Pelizaeus-Merzbacher Disease and Hypomyelinating Leukodystrophies

The PLP1 spectrum (connatal, transitional and classic forms, PLP1 null syndrome, HEMS, SPG2 and symptomatic heterozygotes) and the class of hypomyelinating leukodystrophies HLD1–HLD28 and related entities

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

The table brings together the main entity, the PLP1 spectrum, and the four hypomyelinating leukodystrophies with their own GeneReviews chapter that are most often confused with it. The full list of the 28 types numbered by OMIM (Online Mendelian Inheritance in Man) and of the related unnumbered entities is in subsection 1.5.

1. Introduction

1.1. Original description and historical overview

Pelizaeus-Merzbacher disease is named after two authors who described, in families with several affected males, a white matter disease with absence of myelin; by 1993 it had been recognised as a clinical entity for more than a century [21]. The original papers by Pelizaeus and by Merzbacher are not indexed in the bibliographic databases consulted and were not read; the history of the entity was reviewed by Koeppen in 2005, and Seitelberger published in 1954 the clinicopathological study that placed it among the “diffuse scleroses” and, in 1995, a review of the neuropathology and genetics of the disease [22–24]. In the pre-molecular era, Boulloche and Aicardi (1986) defined genetic and clinical criteria from seven cases in three families and a review of 148 cases from 19 families in the literature: several males in a pedigree compatible with X-linked recessive inheritance, early nystagmoid movements, early psychomotor deterioration and progressive pyramidal, dystonic and cerebellar signs; laryngeal stridor, present in 2 of the 7 cases, was suggested as a possible presenting manifestation [25].

Neuropathology made it possible to separate PMD from the demyelinating disorders: it is a dysmyelination, due to deficient production of the main myelin protein of the central nervous system (CNS), proteolipid protein (PLP), and not destruction of previously formed myelin, as in adrenoleukodystrophy [21]. This distinction anticipated the current concept of hypomyelination, defined as a primary lack of myelin deposition [26].

1.2. Milestones of molecular discovery

In 1985, Willard and Riordan mapped the cDNA of myelin proteolipid protein (lipophilin) to the middle region of the long arm of the X chromosome (Xq13–Xq22) and noted that the murine gene, also on the X, was a candidate for the mouse jimpy locus, a model of X-linked dysmyelination [27]. In 1989 the first human point variants were described: a T→C transition replacing tryptophan with arginine in one of the four hydrophobic domains, paralleling the point mutation of the jimpy mouse [28], and, in a family with the classic form, a C→T transition replacing proline with serine at the carboxy-terminal end [29]. This second variant, described in historical numbering as codon 215, corresponds in current HGVS (Human Genome Variation Society) nomenclature to NM_000533.5:c.646C>T p.(Pro216Ser), registered in ClinVar as VCV000011073 [7, 29, 30]. The same authors proposed that the classic (type I) and connatal (type II) forms resulted from mutation in PLP, and that “types III to VI” of the clinical classification of the time might correspond to other genes [29].

Sequencing of the coding regions explained only a minority of cases: in 1993 a coding variant was identified in about 30% of patients diagnosed with PMD, and there were families without a coding variant but with linkage to the PLP locus [21]. In 1994, Ellis and Malcolm described the PLP gene dosage effect in PMD [31]. In 1996, Inoue and colleagues, faced with exonic variants in only 10–25% of cases, detected by comparative multiplex polymerase chain reaction (PCR) a duplication of the gene in 4 of 5 families without an exonic variant, by analogy with the PMP22 duplication in Charcot-Marie-Tooth disease type 1A [32]. In 1998, interphase fluorescence in situ hybridisation (FISH) confirmed duplications of at least 500 kb, with proximal breakpoints differing between families, and also detected them in the four asymptomatic carrier mothers studied [33]. There followed the description of three or more copies of PLP1 in atypically severe forms (2005) [34], the characterisation of the PLP1 null syndrome, with length-dependent axonal degeneration and without demyelination (2002) [35], and the explanation of HEMS by variants that alter alternative splicing between the PLP1 and DM20 isoforms (2015) [36].

1.3. Nomenclature and classifications

PMD has also been called sudanophilic or orthochromatic leukodystrophy; SPG2 is also called HSP-PLP1, according to the movement disorders nomenclature system of the International Parkinson and Movement Disorder Society; and HEMS is a subtype of complicated SPG2 with its own magnetic resonance imaging (MRI) pattern [1]. The gene was called PLP; the numeral was added after the discovery of a similar gene expressed mainly in the intestine [1]. The older literature numbers the amino acids from the glycine of codon 2, because the initiator methionine is removed after translation; the one-residue difference between historical and HGVS nomenclature is confirmed in the example Pro215Ser (historical) = p.(Pro216Ser) (HGVS), and any other conversion must be confirmed variant by variant [1, 7, 30].

In clinical practice and in trials, scales are used that rank the PLP1 spectrum by the best motor ability acquired. On the Cailloux scale, forms 0 and 1 correspond to connatal PMD, forms 2 and 3 to classic PMD and form 4 to SPG2; duplications are associated mainly with forms 1 and 2, point variants are distributed from form 0 to 4, and null variants and deletions are concentrated in forms 3 and 4 [37]. The motor scale used by Sarret and colleagues (PMD0, no motor acquisition, to PMD4, independent walking) classifies patients by best function before age 5 years [38].

