointensity without a defined eye-of-the-tiger sign and markedly reduced putaminal DaTscan uptake [57]. Other diseases to consider are neuronal ceroid lipofuscinoses, childhood-onset spinocerebellar ataxias (SCA3, SCA7), DYT1 dystonia, juvenile Huntington disease, Lesch-Nyhan syndrome, Wilson disease, recessive hereditary spastic paraplegia and Tourette syndrome [3]. Carnitine palmitoyltransferase 1 (CPT1) deficiency enters the biochemical differential because the classic PKAN acylcarnitine profile may mimic it [70].

Neuroacanthocytoses fall into two groups: those with lipid malabsorption (familial hypobetalipoproteinaemia types 1 and 2 and abetalipoproteinaemia), with spinocerebellar degeneration, neuropathy, areflexia and pigmentary retinopathy but no basal ganglia involvement; and those with Huntington-type chorea — McLeod syndrome (XK, X-linked), chorea-acanthocytosis (VPS13A, AR, mean onset 35 years) and Huntington disease-like 2 (JPH3, AD, almost exclusively in people of African ancestry) [3, 66].

6.3. Radiological and clinical phenocopies

Table 6.2 — Conditions mimicking NBIA

Source: [1], Table 4.

TBCE-related progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) may show, from the second decade, pallidal and substantia nigra hypointensity similar to that of NBIA; distal motor neuronopathy points to the diagnosis.

The French PNDS stresses that the differential diagnoses of NBIA are mainly radiological, because symptoms alone do not allow the diagnosis [28]. In Wilson disease, MRI shows T2 hyperintensity of the basal ganglia (mainly the striatum), brainstem and cerebellum, often with subcortical atrophy, and copper studies show low total serum copper, increased 24-hour urinary copper and low caeruloplasmin [28]. Basal ganglia calcifications (Fahr disease) are hypointense on T2, like iron, but hyperdense on CT, and manganese transport disorders produce deposits that are hyperintense on T1 and isointense on T2 [28]. In mitochondrial cytopathies, such as Leigh syndrome, T2 hyperintensities extending beyond the putamen predominate; involvement of the colliculi is highly specific for mitochondrial disease, supratentorial or infratentorial leukodystrophies frequently coexist, and MR spectroscopy often shows a lactate peak [28]. Common neurodegenerative diseases (Alzheimer, Parkinson, Huntington) and physiological ageing also increase iron in the basal ganglia; to avoid overdiagnosis, the PNDS recommends weighing the associated atrophy and requesting review of the MRI by an experienced neuroradiologist [28].

6.4. Differential diagnosis of the remaining NBIAs

PLAN. In infantile disease, the differential includes mitochondrial diseases (particularly Leigh-like), lysosomal diseases, leukodystrophies, pontocerebellar hypoplasia (TSEN54), ataxia-telangiectasia (ATM; elevated alpha-fetoprotein, immunodeficiency), infantile SCA2 (spasms with hypsarrhythmia, retinitis pigmentosa), SCA7 (retinal dystrophy), KIF1A disease, Rett syndrome (MECP2), Pelizaeus-Merzbacher (PLP1), PMM2-CDG, CLN1 (PPT1) and spinal muscular atrophy (SMN1; without spasticity or cerebellar atrophy) [4]. Juvenile disease is often first diagnosed as ASD or cerebral palsy [4]. Adult disease differentials include other NBIAs and early monogenic dystonia-parkinsonism (ATP1A3, ATP7B, FBXO7, HTT, PARK7, PINK1, PRKN, PRKRA, SLC6A3, SNCA, SPG11, TAF1, TOR1A, VPS35), distinguished by absence of PLAN MRI findings [4].

BPAN. In childhood: Rett and Angelman syndromes, α-fucosidosis and epileptic encephalopathies (Dravet, West, Lennox-Gastaut, electrical status epilepticus during sleep, Landau-Kleffner); in adults, PINK1 or PRKN dystonia-parkinsonism, distinguished by clinical features and iron [6].

Aceruloplasminaemia. Atypical PKAN and neuroferritinopathy have focal brain iron without visceral iron; Wilson disease has low caeruloplasmin due to inability to incorporate copper; HFE haemochromatosis, the most common iron metabolism disease, has visceral iron, and aceruloplasminaemia differs from it through marked brain iron and low serum iron; aceruloplasminaemia may be misdiagnosed as mild haemochromatosis with hypocaeruloplasminaemia or mild Wilson disease with haemosiderosis [7]. Hereditary haemochromatosis and Wilson disease are part of the differential diagnosis.

Neuroferritinopathy. SCA2, SCA3, SCA17, Huntington, Niemann-Pick C, PKAN (very similar MRI, including an eye-of-the-tiger sign, but earlier onset), INAD, parkin, DYT1, mitochondrial diseases, chorea-acanthocytosis and McLeod; onset age, inheritance and T2* MRI distinguish them [8].

FAHN. MPAN, PKAN, juvenile PLAN, CoPAN, Wilson disease, Friedreich ataxia, ARSACS, PLP1 diseases (SPG2), SPG11, SPG15, SPG44, juvenile metachromatic leukodystrophy, hypomyelination with basal ganglia and cerebellar atrophy (TUBB4A), POLR3 leukodystrophy, juvenile hexosaminidase A deficiency and GCH1 levodopa-responsive dystonia [9].

Woodhouse-Sakati syndrome. Isolated GnRH deficiency and Kallmann syndrome (without alopecia), Perrault syndrome (hearing loss and ovarian failure), Cockayne, Hutchinson-Gilford progeria, alopecia-neuropathy-endocrinopathy syndrome (RBM28), Gordon Holmes (RNF216, PNPLA6) and deafness-dystonia-optic neuronopathy syndrome (TIMM8A), alongside other NBIAs and hereditary dystonias and hearing loss [10].

7. Treatments and Risk Management Strategies

7.1. Principles and guidelines

No NBIA has approved disease-modifying treatment. Treatment is symptomatic, palliative in the technical sense, multidisciplinary and tailored to type and individual [1, 22]. Recommendations rely on expert consensus without formal evidence grades, and negative randomised trials whose conclusions also guide practice.

Table 7.1 — Register of guidelines and consensus documents

Sources: [1, 2, 4, 23, 24, 28, 74]. The PKAN consensus was developed by experts with more than 10 years' experience, reviewed by association leaders, nine families and through open consultation, and funded by lay associations [23]. The French PNDS follows the 2012 HAS method for rare disease protocols, with declarations of interest analysed, and had the participation of two patient associations [28].

Divergences between the French PNDS and the other guidelines. (1) Deferiprone: the PNDS reads TIRCON as suggestive of slowed progression and accepts open-label conservative chelation at 30 mg/kg/day with full blood count monitoring, particularly in the early phase; the CHMP considered the study negative and the benefit–risk balance unfavourable, and the BPAN consensus advises against chelation outside a trial (section 7.6) [24, 28, 75]. (2) GPi DBS: the PNDS considers efficacy demonstrated in PKAN when performed early, before very disabling dystonia and deformities; the PKAN consensus describes mixed results with greater benefit in the atypical form, and the individual patient data meta-analysis shows a mean gain of 16% in the classic form (section 7.3) [23, 28, 76]. (3) Genetic strategy: panel as first line even with the eye-of-the-tiger sign, as opposed to the single-gene testing preferred by GeneReviews in that scenario (section 5.4) [1, 28]. (4) Presymptomatic testing: adults only, by French legal requirement, as opposed to the assessment of minor siblings recommended by GeneReviews in aceruloplasminaemia and Woodhouse-Sakati syndrome (section 8.4) [7, 10, 28]. (5) Annual ophthalmology for all NBIAs, as opposed to 1–2-year intervals in MPAN and BPAN in GeneReviews (section 11.2) [5, 6, 28]. (6) Dopaminergic drugs: the PNDS agrees with the PKAN consensus on the poor response of PKAN to levodopa and with GeneReviews on the good response of PLAN, MPAN, BPAN and Kufor-Rakeb syndrome, and generally advises against dopamine agonists because of neuropsychiatric risk [6, 23, 28]. (7) Doses: the PNDS gives only the dose of deferiprone; for the other drugs it proposes, Table 7.6 brings together the doses from the official labels as an extrapolation.

7.2. PKAN: pharmacological treatment of dystonia and other motor symptoms

Dystonia is the most disabling motor symptom and principal target; the aim is to relieve the most disabling symptom with minimal off-target effects [23]. The consensus recommends introducing one drug at a time, starting low and titrating to efficacy or intolerance; tapering if no benefit occurs 4–6 weeks after reaching the target dose (2 weeks for second-line agents); and critically reviewing the regimen annually, because children tolerate significantly higher doses than adults and a previously tolerated regimen may cause adverse effects in adolescence or adulthood, particularly with anticholinergics [23]. Neither consensus nor GeneReviews provides numerical doses for these drugs, which experienced neurologists titrate individually; all are used outside a specific PKAN indication [3, 23].

Table 7.2 — Symptomatic drugs in PKAN

Sources: [3, 10, 23].