The class of hypomyelinating leukodystrophies fits into two classifications of the leukodystrophies. The Global Leukodystrophy Initiative (GLIA) case definition, obtained by a modified Delphi process with 13 experts, classified 30 disorders as leukodystrophies and set apart the genetic leukoencephalopathies (gLE) with primary neuronal involvement or prominent systemic manifestations [39]. The pathological and pathogenetic classification of van der Knaap and Bugiani (2017) places the hypomyelinating leukodystrophies among the myelin disorders due to a primary defect of the oligodendrocyte or of myelin, alongside the demyelinating disorders and those with myelin vacuolisation, and distinguishes them from the astrocytopathies, leuko-axonopathies, microgliopathies and leuko-vasculopathies [40].

Within the class, OMIM groups the entities into a phenotypic series (“Leukodystrophy, hypomyelinating”, PS312080) numbered HLD1 to HLD28 as of October 2026, to which are added entities with hypomyelination but without an HLD number [4]. Three reclassifications directly affect the reading of the literature: PMLD became HLD2 [2]; the five phenotypes described before the genes (4H; ataxia, delayed dentition and hypomyelination, ADDH; tremor-ataxia with central hypomyelination, TACH; leukodystrophy with oligodontia, LO; hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum, HCAHC) came to form the POLR3-related leukodystrophy spectrum [3, 41]; and DYT4 dystonia became DYT-TUBB4A [5]. The GeneReviews chapter on PLP1 assigns to POLR1A the number “HLD18 (OMIM 620675)”; the OMIM series assigns 620675 to HLD27 and reserves HLD18 (618404) for DEGS1; the numbering used below is that of OMIM [1, 4].

1.4. Definition of the entities covered

Connatal PMD presents at birth or in the first weeks, with pendular nystagmus, hypotonia, stridor and sometimes seizures, without acquisition of walking [1]. Classic PMD begins in the first 5 years, usually with nystagmus in the first months, hypotonia, titubation, ataxia and spastic tetraparesis; walking, when acquired, requires support and is lost in late childhood or adolescence [1]. The transitional form is intermediate between the two [1]. The PLP1 null syndrome results from the absence of PLP1 protein and is characterised by absence of nystagmus, mild lower-limb-predominant spastic tetraparesis, ataxia and mild demyelinating peripheral neuropathy [1]. SPG2 is a spastic paraparesis, pure or complicated by ataxia, nystagmus and autonomic dysfunction; HEMS is the form of complicated SPG2 with hypomyelination of the early myelinating structures [1, 36]. Symptomatic heterozygotes are female carriers of a PLP1 variant with neurological signs, usually identified during evaluation of relatives [1]. These forms do not separate into distinct syndromes: they are points on a continuum, and PMD and SPG2 have been observed in different males of the same family [1, 21, 42].

The hypomyelinating leukodystrophies are genetic disorders in which CNS myelin is never deposited in normal quantity; they usually present in infancy or childhood, but there are mild forms with onset in adolescence or adulthood, and almost all patients show slow clinical decline after a long phase of stability [26]. The genes of the class encode structural myelin proteins, components of the RNA transcription and translation machinery and some lysosomal or cellular trafficking proteins [26, 43].

1.5. The HLD series: table of all types and related entities

Numbering, genes and inheritance follow the OMIM PS312080 series page consulted on 26/10/2026, which has 28 entries, from HLD1 (PMD) to HLD28, without HLD29; the clinical summaries come from the OMIM definitions reproduced in MedGen and the inheritance annotations from the Human Phenotype Ontology (HPO) [4, 44, 45]. OMIM marks HLD20, HLD24 and HLD28 with “?”, indicating a provisional gene–phenotype relationship [4].

In 2024–2026, genes not yet assigned an HLD number in the indexed OMIM were described: PIKFYVE (5 individuals from 3 families, with hyperintensities of the inferior olives, thalami and optic nerves) [57], BLOC1S1 (11 individuals from 7 families, with epileptic encephalopathy, optic atrophy and, in a subgroup, ocular albinism) [58] and CLDN25 (one patient with a de novo variant, limited evidence) [59].

1.6. Scope of the article

The PLP1 spectrum is covered in detail and, uniformly for the class, so are POLR3-related leukodystrophy, TUBB4A-related leukodystrophy, PMLD1 and HCC, with shorter subsections for NKX6-2, PI4KA and the remaining HLD types. SPG2 and SPG44 also fall within the differential diagnosis of the hereditary spastic paraplegias. Trichothiodystrophy, X-linked adrenoleukodystrophy, Canavan disease and Alexander disease enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The PLP1 gene and the PLP1 and DM20 proteins

PLP1 is located at Xq22.2 and encodes myelin proteolipid protein 1, the main CNS myelin protein, which accounts for about 50% of its protein mass [1]. The same gene produces, by alternative splicing, the DM20 isoform, which lacks the PLP1-specific domain (amino acids 117–151, encoded by the part of exon 3 called 3B) [1]. PLP1 and DM20 are four-pass transmembrane proteins, anchored to the bilayer by covalent acyl linkages to fatty acids; there is evidence that PLP1 “cements” the adjacent leaflets of compact myelin, and PLP1, but not DM20, forms dimers through an intracellular cysteine residue, a property that may contribute to the pathogenesis of duplications and of small insertions or deletions [1]. The amino acid sequence is fully conserved between rodents and humans, suggesting little tolerance of variation [1].

2.2. Mechanisms by variant type

PLP1 variants act through four mechanisms that explain the severity of the phenotype [60]. In duplications, the most frequent, an excess of normal PLP1 protein causes oligodendrocyte dysfunction and death and mislocalisation of PLP1, cholesterol and other lipids in the late endosomal and lysosomal compartment; the result is hypomyelination followed by axonal injury [1, 60]. In missense variants, the misfolded PLP1/DM20 protein is retained in the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR); in the jimpy mouse, ER stress kills the cells as oligodendrocyte progenitors mature [1]. In oligodendrocytes derived from patients' induced pluripotent stem cells (iPSCs), mutant cells reach the premyelinating stage and die with hallmarks of ferroptosis (lipid peroxidation, abnormal iron metabolism and hypersensitivity to free iron) [61]. A 2026 preclinical study showed that mutant PLP1 depletes ER calcium and destabilises the COPII vesicles that transport proteins from the ER to the Golgi apparatus; pharmacological restoration of ER calcium rescued vesicle formation, whereas blocking the apoptotic arm of the UPR did not correct the murine phenotypes [62].

In null variants (gene deletion, frameshift, initiation codon missense), myelin forms with mild defects, but length-dependent axonal degeneration appears, without demyelination or inflammation, as shown in Plp1-null mice, in autopsy material and by the reduction of N-acetylaspartate (NAA) on MR spectroscopy (MRS) [35]. The proposed mechanism is the loss of PLP1-mediated axo-glial interactions, with a pattern similar to that of the peripheral nervous system in CMT1A [35]. Because patients without PLP1 expression have comparatively mild phenotypes, suppression of PLP1 has become the rationale for the therapies in development for duplications and toxic variants [63]. Finally, variants of exon 3B and the adjacent intron 3 reduce the PLP1 to DM20 ratio and cause HEMS [1, 36].

2.3. Structural variants and non-coding alterations

Among the pathogenic variants detected, targeted deletion/duplication analysis identifies 60–70%, sequencing 30–40% and other mechanisms (inversion, position effect) less than 1%; these proportions describe variants detected, not the clinical sensitivity of each test [1]. Most dosage alterations are tandem duplications at Xq22 that include the whole gene [1]. In a study of 50 males with PLP1 copy gain and PMD, using high-density array and junction sequencing, 33 (about 66%) had a simple duplication and 17 (about 34%) complex genomic rearrangements; in the meta-analysis of 150 individuals and 159 junctions, simple duplication accounted for about 54%, the most frequent complex pattern was triplication flanked by duplications, and about 32% of junctions had a microhomeology signature, compatible with template-switching mechanisms during replication [64]. Triplications, partial triplications and quintuplication also occur [1, 34].

Rarely, the duplicated segment is inserted at a distance: insertions at Xp22, Xq28, 19qter and on the Y chromosome have been described, and in a woman with classic PMD the extra copy was at 1p36 [1]. In females who are simplex cases, the duplication is often associated with complex chromosomal rearrangements [1]. Whole-gene deletions are present in less than 2% of individuals with a PMD phenotype, and the first patient described had a complex rearrangement with deletion, inverted insertion of a distal portion of the X and distal duplication [1].

Alterations that do not touch the coding sequence also cause disease. Position effects have been described: a duplication near PLP1, not including it, in a man with spastic paraplegia, and an X inversion with a breakpoint 70 kb upstream of the gene in a child with a PMD-like syndrome [1]. A microdeletion of about 24.5 kb at Xq22.2 (chrX:103,690,507–103,715,018, hg38), removing distal PLP1 enhancers, cosegregated with spasticity, developmental delay, ataxia and hypomyelination in a family with SPG2, and was confirmed by long-read sequencing; the authors propose transcriptional repression of PLP1 in oligodendrocytes [65]. In a family with 10 affected members, a 75.5 kb loss involving the PLP1 3′ untranslated region (3′UTR) caused SPG2; clinical exome sequencing of four members was negative and only the genome identified the CNV [66]. Some deep intronic variants, outside the splice junctions, cause disease [1, 36].

2.4. Spectrum of point variants and nomenclature

Sequence variants include missense, nonsense, splicing variants and small insertions or deletions. The table brings together the variants cited in the article, normalised in VariantValidator to the MANE Select transcript and checked in ClinVar on 26/10/2026 [7, 30].

The genomic HYCC1 deletion described as “531-439_743+348del” (Arg209fsTer213) has no prefix or transcript in the publication and has been kept in the original notation [6]. The Portuguese codon 216 variant described by Pratt and colleagues in 1995 exists only in historical numbering [72]. Two recent variants illustrate the limits of classification: PLP1 c.197A>T p.(His66Leu), in a Colombian family with SPG2, was classified as a variant of uncertain significance (VUS) despite cosegregating in several males [73], and PLP1 c.737G>A, in a Chinese child with the classic form and no CNV, shows that rare point variants also cause classic PMD [74].