Antipsychotics used for tics or psychosis carry risks of acute and tardive dystonia, difficult to detect in an already dystonic patient, and atypical neuroleptics should be used cautiously; cognitive behavioural therapy may benefit psychiatric symptoms [23]. Seizures are not characteristic of PKAN and, when present, are presumed unrelated and treated conventionally [23]. Cascone's review includes levodopa among treatments for parkinsonism in NBIAs generally, differing from the PKAN consensus; in PKAN, the consensus recommendation takes precedence, whereas in adult PLAN, BPAN, MPAN and Kufor-Rakeb syndrome, levodopa has a specific role (subsections 7.8–7.12) [22, 23].

7.3. PKAN: intrathecal baclofen, deep brain stimulation and ablative surgery

Intrathecal and intraventricular baclofen. Central administration is considered when maximal oral dosing fails or causes unacceptable effects, with an outpatient intrathecal test dose before pump implantation; best results occur in still-ambulant patients with lower-limb symptoms, and effects are less robust for opisthotonus in non-ambulant patients [23]. Risks include skin breakdown over the device and possible acceleration of scoliosis, with contradictory data [23]. Intraventricular administration requires smaller doses and has a theoretical advantage for head, neck and upper-trunk dystonia, but PKAN experience is limited [23].

Deep brain stimulation (DBS). The consensus describes mixed results, with frequent benefit during the first year or years following internal globus pallidus (GPi) DBS, generally not sustained as disease progresses, publication bias and no agreement on candidates, timing or parameters; adolescents and adults with atypical disease are most likely to benefit, and the authors knew of no children with classic disease showing substantial sustained benefit beyond a few months [23]. The individual patient data meta-analysis by De Vloo and colleagues assembled 99 patients from 38 articles (GPi in 87): the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement score improved by 26% (95% CI 15–37%) after one year, 45% in atypical and 16% in classic disease; improvement of at least 30% occurred in 73% of atypical and 34% of classic patients; disability improved 31% in atypical and 5% (95% CI −8 to 17%) in classic disease; surgical infections occurred in 6%, hardware failure in 7% and two deaths in the first 3 months, and data beyond one year were insufficient (level 4 evidence) [76]. No standardised selection criteria exist; postural instability and gait should be discussed because disease progresses after DBS [77]. The consensus recommends referral to an experienced centre, discussing risks, alternatives and realistic goals, and remembering that devices increase the risk of infections that are difficult to treat [23, 66]. The overview GeneReviews acknowledges that DBS reduces dystonic crises for a limited period in some NBIAs [1]. The French PNDS accepts discussion of bilateral GPi DBS in an experienced centre after drugs and botulinum toxin have been tried, and considers efficacy demonstrated in PKAN when the intervention is early, before dystonia becomes very disabling and before orthopaedic deformities appear, on the basis of a multicentre series of pallidal stimulation in NBIA (Timmermann, 2010) and a Chinese series of subthalamic stimulation in PKAN; this reading is more favourable than that of the PKAN consensus and of the individual patient data meta-analysis [23, 28, 76].

Ablative surgery. Pallidotomy and thalamotomy have sometimes provided good relief but are irreversible, a greater concern in children and adolescents; they have largely been replaced by DBS and remain options for selected refractory painful dystonia [3, 23]. Simultaneous bilateral MRI-guided focused ultrasound (MRgFUS) pallidotomy under general anaesthesia resolved refractory status dystonicus within 4 and 12 days in two young people (one with PKAN) with contraindications to open surgery, with transient adverse effects and unclear long-term efficacy [78].

7.4. PKAN: status dystonicus, airway and perioperative care

Status dystonicus has the highest priority: any worsening prompts investigation and treatment of precipitants — occult fractures, occult gastrointestinal bleeding, infection, joint injury or dislocation, faecal impaction, tongue, lip or cheek bites, respiratory compromise from stridor, drug initiation or abrupt withdrawal, anaesthesia or surgery [23]. First-line treatment is to initiate or increase antidystonic agents, particularly benzodiazepines; a minority require intubation with deep sedation, DBS or pallidotomy [23]. Levodopa is not recommended, and D2 antagonists (haloperidol, risperidone) are used cautiously for the shortest possible time [23]. The consensus recommends that all patients have a simplified action plan with a dystonia severity scale and status dystonicus risk scale, and no drug or anaesthetic is contraindicated on rigorous evidence [23]. A 2026 Polish report described directional GPi DBS for refractory status dystonicus in a child [79].

Adductor laryngeal dystonia causes inspiratory stridor in children and adults, often with a painful precipitant; agitation worsens it and may precipitate status dystonicus. Stridor may be tolerated without intervention, but respiratory compromise or agitation requires aggressive treatment; in persistent laryngeal dystonia, botulinum toxin to both thyroarytenoid muscles acts over several days, and tracheostomy is rarely necessary; recurrence is frequent [23].

Anaesthesia and surgery should be limited to what is absolutely necessary, with close team collaboration. Cervical or oromandibular dystonia may complicate intubation, and even light anaesthesia may precipitate acute dystonia exacerbation; postoperative pain and dystonia control is critical. Propofol tends to be avoided in movement disorders, but no evidence indicates increased vulnerability in PKAN and it has been used successfully [23]. The emergency plan should include diagnoses, baseline status, medication, allergies, immunisations, usual strategies, implanted devices (DBS, baclofen pump) with team and manufacturer contacts, and a consensus copy, reviewed at least annually; the American Academy of Pediatrics emergency information form serves children and adults [23, 24].

7.5. PKAN: system-specific supportive care

Feeding and nutrition. Feeding difficulty is almost universal. Classic disease causes progressive chewing and swallowing loss; in atypical disease, the tongue or jaw “freezes” during chewing and patients use sensory tricks [23]. Gastrostomy is recommended when oral intake becomes inadequate through dysphagia or respiratory complications, ideally before 10% weight loss or aspiration complications, introducing it early as a routine strategy rather than end-of-life care; many families report relief after placement [3, 23]. Energy expenditure is increased and many patients need 5–10% more calories than calculated for age and sex; the consensus recommends against low-iron diets, which cause systemic iron deficiency without affecting brain iron, and ketogenic diets, which worsened health and function in Pank2-deficient mice; it allows low-risk experimental supplements with informed consent acknowledging uncertainty [23]. Docosahexaenoic acid (DHA, fish oil) has a theoretical role in retinopathy prevention, without studies or known toxicity [3]. Tracheostomy may be indicated in late-stage classic disease [3].

Oral health. Trauma to mouth, tongue, jaw and teeth is very common. Botulinum toxin is first-line when sensory tricks fail, ideally administered by experienced otorhinolaryngologists because injection for jaw-opening dystonia may worsen dysphagia; bite blocks or cemented custom splints are used, with attention to choking risk, and dental treatment should be conservative owing to dystonic crisis risk [3, 23]. The consensus allows total dental extraction in extreme cases; the GeneReviews main text recommends every effort to avoid it, although its summary still mentions it [3, 23].

Sialorrhoea. Bibs and towels usually suffice; trihexyphenidyl may reduce it; glycopyrrolate, hyoscine patches or salivary gland botulinum toxin are reserved for absolute necessity because of morbidity [23].

Skeleton. Risks of scoliosis, hip subluxation or dislocation, spinal cord injuries and fractures are increased. Any increase in dystonia or distress should prompt systematic investigation for occult fractures, often overlooked for days. Bone densitometry (DEXA) is useful at baseline; standing weight-bearing, adequate calcium and vitamin D, and soft rather than rigid casts are recommended [1, 23].

Vision. Regular clinical ophthalmological examinations; ERG only for rare clinical indications; first-line botulinum toxin for disabling blepharospasm; low-vision services [3, 23].

Respiratory. Regular respiratory function monitoring and pulmonary hygiene if managing secretions is difficult or aspiration risk exists [23].

Rehabilitation and exercise. Maintain range of motion in all joints through physiotherapy, occupational therapy, speech and language therapy and rehabilitation medicine; review adaptive equipment regularly; start exercise programmes early, with no evidence-based restriction; dystonia fluctuations guide daily therapy and weight-bearing in standers may preserve bone mass [23].

Speech and communication. Dysarthria, palilalia, cluttering and hypophonia benefit from early speech and language therapy and augmentative communication; hand-tapping to mark rhythm or delayed auditory feedback devices improve palilalia and cluttering [23].

Pain and sleep. Pain feeds dystonia; each exacerbation prompts investigation for treatable causes, after which pain control is a central goal, with early pain and palliative care team involvement [23]. Dystonia disappears during sleep; melatonin or chloral hydrate may improve sleep induction, and bedtime clonazepam sedates and reduces dystonia and spasticity [23].

Education, immunisation and psychosocial support. Educational needs are reassessed frequently, with individualised programmes; immunisation follows the standard schedule, with no known immunological effects contraindicating it; isolation is frequent in adolescents and young adults, and day, occupational and caregiver respite programmes are recommended [23]. Palliative care may be involved at any point after diagnosis, alongside treatment, with an end-of-life plan and advance directives potentially including brain and tissue donation for research [23].

7.6. PKAN: mechanism-directed therapies

High-dose pantothenate (vitamin B5). The rationale is substrate loading, requiring residual PANK2 activity, predicted particularly in atypical disease [23]. No efficacy trial exists. The consensus recommends considering a therapeutic trial for at least 3 months in all patients regardless of phenotype, starting with 250 mg orally and increasing by 500 mg weekly to a daily dose of 2–5 g or until adverse effects occur, and discontinuing without benefit [23]. Oral pantothenic acid or calcium pantothenate doses up to 10 g/day for several weeks do not appear toxic [3]. Some adults with atypical disease report improved gait, speech and clarity of thought; most children with classic disease have little or no benefit [23]. This is a supplement without an approved PKAN indication.