2.5. Genotype–phenotype correlations in the PLP1 spectrum

The European clinical network of Clermont-Ferrand sequenced 52 families with PMD and 28 with spastic paraplegia without a large duplication or deletion and identified 29 and 4 abnormalities, respectively; single amino acid substitutions in conserved regions of DM20 were associated with the most severe forms, whereas substitutions of less conserved amino acids, truncations, absence of protein and PLP1-specific variants (which spare DM20) were associated with mild PMD and SPG [42]. GeneReviews summarises: most duplications cause classic PMD; some connatal forms have three or more copies; non-conservative missense and other sequence variants cause the most severe phenotypes; SPG2 results mainly from conservative substitutions; variants of the PLP1-specific domain and of intron 3 tend to be milder; and null variants cause relatively mild demyelinating peripheral neuropathy [1]. Of five boys with three copies (one with five), without stable head control and with severe intellectual impairment, two died before age 1 year; the patient with five copies was no more severe than those with triplication [34].

Recent cohorts qualify the relationship between duplication and moderate form. In the Chinese cohort of 111 patients, point variants predominated in the severe group and duplications in the mild group (p<0.001) [75]. In the international GLIA-PMD cohort of 111 patients, the percentage of developmental milestones achieved did not differ between overexpression and other genotypes (37.5% vs 35.3%; p=0.636), almost half of those with duplications did not achieve the milestones assessed, and presenting stridor, present in 20 patients, was associated with gain-of-function missense variants in 17 of them (85%) [15]. In a Japanese series of 19 patients, diffuse T2 hyperintensity of the brainstem occurred only with point variants and was associated with greater severity [76].

2.6. Inheritance, penetrance and expression in heterozygous females

Penetrance is considered complete in hemizygous males [1]. In heterozygous females, expression is inversely related to the severity in the males of the family: in families with severely affected males, heterozygotes rarely have signs, and in families with mildly affected males they are more likely to have them [1]. A review of 40 pedigrees from Wayne State University formalised this relationship: highest risk in carriers of nonsense, small indel or null variants, moderate risk with missense variants and lowest risk with duplications, which make up the majority of PMD families [77]. The proposed explanation is cellular: severe alleles cause early apoptosis of the oligodendrocytes that express them, which are replaced by oligodendrocytes expressing the normal allele, whereas mild alleles do not cause apoptosis and the abnormal oligodendrocytes persist [1]. X inactivation in blood was preferentially skewed against the X carrying the duplication in 7 of 11 duplication carriers and was random in carriers of point mutations and deletions; because skewing was also present in 2 of 5 non-carrier relatives, the inactivation pattern cannot be used as a carrier test [78]. Women with PMD due to unfavourable X inactivation in the brain have been described, some improving after infancy, as well as women with complex rearrangements [1].

2.7. GJC2 and connexin 47 (PMLD1)

GJC2 (formerly GJA12) has two exons: exon 1, non-coding, contains transcription factor binding sites, and exon 2 contains part of the 5′UTR, the coding sequence and the 3′UTR [2]. Connexin 47 (Cx47), with 439 amino acids, is expressed mainly in oligodendrocytes of the brain and spinal cord [2]. Gap junctions couple oligodendrocytes with one another and with astrocytes in a glial syncytium; astrocytes express Cx43 and Cx30, oligodendrocytes Cx47 and Cx32, and astrocyte–oligodendrocyte channels are heterotypic (Cx47/Cx43, Cx32/Cx30) [2, 79]. Mice lacking Cx47 have a normal phenotype with myelin vacuoles, and mice lacking both Cx47 and Cx32 have seizures, tremor and generalised vacuolisation [2]. PMLD1 variants cause loss of function: Cx47 does not reach the surface or is retained in the ER, or it localises normally but fails to couple Cx47/Cx47 or Cx47/Cx43; in the mouse model, the decisive effect is the reduced number of coupled cells in the glial networks [2]. Among 51 individuals described, 22 had variants in non-coding exon 1 (c.-167A>G in 20 and c.-170A>G in 2) [2].

2.8. RNA polymerase III and POLR3-related leukodystrophy

RNA polymerase I transcribes pre-rRNA (18S, 5.8S, 28S); polymerase II the coding genes and most miRNAs; polymerase III (Pol III) all tRNAs, 7SL RNA, 7SK, Alu and B2 elements, 5S rRNA and vault RNAs [3, 41]. POLR3A and POLR3B encode the two largest of the 17 Pol III subunits and form its catalytic core; POLR1C encodes a subunit shared by polymerases I and III [3]. Reduced POLR3A lowers the tRNA pool and dysregulates transcription of non-coding RNAs, but the pathogenesis of the changes in myelin, teeth, bone and adipose tissue remains unclear [41]. No patient has two null variants of POLR3A or of POLR3B, indicating that some residual function is necessary for embryonic survival [3, 67]. In fibroblasts and in the brain of a patient with 4H, POLR3A was reduced, more in white matter than in cortex [67]. The POLR1C variants that cause leukodystrophy, such as p.(Asn32Ile) and p.(Asn74Ser), impair the assembly and nuclear import of Pol III, but not of Pol I, and differ from those that cause Treacher Collins syndrome [69].

The allelic spectrum has broadened since the 2017 GeneReviews chapter. Biallelic hypomorphic POLR3A variants, especially the deep intronic c.1909+22G>A, which activates a cryptic splice site in a tissue- and stage-specific manner, were found in compound heterozygosity in about 3.1% of 618 index cases of hereditary spastic paraplegia or cerebellar ataxia (proportion in a selected cohort, not a population rate) and cause adolescent-onset spastic ataxia without a hypomyelination pattern [68]. Biallelic truncating or splicing POLR3A variants cause Wiedemann-Rautenstrauch syndrome (WRS), a neonatal progeroid syndrome [80]. Heterozygous de novo POLR3B missense variants cause afferent ataxia, spasticity and predominantly demyelinating peripheral neuropathy, through aberrant subunit association [8]. In 2026, monoallelic POLR3A missense variants (11 patients from 8 families) were associated with early-onset progressive sensorimotor polyneuropathy, without white matter changes [9]. The database of Pol III-related disorders brings together the genes POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H and POLR3K, with phenotypes of the CNS, eyes, bone, teeth and the endocrine and reproductive axes [81]. HLD21, due to biallelic POLR3K variants, completes POLR3-related leukodystrophy [4].

2.9. TUBB4A and microtubules

TUBB4A encodes tubulin β-4A, expressed mainly in the CNS, particularly in the cerebellum, putamen and white matter; β-tubulins associate with α-tubulins to form microtubules, and heterozygous variants alter the structure and affect polymerisation or stability [5]. The mechanism is gain of function [5]. The p.(Asp249Asn) variant affects a conserved asparagine at the intradimer α/β-tubulin interface [70]. Penetrance is apparently complete in the leukodystrophy and reduced in DYT-TUBB4A [5].

TBCE, a tubulin folding cofactor, causes progressive encephalopathy with amyotrophy and optic atrophy (PEAMO), with white matter changes and diagnosis described by a hypomyelinating leukodystrophy panel.

2.10. Hyccin, PI4KA and phosphatidylinositol 4-phosphate

Hyccin, encoded by HYCC1, is a subunit of the PI4KA lipid kinase complex, required for the synthesis of phosphatidylinositol 4-phosphate, which is essential for myelin sheath growth [6]. Complete absence of hyccin causes the full phenotype (bilateral cataract, central and peripheral hypomyelination), and partial deficiency causes a milder form without peripheral neuropathy [6]. Biallelic variants of PI4KA itself cause a multisystem neurological, gastrointestinal and immunological phenotype [56]. NKX6-2 encodes a homeodomain transcription factor; biallelic variants in the homeodomain are associated with a severe phenotype with neonatal onset [55].

2.11. Other mechanisms within the class

Saudubray's mechanism-based classification distributes the causes of hypomyelination into four groups [43]. The small-molecule group includes defects of folate transport and metabolism, untreated galactosaemia, serine synthesis defects, PYCR2 and cytochrome b5 reductase deficiency (CYB5R3). The energy metabolism group includes the mitochondrial HSP60 chaperonopathy (HSPD1). The complex molecule group includes fucosidosis, sialidosis, POLR3-related leukodystrophy and the aminoacyl-tRNA synthetases (KARS1, RARS1, DARS1, EPRS1, AARS1) with the associated proteins AIMP1 and AIMP2. The cellular trafficking group includes the connexins (GJC2, GJA1), TUBB4A and VPS11. PMD, TMEM106B (lysosomal trafficking), TMEM63A (mechanosensitive ion channel), trichothiodystrophy and Cockayne syndrome fall into categories of their own [43]. Dihydroceramide Δ4-desaturase deficiency (DEGS1, HLD18) accumulates dihydrosphingolipids and has a blood biomarker [50]. The genes described in 2026 point to the endolysosomal system: PIKFYVE (fibroblasts with enlarged, hyperacidic vacuoles and less PI(3,5)P2) [57] and BLOC1S1 (loss of function of the BORC complex) [58].

2.12. Allelic disorders

3. Clinical Spectrum and Manifestations by System

3.1. Sources of clinical data

The clinical description of the PLP1 spectrum rests on case series and retrospective cohorts, not on prospective population-based studies. The classic series are those of Boulloche and Aicardi (1986), Hodes (1993) and Cailloux (2000) [1, 21, 25, 42]. The recent cohorts are the Chinese cohort of Duan (2022; 111 patients, median follow-up of 53 months) [75], the French cohort of Sarret (2016; 35 patients followed prospectively for 7 years with 63 MRI scans) [38] and the international GLIA-PMD cohort (2026; 111 patients with data from clinical records supplemented by caregiver interviews in 26) [15]. All the data describe the disease under supportive care, because no disease-modifying therapy exists.

3.2. The PLP1 spectrum

Source: GeneReviews PLP1, Table 2 [1].

3.3. Connatal PMD

The connatal form becomes apparent at birth or in the first weeks, with pendular nystagmus, hypotonia, stridor and, in some cases, seizures; motor deficits are severe, without head control [1]. Short stature and poor weight gain follow, and hypotonia evolves to severe limb spasticity; children do not walk or use their upper limbs effectively, verbal expression is very limited but comprehension may be considerable, and dysphagia may require a feeding tube or gastrostomy [1]. Death often occurs in childhood, usually from aspiration; with attentive care, survival may reach the 3rd decade or beyond [1]. The Oxford Desk Reference describes the same presentation, with neonatal hypotonia, rotatory nystagmus and stridor, and early death [83].