Deferiprone (Ferriprox®). Deferiprone is an oral bidentate chelator crossing the blood–brain barrier and removing intracellular iron [3, 8]. Pilot studies using 25–30 mg/kg/day for 6–12 months (Abbruzzese, Zorzi, Cossu) showed reduced pallidal iron and weak evidence of improvement [75]; in Zorzi's phase II trial, the nine completers tolerated treatment well, with significantly reduced pallidal iron and no clinical change [3]. In an uncontrolled Iranian pilot study with five patients and 15 mg/kg twice daily, pallidal iron decreased in all and four improved clinically during the first 12 months [80].

TIRCON2012V1 was a phase 3, 2:1 randomised, double-blind, placebo-controlled trial lasting 18 months with a preplanned additional 18-month open-label extension, at four hospitals in Germany, Italy, England and the US [81]. It enrolled patients aged at least 4 years with genetically confirmed PKAN, a Barry-Albright Dystonia (BAD) score of at least 3 and no iron deficiency, neutropenia or hepatic or renal dysfunction, stratified by onset age [81]. The dose was 30 mg/kg/day oral solution in two equal doses, reached by titrating from 5 mg/kg twice daily to 10 mg/kg and finally 15 mg/kg twice daily over 12 weeks [75, 81, 82]. This was the fixed target dose of the protocol, with no maximum dose defined for PKAN in the source; the label maxima for transfusional iron overload are given in Table 7.5. Between December 2012 and April 2015, 88 patients were randomised (58 deferiprone, 30 placebo), and 76 completed; ClinicalTrials.gov and the European Medicines Agency (EMA) report count 89 enrolled (59 and 30), a difference the sources do not explain; the publication's number is used here [75, 81, 82]. BAD worsened by 2.48 points with deferiprone and 3.99 with placebo (difference −1.51; 95% CI −3.19 to 0.16; p=0.076), and Patient Global Impression of Improvement (PGI-I) was 4.6 and 4.7 (p=0.728): both coprimary outcomes failed [81]. No secondary outcome was significant, including Unified Parkinson's Disease Rating Scale (UPDRS) part III and the functional independence measure [82]. In the extension, the group switching from placebo to deferiprone went from 4.4 to 1.4 points of worsening (p=0.021), without PGI-I change [81]. Deferiprone reduced basal ganglia iron [81]. Anaemia occurred in 21% of the deferiprone group and in no placebo patients, without anaemia-related withdrawals; three patients withdrew for moderate neutropenia; one aspiration death occurred in each group during the extension, considered unrelated [81]. The EMA report additionally records related adverse events in 79.3% versus 43.3%, adverse-event withdrawal in 6.9% versus 0%, decreased ferritin as the most common adverse reaction (29.3%), neutropenia in 8.5% versus 6.7% and no agranulocytosis during the trial, the extension, compassionate use or Friedreich ataxia studies [75]. The authors interpreted the results as non-significant slowing and PGI-I as perhaps unsuitable [81]. The Committee for Medicinal Products for Human Use (CHMP) considered the study negative: the BAD difference was almost 70% below the planned effect of at least 5 points, atypical subgroup benefit was exploratory, and iron reduction (measured by R2* in a subset, not the full population) was not associated with clinical improvement [75].

The 2022 French PNDS grounds conservative chelation — removal of iron from sites of excess and its redistribution throughout the body, without anaemia or global iron loss — in the marked lipid peroxidation of NBIA, which points to ferroptosis, a form of regulated cell death that chelators inhibit, and considers it an option mainly in NBIAs in which iron accumulates late [28]. It describes patients with PKAN treated open-label with deferiprone 30 mg/kg/day, with strict full blood count monitoring, without symptomatic benefit but with apparent slowing of decline, particularly when treatment began with mild disability; it reads TIRCON as a trial in which deferiprone was well tolerated, reduced iron and appears to slow progression, and mentions the request for a new study before registration [28]. The PNDS places the risk of neutropenia or agranulocytosis below 2%, but the published values differ for the two events: in the US label, agranulocytosis occurred in 1% and neutropenia in 7% of 642 patients with thalassaemia, and in TIRCON neutropenia affected 8.5% of the deferiprone group, without agranulocytosis [75, 83]. The PNDS also describes a reduction in worsening demonstrated in the group treated for 36 months compared with the group treated only in the final 18 months; the published extension comparison is within-group, in the group that switched from placebo to deferiprone (4.4 to 1.4 points of worsening), without a control [28, 81]. This reading diverges from the CHMP assessment, which considered the study negative, and from the withdrawal of the marketing authorisation application in 2020; the PNDS does not state duration, maximum dose or monitoring frequency, which for the full blood count are given in the labels (Table 7.5) [75, 83, 84].

Fosmetpantotenate. This PANK2 bypass substrate was tested in the phase 3 randomised, double-blind, placebo-controlled FORT trial at US, Canadian and European centres, with 84 patients aged 6–65 and PKAN-ADL scores of at least 6, receiving 300 mg orally three times daily for 24 weeks [85]. PKAN-ADL, developed for the trial from UPDRS part II, with 12 items and clinimetric validation in 40 patients, was the primary outcome [86]. At week 24, the least-squares mean difference was −0.09 (95% CI −1.69 to 1.51; p=0.91), without UPDRS-III difference; serious adverse events occurred in 19.5% versus 14.0%, with two deaths from PKAN complications in the placebo group [85, 87]. The study was terminated because it showed no significant effect or clinical benefit [87].

4'-Phosphopantetheine (CoA-Z and 4'-PPT). 4'-Phosphopantetheine is an intermediate downstream of the PANK2 block that corrected CoA, iron and dopamine defects in mammalian models, without adverse effects in a 15-day mouse toxicity study [11, 22]. NCT04182763 (OHSU), registered as a dietary supplement study (“phase not applicable”), randomised 77 patients aged 3 months to 89 years residing in the US or Canada to three doses or placebo for 6 months, followed by 18 open-label months with the intermediate dose; it ended in January 2025 and posted safety results in the registry in October 2025 [88]. Adjusted treatment-emergent adverse-event rates were 1.15, 1.38 and 1.14 in active groups and 0.86 with placebo (p=0.50); serious adverse events during the blinded phase were 8/15, 7/17 and 5/17 versus 3/16; there was one death in the blinded phase and eight in the open phase, without specified causes; COASY mRNA expression showed no dose-dependent trend [88]. By 10 October 2026, no peer-reviewed efficacy results publication had been identified, and the product has no Food and Drug Administration (FDA) approval [11, 88]. In the United Kingdom, UK-PKAN-B5D (ISRCTN10664670, Great Ormond Street/UCL) tests 4'-PPT capsules once daily orally or by tube in patients aged 12 months to 25 years, for 24 randomised placebo-controlled weeks and 24 open-label weeks, with safety primary and PKAN-ADL and PKAN-DRS secondary outcomes; it recruited 15 participants between April 2025 and January 2026, with completion expected in March 2027 and intended development as a food for special medical purposes [89].

Other approaches. Oral pantetheine has anecdotal reports of improved attention [23]. BBP-671, a pantothenate kinase activator, increased brain CoA and improved survival and motor deficits in neuronal Pank1 and Pank2 knockout mice, and in a phase 1 healthy volunteer study was detected in CSF and increased blood acetyl-CoA; no patient trial was identified [90]. Pantazines, leriglitazone, α-lipoic acid and AAV9-PANK2 gene therapy are preclinical [22]. Phosphopantothenate is not a practical option because transmembrane transport is unlikely [3].

Table 7.3 — Trials and interventional studies in PKAN and other NBIAs

Sources: [1, 3, 80–82, 85, 87–89, 91].

Trials cannot be compared because populations, ages, scales and durations differ, and none demonstrated clinical benefit on its primary outcome. The 1.51-point BAD difference favouring deferiprone should be considered against approximately 4 points of worsening over 18 months with placebo and the minimum 5-point effect considered clinically relevant in the design; radiological iron reduction did not translate into demonstrated clinical benefit [75, 81]. Open-label extension and subgroup results are exploratory. The 4'-phosphopantetheine trial has only safety data and permits no efficacy conclusions [88].

7.7. Regulatory status

Table 7.4 — Regulatory status of targeted therapies

Sources: [11, 22, 75, 83, 84, 92–94]. BGT-INAD designation is known through UCL Business press releases and Cascone's review, rather than direct consultation of official registries [22, 94].

Table 7.5 — Deferiprone dosing and safety in labels and TIRCON

Sources: [75, 81, 83, 84, 93]. In neuroferritinopathy, serum ferritin already below 20 µg/L requires particular caution with any chelation [11].