3.4. Classic and transitional PMD

In classic PMD, nystagmus is rarely absent, but may only be recognised at several months; hypotonia, titubation (tremor of the head and neck), ataxia and spastic tetraparesis develop in the first 5 years, with some voluntary control of the upper limbs [1]. Walking, when acquired, is with crutches or a walker and is lost as spasticity worsens in late childhood or adolescence; cognition is mildly to moderately impaired, language generally develops, and dystonia and athetosis may appear [1]. Bone density falls with immobility [1]. Survival into the 6th–7th decade has been observed [1]. The typical course is slowly progressive, with a static motor phase in adulthood followed by late deterioration [83]. The transitional form lies between the connatal and the classic forms [1].

3.5. PLP1 null syndrome

The null syndrome is distinguished by the absence of nystagmus, relatively mild lower-limb-predominant spastic tetraparesis, ataxia and a mild multifocal demyelinating peripheral neuropathy [1]. Walking is better than in classic PMD, but patients may lose abilities and progress faster because of axonal degeneration, inferred from the reduction of white matter NAA on MRS [1, 35].

3.6. SPG2 and HEMS

Complicated spastic paraparesis and HEMS combine autonomic dysfunction (spastic bladder), ataxia and nystagmus; there are no objective criteria separating complicated SPG2 from mild PMD, such as the null syndrome [1]. Pure SPG2 runs its course without other significant CNS signs, may have a spastic bladder and has a normal life expectancy; men with SPG2 have reproduced, unlike men with the PMD phenotype [1]. HEMS was delineated by MRI criteria in 16 patients from 10 families, all with hemizygous variants in exon 3B or intron 3 [36]; the clinical picture includes infantile nystagmus, ataxia, axial hypotonia and dysarthria, with or without spasticity [3]. Orphanet counted about 100 cases or families with SPG2 and 20 cases of HEMS [10]. In 2026 the first Colombian family with SPG2 was described: a 53-year-old man with lower limb weakness since childhood, wheelchair use at 47 years, periventricular leukodystrophy and affected maternal relatives, without cerebellar signs; the authors counted 36 SPG2 families described worldwide [73]. In the family with the 3′UTR CNV, the males had early-onset progressive paraplegia with neurocognitive decline [66].

3.7. Symptomatic heterozygotes

Heterozygous females may or may not have manifestations; the risk of signs is highest in families with the null syndrome, followed by families with SPG2 or HEMS, and lowest in duplication carriers, who usually have favourably skewed X inactivation [1, 77]. Manifestations may be transient and regress, or persist, and urge incontinence may be present [1]. In the family with the 3′UTR CNV, some heterozygous women had spastic paraparesis at 30–40 years and one remained asymptomatic [66]. In the Brazilian family of the clinical case, the heterozygous mother had head and upper limb tremor resembling essential tremor, an observational report without causal assessment [37]. Women with a PMD picture have been described, attributed to unfavourable X inactivation in the brain, some with considerable improvement after infancy [1]. Orphanet records PMD in carriers with onset in adulthood [10].

3.8. Natural history of PMD in recent cohorts

In the GLIA-PMD cohort, 144 patients had molecularly confirmed PMD and 111 (78.7%) were included; 60.4% lived outside the USA and 37.8% in the USA [15]. The genotype was overexpression (duplication or multiplication) in 51 (45.9%); of the remaining 60, 36 (60.0%) had gain-of-function missense variants, 17 (28.3%) HEMS-type splicing variants and 7 (11.7%) loss-of-function variants [15]. The median age at onset was 0.10 years (IQR 0.00–0.33), with neonatal onset in 46 (41.4%), and the median age at diagnosis 1.54 years (IQR 0.90–2.93; maximum 32 years) [15]. Presenting symptoms were nystagmus in 81 (73%), tone abnormalities in 32 (28.8%), stridor in 20 (18.0%), feeding problems in 18 (16.2%) and ataxia in 17 (15.3%) [15].

Milestones were acquired heterogeneously: 68.5% rolled, 34.9% sat, 10.0% walked independently, 41.1% achieved a thumb–index finger pincer grasp and 52.3% said a word; head control was present in 18.3% (20/109) at 3 months, 23.9% at 9 months and 37.6% (41/109) at 12 months [15]. The authors proposed three developmental subtypes: profoundly affected (stridor at presentation; n=20; 85% gain-of-function missense), severely affected (no stridor and no head control at 12 months; n=50; 60% overexpression) and moderate (no stridor, with head control at 12 months; n=41; 48.8% overexpression) [15]. No patient with stridor sat without support, one in 18 achieved a pincer grasp and five in 20 said a word [15]. Regression was confirmed: 11 of the 40 assessed in the moderate subgroup lost at least one skill [15].

Complications, with denominators varying according to data availability, were nystagmus in 91.5% (97/106), poor weight gain in 63.3% (38/60), feeding tube or gastrostomy in 49.4% (44/89), stridor in 46.3% (25/54), scoliosis in 45.2% (38/84), hip dislocation in 45.3% (34/75), incontinence in 40.9% (27/66), artificial ventilation in 24.3% (18/74), epilepsy in 14.0% (12/86) and aspiration pneumonia in 11.9% (8/67) [15]. Median times to event were 0.2 years for nystagmus, 4.4 years for poor weight gain, 10.5 years for hip dislocation, 13.0 years for feeding tube and for scoliosis and 18.6 years for incontinence; in the profound subtype, the feeding tube was placed at a median of 0.8 years (sometimes at 4 months) and scoliosis appeared at 9.0 years [15]. Mortality could not be estimated, and the data come from clinical records with short follow-up [15].

In the Chinese cohort, 78.4% achieved head control, 72.1% said words, 9.0% stood and 4.5% walked without support; nystagmus improved in more than half, and hypotonia evolved in part to spasticity and other movement disorders [75]. In a series of 16 patients with duplication (7–48 years), assessed with a 31-point functional disability scale, all had onset in the 1st year, none acquired independent walking and all had some cognitive acquisition; some non-verbal patients used communication devices [84]. In a survey of 100 caregivers, most symptoms appeared before age 2 years; the most bothersome symptoms were difficulty crawling, standing and walking, followed by constipation, sleep, manual dexterity and speech, and mobility and communication were the priority therapeutic goals [85].

3.9. Manifestations by system in the PLP1 spectrum

In the nervous system, nystagmus, hypotonia, spasticity, ataxia, dystonia and cognitive impairment vary with the form (subsections 3.2–3.6). Visual, auditory and somatosensory evoked potentials show normal or near-normal peripheral latencies and very prolonged or absent central latencies; this does not indicate profound deafness, and hearing is generally clinically normal [1]. Peripheral nerve conduction is normal, except with null alleles, PLP1-specific domain variants and some splicing variants; when neuropathy is present, it is mild, with more marked slowing at compression sites (wrist, elbow) [1]. PMD is among the leukodystrophies with peripheral nerve involvement and pain, so dysaesthesia should be sought [17].

In the musculoskeletal system, scoliosis, hip dislocation and low bone density accompany the loss of mobility [1, 15]; in the GLIA consensus, an epidemiological study of orthopaedic manifestations in leukodystrophies found scoliosis in 70% and hip dysplasia in 89% (denominator not stated), and Figure 1b of the consensus shows coxa valga with bilateral dislocation in a patient with PMD [17]. In the digestive sphere, dysphagia, poor weight gain and constipation are frequent; in the respiratory system, stridor and aspiration dominate in the severe forms; and in the urinary system, spastic bladder and incontinence appear mainly in the milder forms with longer survival [1, 15]. Fever may transiently worsen the neurological manifestations [1].

3.10. PMLD1 (GJC2)

PMLD1 is a slowly progressive leukodystrophy, with neonatal or early infantile onset, nystagmus (rotatory or horizontal, not always present), hypotonia, motor delay, speech delay and dysarthria [2]. Hypotonia evolves to pyramidal spasticity, more in the lower than the upper limbs, and most patients are wheelchair-dependent in the 1st decade; cerebellar signs appear in childhood and, in some, choreoathetosis and dystonia that may be disabling [2]. Dysphagia, hip dislocation and scoliosis are frequent; cognition is relatively preserved (normal or mild ID), although dysarthria may severely compromise communication in adolescents and young adults [2]. Seizures, sensorineural deafness and optic atrophy are less common; the connatal form is very rare [2]. Some patients worsen with febrile illness or infection [2]. There is no genotype–phenotype correlation for the recurrent variants, and the overall prognosis is better than in PMD [2, 46]. The allelic forms are SPG44, described in three individuals with isolated adult-onset spastic paraplegia, and hereditary lymphoedema IC, with pubertal onset in the lower limbs [2, 82].

3.11. POLR3-related leukodystrophy

POLR3-related leukodystrophy combines four groups of major findings: neurological dysfunction, abnormal dentition, endocrine abnormalities and myopia [41]. Onset is typically in early childhood; in the multinational study of 105 cases with POLR3A or POLR3B variants, most began before age 6 years with gross motor delay or regression and 10% after age 10 years [12]. Cerebellar manifestations dominate: progressive gait disturbance, dysmetria, dysdiadochokinesia, dysarthria and oculomotor abnormalities (saccadic pursuit, hypo- or hypermetric saccades, gaze-evoked nystagmus), with progressive restriction of vertical more than horizontal gaze [3]. Dystonia is almost always present, pyramidal signs are mild, upper limb tremor may be the presenting sign, and hypersalivation and dysphagia appear late [3]. Minor infections may trigger episodes of more rapid deterioration [41]. Cognitive decline is generally late, except in the roughly 10% with late onset and slow progression, who present with school difficulties, a learning plateau and behavioural changes [3].

Dental abnormalities include delayed dentition, hypodontia, oligodontia and malpositioned or abnormally shaped teeth, sometimes subtle [3]. In the 2015–2016 cross-sectional study of 150 patients, delayed puberty was present in 57 of 74 assessed (77%; 64% in males and 89% in females), short stature in 57 of 93 (61%) and abnormal thyroid function in 13 of 59 (22%), with endocrine manifestations under-investigated [13]. Growth hormone (GH) deficiency also occurs [3]. Progressive myopia, which becomes severe over several years before stabilising, is the most common non-neurological manifestation, and its near-universality was confirmed in the study of 105 cases [3, 12]. Retinal detachment is a described complication [17]. Seizures, optic atrophy and cataracts are rare, and nerve conduction is normal [3]. POLR3A is associated with later onset and faster progression; POLR3B with earlier onset, a slower course, more cerebellar atrophy and better preservation of corticospinal tract myelin; and homozygosity for POLR3B c.1568T>A causes a very mild phenotype, sometimes asymptomatic in early adulthood [3, 12].