7.8. PLAN

The 2026 GeneReviews incorporates the PLAN consensus guideline published in 2025: there is no cure and care is supportive and multidisciplinary [4]. In infantile and juvenile disease, spasticity and dystonia are treated with trihexyphenidyl, gabapentin, clonidine, clonazepam, oral or intrathecal baclofen and botulinum toxin, with reassessment during progression; levodopa helps late-stage juvenile parkinsonism; standing activities and vitamin D protect bone; seizures are treated with standard antiseizure medicines [4]. Unexplained chronic irritability in early infantile disease may respond to gabapentin or melatonin, and sleep disturbances justify individual trials of melatonin, an H2 blocker, gabapentin or baclofen [4]. Gastrostomy is frequently necessary; constipation is treated with fibre, stool softeners and laxatives; dysautonomia requires temperature monitoring and warming and cooling strategies; weakness, immobility, dysphagia and scoliosis predispose to pneumonia, prevented through airway clearance, secretion management, routine and seasonal immunisation, prophylactic antibiotics particularly in winter and, in late stages, non-invasive ventilation [4]. Cognitive assessments should recognise that motor deterioration is often faster than cognitive deterioration [4].

In adult PLAN, levodopa and other antiparkinsonian agents produce an initially potentially dramatic response followed by early dyskinesias at lower doses than in idiopathic Parkinson disease; dystonia is treated with baclofen, clonazepam, trihexyphenidyl, clonidine and botulinum toxin; DBS successfully treated parkinsonism and dystonia in a small number of patients [4, 11]. Sialorrhoea may be treated with off-label sublingual atropine drops or a scopolamine patch, and gastrostomy should be discussed early [4]. Psychiatric manifestations are common and problematic: first-generation antipsychotics and most second-generation agents block dopamine receptors and worsen parkinsonism, making quetiapine, clozapine or pimavanserin safer alternatives [4]. No randomised PLAN trials have been published [11].

Among investigational therapies, GeneReviews authors recommend age-appropriate DHA, without a specified dose, based on low risk and mouse model data in which iPLA2-β selectively hydrolyses DHA, without patient trials [4]. Desipramine, blocking ceramide accumulation in models, had a four-patient open-label trial terminated early [1]. RT001 (deuterated linoleic acid), intended to reduce lipid peroxidation, had a single-arm open-label study in 19 children with INAD without published results, and Cascone's review mentions preliminary stabilisation in two patients [22, 91]. Gene therapy (AAV-PHP.eB-PLA2G6 and AAV9-PLA2G6) is preclinical [4, 22, 94]. Deferiprone has not been studied in a PLAN trial [4].

7.9. MPAN

Treatment is symptomatic: oral baclofen, trihexyphenidyl, botulinum toxin and a trial of intrathecal baclofen for dystonia and spasticity; levodopa for parkinsonism, with variable response, sometimes very good for several years; low-vision aids for optic atrophy; alternative communication for dysarthria, complicated by cognitive decline; nutritional supplements, gastric tube feeding, glycopyrrolate or scopolamine patches for secretions and possible tracheostomy for dysphagia; fibre and stool softeners for constipation [5]. GeneReviews authors encourage early tube-feeding discussions because many families wish placement had occurred earlier, and recommend clinical ethics consultation for difficult decisions [5]. Some patients choose off-label deferiprone: in a 13-year-old boy treated for 2 years, substantia nigra iron decreased without pallidal iron or clinical change; another patient stopped because of gastrointestinal effects; in two siblings, one maintained stabilisation for 4 years and the other had no benefit [5, 22].

7.10. BPAN

The 2021 consensus focuses management on the greatest quality-of-life impacts — seizures, behaviour, communication, sleep and neurological regression — with anticipatory family guidance [24].

Epilepsy. An antiseizure medicine is considered in children with recurrent unprovoked seizures; none has proved superior in BPAN. Cannabidiol may be used on-label if the child meets Lennox-Gastaut syndrome criteria, without specific data; ketogenic diets and vagus nerve stimulation are options for refractory cases [24]. Infantile spasms follow standard assessment and treatment, and GeneReviews mentions early short-term adrenocorticotrophic hormone (ACTH), prednisolone or vigabatrin according to North American and International League Against Epilepsy consensus [6, 24]. Stereotyped episodes on waking may be epileptic, and a negative scalp EEG does not exclude them [24]. Because seizures usually cease in adolescence, a trial of antiseizure medicine withdrawal should be proposed after 2 seizure-free years [24].

Communication, motor function and behaviour. Oral language expectations should be realistic, with early assessment by a speech and language therapist experienced in augmentative and alternative communication; all children should have formal audiological assessment; children with ASD should receive comprehensive treatment, potentially including applied behaviour analysis (ABA); physiotherapy supports motor development with realistic goals and continues in adolescence; behavioural problems require a psychologist or psychiatrist experienced in intellectual disability [24].

Sleep. Sleep disturbance may be multifactorial (cycle dysregulation, sleep-disordered breathing, seizures, reflux, spasticity). Sleep studies, EEG for suspected nocturnal seizures and serum ferritin for restless sleep are suggested. Non-pharmacological treatment includes bedtime routines, limited naps, white noise, weighted blankets and graduated extinction. No drugs are FDA- or EMA-approved for paediatric insomnia; melatonin is first-line, alpha agonists (clonidine) second-line, and third-line options include antihistamines (hydroxyzine, diphenhydramine, which may lower the seizure threshold), antidepressants (trazodone, mirtazapine), benzodiazepines, gabapentin, zolpidem and atypical antipsychotics (risperidone, which may worsen parkinsonism) [24]. In the EU, prolonged-release melatonin (Slenyto®) has been authorised since 20 September 2018 for insomnia in children aged 2 to 18 years with autism spectrum disorder and/or Smith-Magenis syndrome, and the Commission decision of 26 August 2024 extended the indication to neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, which makes the absence of an approved drug cited in the 2021 consensus outdated for the EU [95].

Endocrinology, vision and nutrition. Isolated early adrenarche (pubic or axillary hair, acne or body odour without breast development, menarche or testicular enlargement) requires no assessment; true precocious puberty, which is rare, does [24]. Regular ophthalmology and early low-vision assessment are recommended [24]. No dietary or supplement benefit is demonstrated; the consensus recommends against low-iron diets; childhood hyperphagia requires behavioural management and elevated body mass index does not persist in adults; dysphagia should be enquired about at every consultation and may require gastrostomy; cannabidiol use for mood, autism, insomnia or behaviour rests on very limited data and should be discussed with families [24].

Regression, dystonia and parkinsonism. Dopaminergic medication is appropriate because response is typically robust, but unstable motor fluctuations and dyskinesias, sometimes with painful dystonia, require a movement disorder neurologist [24, 61]. With advanced cognitive impairment, carbidopa/levodopa may have lower neuropsychiatric risk than dopamine agonists; amantadine may help dyskinesias, with hallucination and agitation risks at high doses; trihexyphenidyl may worsen cognition in advanced stages [6]. No BPAN DBS data exist, and potential cognitive worsening warrants caution [24]. Iron chelation is not recommended outside trials: two adults with BPAN treated with deferiprone had no benefit, and in one parkinsonism worsened and improved after discontinuation [22, 24].

Palliative care, transition and education. Palliative care is particularly useful in declining adults and severely disabled patients; transition to adulthood requires ongoing dialogue among family, healthcare professionals, educators and social workers; individual education plans should be reassessed at least annually; and all patients should have an emergency care plan and standard immunisation [24]. Families of young children may experience renewed anxiety and grief on learning of expected regression, and some become hypervigilant about every new symptom [24].

7.11. Aceruloplasminaemia

There are no large series or universally accepted regimen, and no chelator has an approved aceruloplasminaemia indication in the labels consulted [7, 83, 84]. Early diagnosis and treatment are crucial because neurological complications are generally irreversible [64]. Desferrioxamine may be considered in symptomatic patients with haemoglobin above 9 g/dL; the GeneReviews regimen is 500 mg dissolved in 100 mL normal saline, infused intravenously over one hour twice weekly for 6–10 months [7]. With this treatment, Miyajima (1997) observed reduced ferritin and hepatic and brain iron, with improved anaemia and diabetes; Mariani (2004) removed hepatic iron without brain MRI change after more than a year; and Pan (2011) described improved basal ganglia hypointensities in a 52-year-old patient receiving 500 mg intravenously in 5% glucose weekly for 4 years [7]. Oral deferasirox produced mild improvements in cognition, gait and balance in a patient unresponsive to desferrioxamine or plasma and may prevent hepatic and pancreatic injury; deferiprone did not benefit one patient, although early initiation in caeruloplasmin- and hephaestin-deficient mice protected the retina and increased survival [7]. Intravenous fresh frozen plasma supplies caeruloplasmin and increases serum iron for hours; combined with desferrioxamine, it reduces hepatic iron further, and repeated administration may improve neurological manifestations [7]. Vitamin E with a chelator, or oral zinc, may prevent hepatic and pancreatic injury, and chelator plus zinc may decrease iron accumulation [7]. Diabetes is treated conventionally, anaemia requires no transfusion, and there is no specific retinal treatment [7]. Iron supplements should be avoided: patients incorrectly treated for iron-deficiency anaemia had accelerated accumulation [7]. ClinGen classified aceruloplasminaemia actionability as moderate in adults and strong in the paediatric context [11]. An early phase 1 deferiprone trial with five patients in China is registered with unknown status [91].

7.12. Neuroferritinopathies

In FTL neuroferritinopathy, treatment is empirical, guided by the predominant symptom and without formal trials: levodopa, tetrabenazine, orphenadrine, trihexyphenidyl, sulpiride, diazepam, clonazepam and deanol at standard doses, with responses in only some patients; botulinum toxin is useful for painful focal dystonia; tetrabenazine produced a dramatic response in stereotypies and facial tics in the first US cases [8]. Anecdotal improvements with oral deferiprone and conservative chelation exist, without trials [8]. Iron supplements are not recommended in patients or at-risk individuals, although carefully monitored replacement may be necessary for coincident iron-deficiency anaemia; no evidence supports avoiding iron-rich foods [8]. Among allelic diseases, hyperferritinaemia-cataract syndrome should not be treated with phlebotomy, which is inappropriate and potentially harmful, and only cataracts are treated; in a 2026 report, a 58-year-old man with c.-168G>A underwent phlebotomy before diagnosis [11]. In FTH1 neuroferritinopathy, there is no disease-modifying treatment or guideline; chelation is unproven, and allele-specific antisense oligonucleotides rescued fibroblast phenotypes (preclinical) [11].

7.13. Kufor-Rakeb syndrome, FAHN and CoPAN

In Kufor-Rakeb syndrome, levodopa is the basis of parkinsonism treatment, with a therapeutic window narrowing over time [11]. The US carbidopa/levodopa label (Sinemet®) indicates Parkinson disease and postencephalitic or symptomatic parkinsonism without a specific Kufor-Rakeb indication; paediatric safety and efficacy are not established and use below 18 years is not recommended; concomitant non-selective monoamine oxidase inhibitors are contraindicated [11]. No ATP13A2-directed therapy exists [11].

In FAHN, dystonia and spasticity are treated with oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines or dantrolene and botulinum toxin for cocontractions; levodopa merits a trial, continued only with clear benefit; pallidotomy or thalamotomy may help, with possible recurrence; weighted gloves reduce dysmetria; riluzole has been recommended for cerebellar ataxia generally, without a FAHN trial; seizures respond well to traditional antiseizure medicines; gastrostomy is indicated with inadequate nutrition or aspiration risk [9].

CoPAN has no specific therapy; future downstream or genetic strategies differ from precursor bypass or PANK activation used in PKAN, and there are no AAV studies [11, 22].

7.14. Woodhouse-Sakati syndrome

Hypogonadism is treated with sex hormone replacement at the usual age of puberty to induce and maintain sexual characteristics and bone health; this does not promote fertility, but gonadotrophin testicular stimulation and sperm collection for assisted reproduction are possible [10]. Hormone therapy at puberty is the most urgent intervention, justifying early identification of affected siblings [11]. Recombinant IGF-1 is not recommended because evidence is lacking, and IGF-1 may rise with sex hormones [10, 37]. Diabetes is treated conventionally and hypothyroidism with levothyroxine; alopecia is managed cosmetically [10]. Dystonia treatment starts with oral agents — anticholinergics (trihexyphenidyl, moderately effective in 40–50%, titratable to approximately 100 mg/day in young people with close cognitive adverse-effect monitoring), baclofen, benzodiazepines (particularly clonazepam), levodopa, carbamazepine and dopamine depleters (reserpine, tetrabenazine) — and botulinum toxin is the treatment of choice for focal dystonia [10]. GPi DBS is effective in some refractory primary generalised dystonias, without documented use in this syndrome [10]. Dysphagia benefits from thickened fluids, puréed food and, if needed, gastrostomy; tricyclic antidepressants and anticholinergics may reduce secretions [10]. Patients with dystonia should avoid situations with increased fall risk [10].

7.15. Cross-cutting symptomatic treatment and organisation of care (French PNDS)

The French PNDS organises the symptomatic treatment of all NBIAs by domain rather than by entity. The approach is global and multidisciplinary, coordinated by a physician from the reference or competence centre in liaison with the attending physician, and aims to preserve autonomy, quality of life, family balance and financial resources for as long as possible; support from a clinical psychologist with specific training is recommended from diagnosis and throughout the course of the disease [28]. As several drugs are used outside their authorised indications, the PNDS recalls the French framework: prescription is possible when there is no suitable alternative or under a temporary recommendation for use (RTU), with information to the patient on the off-label nature, the risks and the reimbursement conditions, express mention on the prescription and justification in the medical record; reimbursement under these conditions is exceptional and temporary, after an opinion from HAS [28].

Dystonia. Active and passive kinesitherapy is recommended at all stages, to maintain joint range of motion and prevent deformities and tendon retractions. Benzodiazepines and baclofen and, if cognition allows, trihexyphenidyl may be used; botulinum toxin in focal dystonia (cervical, knee flexion, equinus foot, jaw) is indicated by a movement disorder specialist and repeated if effective and well tolerated; DBS is discussed in an experienced centre (section 7.3); custom-made wheelchairs and seating optimise positioning [28].

Chorea. It is treated when it bothers the patient. Tetrabenazine, subject in France to an exceptional medical prescription, has a beneficial effect but should not be prescribed to patients with depressive symptoms; atypical antipsychotics, without an approved indication for chorea, are the first choice when chorea coexists with behavioural disturbance, active depression or psychosis, and low doses may suffice [28].

Rigidity and parkinsonism. Levodopa is introduced progressively; the response is generally poor in PKAN and good in PLAN, MPAN, BPAN and Kufor-Rakeb syndrome, and dyskinesias frequently appear in a second phase. Dopamine agonists are little used, because of the risk of worsening neuropsychiatric disturbances, and with advanced cognitive impairment levodopa is adjusted cautiously, because of the risk of cognitive deterioration; rehabilitation (physiotherapy, occupational therapy, psychomotor therapy and relaxation) complements treatment [28].

Spasticity. Before intensifying treatment, a nociceptive stimulus that aggravates it (pain, infection, faecal impaction, fracture) is sought. The options are physiotherapy with stretching and exercise, oral or intrathecal baclofen, botulinum toxin provided that the underlying strength remains useful for function and, finally, surgery such as tenotomy [28].

Swallowing, gait and balance. Dysphagia should be assessed and prevented early, with speech and language therapy combining advice on posture and positioning at meals, texture modification, praxis training and elimination of distractions; in severe forms gastrostomy is discussed, which does not prevent some oral feeding from being maintained [28]. Gait and balance disturbances are treated with physiotherapy and psychomotor therapy and with assistive devices (walking frame, cane, wheelchair) and protective equipment to reduce falls and their consequences, chosen with the occupational therapist; progression requires regular reassessment of the functional impact [28].

Intellectual disability and schooling. The spectrum ranges from learning disorders to severe encephalopathy. A formal age-appropriate assessment is recommended, with the Wechsler scale (WISC-V) at around 5–6 years, before primary school, if the child is able to complete it, and assessments targeted at areas of weakness (speech and language therapy, physiotherapy, psychomotor therapy, occupational therapy, orthoptics) [28]. The result guides the educational plan (mainstream schooling with or without a support assistant, school inclusion units or special education) and rehabilitation, in private practice or in coordination structures (in the French system, CAMSP before 6 years, CMP and SESSAD); autism spectrum disorder is assessed at an autism resource centre when there is a communication disorder, and augmentative communication systems (PECS, Makaton) are introduced with the speech and language therapist if language delay persists beyond 3 years [28]. Transition ages (start and end of preschool, end of primary school, end of lower secondary school and transition to adulthood) require particular attention, given the possibility of regression [28].

Cognitive decline and psychiatry. Cognitive regression or dementia may appear at any age; in adults there is no specific treatment, and there are no studies or approved indications for cholinesterase inhibitors or memantine in NBIA [28]. Depression is frequent at disease onset and when symptoms with functional impact appear, but may arise at any stage: a selective serotonin reuptake inhibitor (SSRI) or a serotonin-noradrenaline reuptake inhibitor (SNRI) is recommended as first line, chosen on the basis of interactions and tolerability, with psychological support when the patient is able to engage. Anxiety is addressed by looking for triggers, by reassurance measures and by psychological support, with an occasional benzodiazepine in acute or subacute crises, to avoid dependence, or with an SSRI or SNRI. In agitation, a somatic cause that the patient cannot express (urinary retention, faecal impaction, pain) is sought first; an occasional benzodiazepine is used when there is anxiety and, in severe or persistent agitation, second-generation antipsychotics [28].

Sleep. Disturbances (insomnia, daytime sleepiness, phase delay) have varied causes, including depression, anxiety and involuntary movements that wake the patient. The first measure is sleep hygiene (fixed schedules, avoiding stimulants in the evening, short naps), with treatment of underlying depression or anxiety; if this fails, melatonin is prescribed (in France, as a compounded preparation) and, if necessary, hypnotics at the lowest effective dose and for the shortest possible time [28]. Overnight ventilatory polysomnography clarifies suspected sleep-disordered breathing or REM sleep behaviour disorder (Table 11.1).

Pain, oral health and nutrition. With communication disorders, pain is expressed through changes in behaviour or worsening of abnormal movements; the cause is treated and analgesics are used according to the World Health Organization ladder [28]. Oral health is weakened by abnormal movements, by drugs that alter salivation and by dental trauma; regular follow-up with annual scaling, care under light sedation or general anaesthesia in hospital facilities used to people with disabilities, and protective splints for recurrent biting are recommended [28]. Nutritional status is fragile, because pain and feeding difficulties lead to food refusal and abnormal movements increase energy expenditure; the strategy begins with food enrichment, continues with oral nutritional supplements and a dietetics consultation, and may lead to gastrostomy [28]. Acute digestive symptoms always require a search for a digestive cause; in its absence and when they become chronic, constipation due to inactivity, dysautonomia or drugs (neuroleptics, antidepressants), dysautonomic diarrhoea or diarrhoea alternating with constipation once faecal impaction has been excluded, and vomiting due to abnormal movements, dysphagia, drugs or gastroparesis are considered. Faecal impaction can cause overflow diarrhoea and vomiting, and effective prevention of constipation sometimes resolves recurrent episodes; splitting meals and posture during meals complete symptomatic treatment [28].

Sialorrhoea. Hypersalivation results from poor lip closure or a swallowing defect and increases the risk of aspiration. The PNDS proposes transdermal scopolamine, oral atropine or another drug with an anticholinergic effect, such as amitriptyline, with monitoring for the risk of confusion, constipation and acute urinary retention, and botulinum toxin injections into the salivary glands when these measures fail [28].

Disclosure, therapeutic education and advance directives. The diagnosis is disclosed in a dedicated consultation, with active listening, involvement of a clinical psychologist if needed, a care plan with presentation of the multidisciplinary team, and contact details of patient associations [28]. The psychological distress of the patient and family, associated with the motor symptoms, learning difficulties, transmissibility and unpredictability of the course, is often little expressed and should be sought at each consultation; reference and competence centres provide information with up-to-date medical data, in partnership with the associations, to counter outdated or alarmist information, and provide genetic counselling [28]. As advanced forms compromise communication, the PNDS recommends addressing early, in a context of trust, the advance directives and the designation of a trusted person provided for in French law (Leonetti law of 2005, reinforced by the Claeys-Leonetti law of 2016), for example by presenting them as a right of every citizen or with leaflets in the waiting room, and involving psychologists or palliative care teams when necessary; in advanced stages, integration of a palliative care team is justified [28].

Table 7.6 — Reference doses of symptomatic drugs cited without a dose by the PNDS and the PKAN consensus (official labels; extrapolation to NBIA)

Sources: [23, 28, 95–104]. In PKAN, the consensus recommends titrating from a low dose until efficacy or intolerance and reviewing the regimen every year (section 7.2); the doses in the table serve as starting and maximum references and do not replace individual titration by experienced neurologists [23].

7.16. Agents and interventions to avoid

Table 7.7 — Agents to avoid or use cautiously

Sources: [3, 4, 7, 8, 10, 11, 23, 24]. Cascone's review mentions reports of stabilisation with vitamin E and omega-3 in patients and fibroblasts with PLAN, PKAN and BPAN; evidence is weak on both sides and, for PKAN, the consensus recommendation to avoid vitamin E takes precedence [22, 23].

7.17. Pregnancy, lactation, fertility and transition

Women with PKAN have conceived and had healthy children without complications; men have fathered children, but unpublished data suggest abnormalities of sperm motility, morphology and count probably reducing fertility; contraception is recommended for those not wishing to conceive, using usual methods [23]. In adult PLAN, two women had children; because onset may occur up to 30 years, pregnancy may precede or coincide with disease onset; the principal issue is drug teratogenicity and whether pregnancy changes the course is unknown [4]. In BPAN, mildly affected women may reproduce; antiseizure medicines should continue during pregnancy despite risks of some agents, with preconception discussion and transition to the lowest-risk drug [6]. Deferiprone is contraindicated during pregnancy and breastfeeding in the European Union and carries a US warning owing to fetal harm in animals [83, 84]. In Woodhouse-Sakati syndrome, fertility requires assisted reproduction [10]. In BPAN, the consensus recommends discussing financial, occupational and medical plans from 12 years, and in PLAN transition planning should begin in adolescence [4, 6].

7.18. Developments in the last 6–12 months and ongoing research

Between October 2025 and October 2026, relevant developments were as follows, with evidence level indicated. In regulation and clinical guidance, ERN-RND published endorsement of the overview GeneReviews as best practice for all NBIAs on 29 January 2026 (European network opinion, without new content recommendations) [2], and PLAN GeneReviews was updated in April 2026, incorporating the 2025 guideline and prospective infantile natural history study [4]. In trials, CoA-Z posted only safety results in the registry in October 2025, without published efficacy (registry trial result) [88], and the UK 4'-PPT study closed recruitment in January 2026 with 15 participants (ongoing trial) [89]. No new authorisation or application for any NBIA appeared in the sources consulted; the only related approval was a US deferiprone generic in December 2025 for the haematological indication [92].

Clinical and basic research publications included the proposal of SLC27A3 as an NBIA gene based on one patient (human study, single case) [54]; an estimate of lifetime recessive NBIA risk in a Turkish clinical cohort (retrospective genetic study) [105]; a CPT1 deficiency-like acylcarnitine profile in five PKAN patients (case series) [70]; functional measures to prepare BPAN trials (observational study, 53 patients) [63]; the Korean BPAN series [60]; cases of late-onset PSP-like PKAN and directional DBS for status dystonicus (case reports) [57, 79]; and Cascone and colleagues' therapeutic strategy review, classifying pantazines, leriglitazone, autophagy modulators (rapamycin, L-serine, carbamazepine), N-acetylcysteine, acetyl-leucine and PANK2, PLA2G6 and WDR45 gene therapy as preclinical [22]. A Bordeaux BPAN brain iron study is registered with planned initiation in December 2026, and the international TIRCON and ERN-RND European registries continue [91]. A negative registry search does not establish the absence of other programmes.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance pattern

Table 8.1 — Recurrence risks by scenario

Sources: [1, 3–6, 8, 9, 23, 24].

In recessive forms, parental testing is recommended to confirm heterozygosity and assess risk accurately [1]. The proband's uncles and aunts have a 50% carrier probability, and carrier testing requires prior identification of familial variants [1, 3]. Patients with severe recessive forms rarely reproduce, but those with late-onset or atypical disease may have children [1]. Heterozygotes are asymptomatic; in aceruloplasminaemia, data are insufficient to exclude clinical disease in elderly heterozygotes, and an estimated 0.1% of Japanese people with diabetes are heterozygous [7].

8.2. Entity-specific considerations

PKAN. The consensus recommends prioritising sibling assessment (neurological examination, MRI or diagnostic testing), particularly younger siblings or those with signs, and reserving genetic testing for symptomatic siblings; healthy siblings may consider carrier testing in adulthood [23]. The 2017 GeneReviews allowed consideration of neurological assessment, MRI and genetic testing in asymptomatic siblings, particularly those younger than the proband, considering developing therapies and the deferiprone trial [3]. Both documents agree on sibling clinical assessment and differ in presymptomatic testing scope; with negative trials, consensus guidance remains applicable, without prejudice to ongoing trial eligibility, which for 4'-phosphopantetheine included symptomatic siblings [23, 88].

PLAN. Paternal chromosome 22 isodisomy was described in twins with PLAN conceived through in vitro fertilisation [4]. Predictive testing of asymptomatic siblings is possible, but early diagnosis probably does little to reduce morbidity or mortality; in adults it may form part of reproductive planning with counselling and psychosocial support, recognising substantial intrafamilial onset variation [4]. Carrier testing should be offered to partners of carriers or affected individuals, particularly with consanguinity or shared ancestry, especially North African and Bedouin [4].

MPAN. In dominant disease, the variant is most often de novo in exon 3; only two multigenerational families have been described and onset age and progression may differ between heterozygotes in the same family [5]. Some late-onset patients reproduce before symptoms, and predictive testing of at-risk adults should occur with formal counselling on socioeconomic consequences and follow-up [5]. Mosaic carriers may have late, atypical phenotypes, making testing clinically healthy parents important [51].

BPAN. The vast majority of cases are simplex and de novo, but both parents of a female proband or the mother of a male proband should be tested because recurrence through maternal germline mosaicism and mothers with X-inactivation strongly skewed towards the normal allele has been described [6, 24]. Most patients do not reproduce; affected males do not reproduce; mildly affected women should receive genetic counselling as they approach reproductive age [6, 24]. The consensus highlights two rare scenarios: monozygotic twins with low-level mosaicism preceding zygote division and sisters inheriting a variant from a parent with gonadal mosaicism and having favourable X-inactivation, both with increased recurrence risk that is difficult to identify [24]. Annual genetic reassessment keeps families informed [24].

Aceruloplasminaemia. Assessment of older and younger asymptomatic siblings is recommended from 15 years, with molecular testing if variants are known and haemoglobin and HbA1c measurements, because anaemia and diabetes may precede neurological manifestations; the optimal preventive approach is unknown [7].

Neuroferritinopathy. In a simplex case, parents should undergo brain MRI and serum ferritin measurement alongside molecular testing; family history may appear negative through lack of recognition, early death or late onset [8]. Predictive testing is possible with formal counselling, does not predict onset age, severity or progression, and is considered inappropriate in minors because this is an adult-onset disease without benefit from early treatment [8].

Woodhouse-Sakati syndrome. Molecular testing of older and younger asymptomatic siblings is recommended to treat endocrine complications early; an affected sibling's neurological phenotype cannot be predicted from the proband's [10, 11].

8.3. Prenatal diagnosis, preimplantation testing and family planning

After identification of familial variants, prenatal diagnosis and PGT are possible in all NBIAs [1]. In the first successful PKAN PGT, a Thai couple with an affected child underwent one in vitro fertilisation cycle with intracytoplasmic sperm injection; among seven embryos, two were probably affected, three carriers, one unaffected and one failed to amplify; the only unaffected euploid embryo was transferred, amniocentesis confirmed the result and a healthy boy was born at 38 weeks, with normal development at 24 months [72]. Views on prenatal diagnosis vary among professionals and families and decisions are personal; in adult-onset neuroferritinopathy, the National Society of Genetic Counselors position on late-onset diseases applies [1, 8]. Family planning should be discussed before pregnancy with affected, carrier or at-risk young adults, and DNA from probands without molecular confirmation should be banked [1, 3]. In France, the PNDS accepts discussion of prenatal and preimplantation diagnosis with couples, given the severity of the diseases, subject to the opinion of a CPDPN in each case; in BPAN, although the recurrence risk after an affected child is in theory limited to that of germline mosaicism, the PNDS accepts discussing them at the couple's request [28].

8.4. Counselling minors

Testing asymptomatic minors depends on benefit: it is recommended in Woodhouse-Sakati syndrome and aceruloplasminaemia (from 15 years) because it permits early intervention; it is discouraged in neuroferritinopathy; and in PKAN and PLAN it adds no demonstrated therapeutic benefit, with testing reserved for symptomatic siblings at any age [4, 7, 8, 10, 23]. The French PNDS, applicable to all NBIAs, excludes presymptomatic diagnosis in minors (section 4.4); the divergence from GeneReviews in the two entities with useful early intervention stems from the French legal framework and from the scope of the PNDS, which does not analyse aceruloplasminaemia or Woodhouse-Sakati syndrome in detail [7, 10, 28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each number measures

No NBIA has a population prevalence study based on case counting. Available numbers are of four types: expert estimates, proportions in a referral registry, published case counts and allele-frequency modelling. None is a measured national prevalence.

Table 9.1 — Epidemiological estimates and their nature

Estimates diverge. The 2021 BPAN consensus considers BPAN the most common NBIA, whereas the 2017 PKAN consensus and EMA attribute approximately half of cases to PKAN [23, 24, 75]. The difference reflects the era: in Hayflick's laboratory international registry (OHSU), with 850 families assembled over 25 years, BPAN now represents 40–45% of NBIA, PKAN 30–35%, PLAN 10–15% and MPAN 5–10%, with other forms rare [1]. The subtype table of the French PNDS ranks PKAN, PLAN and BPAN as the most frequent, followed by MPAN and then the others, without figures [28]. These proportions are affected by referral bias to one centre and are not population prevalences [1]. The modelled PLAN estimate, exceeding registry enrolment numbers, suggests underdiagnosis [4]. In the Turkish cohort, PLA2G6 contributed most to lifetime risk, followed by PANK2 and C19orf12, and a 2026 review states that PLA2G6, PANK2 and COASY account for up to three-quarters of the combined lifetime risk of recessive NBIAs [22, 105].

9.2. Founder populations and recurrent variants

Dominican Republic. In an isolated south-western region, 46 patients from 34 families had PKAN, 22 classic and 24 atypical; 42 were homozygous for c.680A>G p.(Tyr227Cys) (NM_153638; c.350A>G p.(Tyr117Cys) on MANE) and four compound heterozygotes with p.(Arg532Trp); shared haplotypes are of African origin, with introduction estimated 25–35 generations ago; carrier frequency was 0.8% in the Dominican Republic and 0.18% in people of Dominican ancestry in New York [48]. Some lacked the eye-of-the-tiger sign [3].

Europe. A PANK2 founder effect exists in the Netherlands (3-base-pair deletion) [3] and a founder is hypothesised in Agrigento province, Sicily, where two c.1169A>T p.(Asn390Ile) homozygotes came from the same small town of fewer than 9,000 inhabitants [45]. C19orf12 c.204_214del11 is common in central Europe, particularly Poland, and associated with juvenile onset [1, 5]. Most neuroferritinopathy patients belong to an extended north-east England pedigree with c.460dupA; a Texas patient of German ancestry suggests independent recurrence [8, 26, 107]. The Philadelphia 53-patient BPAN series and international 23-patient series provide the main North American and European natural history data [61, 63].

Turkey and the Middle East. The C19orf12 variant c.32C>T p.(Thr11Met) is frequent in Turkish adults with MPAN [5]. The DCAF17 variant c.436del has a carrier frequency of 0.00243 (approximately 1:411) in Saudi Arabia and explains Saudi and Qatari cases; 67% of patients from the Greater Middle East come from consanguineous marriages [10, 11]. The PLA2G6 variant p.(Val691del) is a founder variant in a North African cohort (Tunisia) and in Israeli Bedouins [4]. The INAD natural history series included 16 patients from Riyadh [50].

Asia. PANK2 p.Arg440Pro is recurrent in Korea [3]. A Chinese typical PKAN case compound heterozygous for c.1213T>G p.(Tyr405Asp) and c.1502T>A p.(Ile501Asn) was published with a review of reported variants, without specifying transcript in the abstract [108]. Aceruloplasminaemia has been quantified predominantly in Japan, and no prevalence data exist outside that country [7]. A Japanese study found high BPAN frequency among patients with intellectual disability and young-onset parkinsonism [6]. BPAN variants occur at similar frequencies across ethnic groups, with published case clusters in North America, East Asia, western Europe and the Middle East [6, 25].

Portugal and Brazil. The sources consulted contain no Portuguese or Brazilian prevalence data. GeneReviews attributes the 2005 description of the only neuroferritinopathy-associated FTL missense variant, c.286G>A p.(Ala96Thr), with early bilateral pallidal involvement, to a Portuguese group (Porto and Braga), and lists Portuguese coauthors in Gregory's PLAN series (2008) [4, 8]. In Brazil, the São Paulo group described ATP13A2 disease without iron accumulation, a 2016 review from centres in São Paulo, Natal, Belo Horizonte and Curitiba proposed an NBIA diagnostic approach, and a Fortaleza textbook includes PANK2 in the Leigh syndrome differential [1, 73, 109]. Brazilian families are among those reported with hyperferritinaemia-cataract syndrome [11]. Absence of data in the sources consulted does not establish the absence of patients or studies.

9.3. Special populations

In BPAN, female predominance is marked and surviving males are mostly mosaic [6]. In neuroferritinopathy, low serum ferritin is much more frequent in men and postmenopausal women than premenopausal women, reducing the biomarker's value in the latter [8]. In Woodhouse-Sakati syndrome and other recessive NBIAs, consanguinity increases risk and guides offering partner carrier testing [4, 10]. Children tolerate higher antidystonic doses than adults, requiring regimen review during transition [23].

9.4. Reference networks, registries and patient associations

ERN-RND is the relevant European network; in 2019 it had 32 centres in 13 Member States and, in the 2026 document, 64 centres and 4 affiliated partners in 24 Member States, which do not include Portugal; the disease group is coordinated by Javier Pérez Sánchez and Sylvia Boesch [2, 74, 110]. The international TIRCON registry (LMU Klinikum, Munich; NCT05522374) is recruiting, with an expected 2,000 participants, and the TIRCON consortium was funded by the European Commission's 7th Framework Programme [5, 91, 111]. NBIAcure, the OHSU centre of excellence, maintains the International Registry for NBIA and Related Disorders and accepts case-by-case consultations [1]. Patient associations include the NBIA Disorders Association (US), Hoffnungsbaum e.V. (Germany), AISNAF (Italy), NBIA Canada, INADcure Foundation, Cure INAD UK, INAD Foundation (Australia), Dystonia UK and Dystonia Medical Research Foundation, united internationally in the NBIA Alliance, which included organisations from eight countries in 2016 [4, 9, 10, 23, 112–114]. The BPAN consensus recommends balanced introduction of these resources because they may overwhelm newly diagnosed families [24].

France. The French PNDS was coordinated by the Bordeaux site of the CRMR Neurogénétique, a reference centre of the BRAIN-TEAM filière (rare diseases of the central nervous system), which brings together six reference sites — coordination at the Pitié-Salpêtrière, Paris, and sites in Angers, Bordeaux, Paris (Trousseau Hospital and Pitié-Salpêtrière) and Strasbourg — and 18 competence centres, including Pointe-à-Pitre (Guadeloupe) and Saint-Pierre (Réunion) [28]. The French patient associations cited are Autour du BPAN and BPAN France, which promote links between families and researchers and fund research; the équipes relais handicaps rares (ERHR) support rare disability situations [28]. In the medico-social domain, the PNDS describes recognition as a long-term condition (ALD), with 100% reimbursement of related care after validation by the health insurance medical adviser, and applications to the departmental houses for persons with disabilities or for autonomy (MDPH/MDA): allowance for adults with disabilities (AAH) and the supplement for independent living, education allowance for a child with a disability (AEEH, up to 20 years), mobility-inclusion card, disability compensation benefit (PCH), invalidity pension (replaced by the old-age pension at the legal retirement age, 62 years at the time of the PNDS), daily allowance for a close carer (AJPA, up to 66 days) and school adjustments, such as extra time in examinations or computer equipment [28]. It recommends reserving a consultation for the medical certificate of the first application, preferably completed at the reference or competence centre, describing on the form the concrete consequences of the disease in daily life and attaching a detailed daily schedule; after 60 years, if the disease began before that age, MDPH benefits may be more advantageous than the personalised autonomy allowance (APA) [28].

10. Illustrative Clinical Case

This case summarises case 1 in Giuliano and colleagues' four-patient Sicilian series published in 2025, investigated in Troina through exome sequencing with Sanger confirmation and annotation on transcript NM_001386393.1 [45].

A boy born at term by caesarean section after an uneventful pregnancy to non-consanguineous parents, with a paternal cousin with intellectual disability and gait difficulty, began walking at 16 months with an unsteady gait and had speech and language delay. At 3 years he had global developmental delay, dysmorphic features, dysarthric speech, spastic paraparesis and diffuse muscle atrophy. MRI at 3 years showed bilateral globus pallidus hyperintensity and periventricular white matter signal changes, a pattern potentially mimicking mitochondrial disease at this stage. At 9 years he had mild intellectual disability, retinitis pigmentosa, bilateral conductive hearing loss and persistent diffuse dystonic movements, and lost ambulation; electromyography showed myogenic changes and repeat MRI revealed the eye-of-the-tiger sign, approximately six years after the first scan. At last assessment, aged 13, he had continuous diffuse dystonic movements and self-inflicted lower-lip, cheek and tongue injuries requiring thermoformed dental plates. Exome sequencing identified homozygous PANK2 NM_001386393.1:c.1169A>T p.(Asn390Ile), described by Zhou in 2001 in classic disease, with a gnomAD frequency of 0.000004 and classified as likely pathogenic under ACMG/AMP criteria [45].

Article Figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12469515/figure/genes-16-01008-f001/) shows bilateral globus pallidus hyperintensity at 3 years in panel A1, periventricular white matter changes in A2 and the eye-of-the-tiger sign at 9 years in A3; panels B1 and C1 show the eye-of-the-tiger sign in cases 2 and 3, and D1 isolated pallidal hypointensity in case 4, a 38-year-old man with advanced disease [45]. Case 4 was homozygous for the same variant and came from the same small town in Agrigento province, leading the authors to propose a founder effect. Case 2, a 7-year-old boy with ataxia, dystonia, bilateral Babinski signs and creatine kinase of 223 U/L, was compound heterozygous for c.1231G>A p.(Gly411Arg), the classical p.Gly521Arg variant in historical numbering, and novel splice variant c.906-1G>A [45, 46].

The case illustrates radiological evolution limiting early MRI value: the eye-of-the-tiger sign may be absent initially and disappear in advanced disease, and isolated pallidal hyperintensity in a young child does not exclude PKAN [3, 45]. The described oral self-injury management — moulded dental plates — corresponds to consensus and GeneReviews recommendations for splints and bite blocks, which also propose botulinum toxin when sensory tricks fail and conservative dental management [3, 23]. The article does not describe patients' pharmacological treatment.

11. Prognosis and Long-Term Follow-up

11.1. Entity-specific prognosis

PKAN. Disease is progressive and lost skills are rarely regained. Progression rate correlates with onset age: most classic patients lose independent walking by 10 years and most early-onset patients require a wheelchair by mid-adolescence; episodes of rapid deterioration, often lasting 1–2 months, alternate with longer stability periods, without demonstrated association with stress or catabolism [3, 23]. In atypical disease, walking loss occurs 15–40 years after onset and some patients remain stable for 5–10 years or longer [3, 23]. Premature death occurs, but improved care enables more patients to reach adulthood; death results predominantly from secondary effects (nutrition-related immunodeficiency, aspiration pneumonia) and only rarely status dystonicus [3]. In TIRCON, the placebo group worsened by 3.99 BAD points over 18 months, providing a progression measure under current care [81]. In the caregiver series, mean disease duration ranged from 9.7 to 15.2 years by severity [58].

PLAN. In infantile disease, most children never walk or speak, many do not survive beyond the first decade and median age at death was 10 years and 8 months in a prospective study; supportive care, including nutrition, may prolong life [4]. Juvenile life expectancy is greater: in the French cohort, five patients were aged 18–25 and two deaths occurred at 10 and 18 years, and in the cohort of 62 median survival was 39 years [4]. In adult disease, death occurred approximately 10 years after onset in reported cases [4].

MPAN. Slow progression, with survival well into adulthood except rare cases with abrupt adult onset and rapid progression; death results from aspiration pneumonia [5].

BPAN. Mortality is low until 39 years, and reported deaths occurred between 30 and 50 years from parkinsonism complications and aspiration; no predictors of neurological deterioration are confirmed, and a prospective natural history study (BPANready) seeks to identify them [24, 25].

Others. Neuroferritinopathy generalises over approximately 20 years, with death described between middle and late adulthood [8]. In aceruloplasminaemia, neurological complications are generally irreversible, justifying diagnosis before neurological involvement [64]. In FAHN, premature death frequently occurs in the third or fourth decade [9]. CoPAN leads to walking loss in the third decade [1]. In Woodhouse-Sakati syndrome, neurological prognosis ranges from absent involvement to severe disease even within a family [10].

11.2. Surveillance

The PKAN consensus recommends against regular brain MRI unless it guides decisions, because children require sedation and clinical examination is the best progression assessment tool; the BPAN consensus likewise does not recommend repeat MRI simply to document progression [23, 24]. The French PNDS recommends annual follow-up at a neurogenetics reference centre, a search for comorbidity or an iatrogenic cause in the event of any rapid deterioration before attributing it to natural history, and integration of palliative care in advanced stages; its ophthalmology interval (annual for all NBIAs) is shorter than that of GeneReviews for MPAN and BPAN (1–2 years) [5, 6, 28].

Table 11.1 — Recommended surveillance

Intervals unspecified in sources remain “regularly” or “every consultation”; sources define no numerical thresholds for most examinations [1, 3].

12. Summary and Final Considerations

NBIA encompasses diseases with distinct mechanisms — coenzyme A biosynthesis, lipid metabolism, autophagy and, in few cases, iron homeostasis — converging on a radiological sign of basal ganglia iron. In most, iron is a consequence rather than a cause, helping explain why chelation, despite reducing brain iron, has not demonstrated clinical benefit in PKAN.

PKAN, the core of this article, is the recessive disease caused by PANK2 variants. Classic disease begins before 6 years with oromandibular dystonia, dysarthria, spasticity and retinopathy, leading to loss of walking at approximately 10 years; atypical disease begins later, with speech and psychiatric changes, and progresses slowly. The eye-of-the-tiger sign is virtually pathognomonic but may be absent initially and disappear in advanced disease. Confirmation requires biallelic variants, and nomenclature must specify the transcript: the classical literature variant p.Gly521Arg is p.Gly411Arg on MANE transcript NM_001386393.1. Treatment is symptomatic and multidisciplinary: first-line trihexyphenidyl, baclofen and clonazepam, botulinum toxin for focal dystonia, intrathecal baclofen and DBS in selected patients — with greater, more sustained benefit in atypical disease — a high-dose pantothenate trial, early gastrostomy, bone and oral protection, and a status dystonicus plan centred on investigating causes of pain. Deferiprone (TIRCON) and fosmetpantotenate (FORT) were negative on primary outcomes; the European deferiprone PKAN authorisation application was withdrawn in 2020 following an unfavourable provisional CHMP opinion, and its use is off-label. 4'-Phosphopantetheine has only safety data.

Other NBIAs have specific clues: in PLAN, cerebellar atrophy with elevated AST and LDH and, in adults, parkinsonism with early dyskinesias; in MPAN, optic atrophy with motor neuronopathy and dominant inheritance in some families; in BPAN, the biphasic course of childhood epilepsy and delay followed by adult parkinsonism and dementia, in an X-linked dominant disease with frequent mosaicism where chelation is not indicated and seizures warrant medicine withdrawal after 2 seizure-free years; in aceruloplasminaemia, undetectable caeruloplasmin with anaemia, diabetes and high ferritin, with off-label chelation and prohibition of iron supplements; in neuroferritinopathy, speech-induced orofacial dystonia with low ferritin and basal ganglia cavitation; and in Woodhouse-Sakati syndrome, hypogonadism with alopecia, where hormone replacement at puberty is the most urgent intervention and justifies sibling testing.

Epidemiological data are estimates, literature counts and registry proportions, not measured prevalences; founder populations (Dominican Republic, Poland, Turkey, Saudi Arabia and Qatar, North Africa, Japan, north-east England) guide targeted testing. The sources consulted contain no Portuguese or Brazilian epidemiological data. In 2026, ERN-RND endorsed the overview GeneReviews as the European reference for all NBIAs, and the international TIRCON registry and NBIA Alliance associations are the main resources for patients and clinicians. In France, the 2022 PNDS proposes a diagnostic pathway with a panel as first line and access to exome or genome sequencing through multidisciplinary agreement, a symptomatic approach by domain for the whole group, and a reading of deferiprone and DBS more favourable than the European assessment and the PKAN consensus.

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