Outside classic hypomyelination, hypomorphic POLR3A variants cause adolescent-onset progressive spastic ataxia, with tremor, involvement of the central sensory pathways and dental problems (hypodontia, early periodontitis), sometimes with extrapyramidal signs [41, 68]. WRS presents in the newborn with intrauterine growth restriction, poor weight gain, a triangular face, a pinched nose, a small mouth, wide fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy and natal teeth [41, 80]. De novo POLR3B variants cause afferent ataxia, spasticity and demyelinating neuropathy [8]. The course of the leukodystrophy is invariably progressive: patients with early onset are at greater risk of death in young adulthood, and those with late onset may survive into the 4th–5th decade [3].

3.12. TUBB4A-related leukodystrophy and DYT-TUBB4A

TUBB4A-related disease ranges from the infant to the adult [5]. The early infantile form, defined by inability to sit independently at 9 months, presents with hypomyelination, severe developmental stagnation, encephalopathy, seizures and hypotonia; the late infantile form achieves sitting and often walking, followed by regression and dystonia; and the juvenile and adult forms are milder, with gait disturbance and progressive dystonia [5]. In the cohort of 216 individuals with paediatric onset, the median age at onset was 0.71 years, developmental delay was present at onset in 66.5% and tone abnormalities in 43.0%; during follow-up, scoliosis appeared in 51 of 142, hip dislocation in 30 of 101 and epilepsy in 51 of 163 [14]. Genotype (p.Asp249Asn or other) and sitting without support at 9 months predicted walking at 3 years; carriers of p.Asp249Asn with late infantile onset reached maximum abilities similar to those of other genotypes, but declined faster (log-rank p=0.0002) [14]. Loss of walking with p.Asp249Asn typically occurs after 8–10 years [5].

Source: GeneReviews TUBB4A, Table 2, with data from Gavazzi 2025 and Bally 2022 [5].

Striatal involvement causes dystonia, oculogyric crises, rigidity, choreoathetosis and perioral dyskinesia, and hemidystonia may be the first manifestation; the movements worsen with changes of position and with visual or acoustic stimuli [5]. Gastrostomy is needed in most infantile forms, scoliosis is frequent and sometimes surgical, and epilepsy affects about 30% overall, with drug resistance in some early-onset cases [5]. In severe cases there is autonomic dysfunction (postural hypotension, constipation, urinary retention, abnormalities of sweating and thermoregulation), microcephaly, short stature, cortical visual impairment, deafness and cardiovascular manifestations (aortic dilatation or calcification, valvular disease, arrhythmias, atrial septal defect) [5]. Cognition is less affected than motor function; many children with classic H-ABC keep up at school for years [5]. In 2026, an 11-year-old boy with p.(Asp249Asn) and spinal cord hypomyelination with posterior column involvement [86] and a Turkish family with adult-onset spasticity and tremor, mild executive dysfunction and subclinical atrophy of the basal ganglia, thalami and cerebellum [87] were described.

DYT-TUBB4A is an isolated dystonia, mild to severe, with onset between early childhood and the 3rd decade, presentation with spasmodic dysphonia or craniocervical dystonia, frequent progression to the limbs or generalisation, and normal MRI [5]. In a series of 4 families and 11 affected individuals from Brazil, Canada and the USA, laryngeal dystonia, often the site of onset, was present in more than 90%, and penetrance was incomplete in two families [88]. The systematic review of all published cases found laryngeal dystonia in more than three-quarters and a “hobby horse” gait in more than 20% [89].

3.13. Hypomyelination and congenital cataract (HYCC1)

Bilateral congenital cataract is the first sign (26 of 30 patients), present at birth or in the 1st month, and almost all undergo surgery in the first months [6]. Nystagmus appears in the first weeks, development is normal until the end of the 1st year, walking with support is acquired between 12 and 24 months and is gradually lost, and most are in a wheelchair between 8 and 9 years [6]. The 30 patients described had developmental delay and mild to moderate ID without cognitive deterioration; 30 of 30 had hyperreflexia and a Babinski sign, 22 of 24 peripheral neuropathy, 11 of 25 cerebellar signs and 4 of 28 seizures [6]. Scoliosis progresses with loss of walking. Life expectancy is unknown; the oldest living patient was 34 years old [6]. There are rare severe early-onset and mild late-onset forms, and partial hyccin deficiency causes a form without congenital cataract [6].

3.14. NKX6-2-related disease, PI4KA-related disease and other types

NKX6-2-related disease forms a spectrum of diffuse hypomyelination: in the severe form, neonatal nystagmus, spastic tetraplegia with contractures and scoliosis, visual and hearing impairment, rapid progression and death in early childhood; in the mild form, normal milestones in the 1st year followed by slowly progressive spastic ataxia [55]. By 2018, 25 individuals from 13 families had been described [55]. PI4KA-related disease combines spasticity, delay, ID, seizures, ataxia and nystagmus with multiple intestinal atresias, inflammatory bowel disease and combined immunodeficiency; of the 16 patients who survived the neonatal period, 9 walked and 15 had ID (3 mild, 5 moderate, 7 severe); rarely it manifests as late-onset pure SPG (SPG84) [56]. Homozygosity for p.(Tyr1623Asp) described in the Amish community causes extensive multiple intestinal atresia and death in the 1st month [56].

Among the remaining HLD types, the course distinguishes two groups. HLD19 (TMEM63A) and HLD25 (TMEM163) present with neonatal nystagmus and motor impairment that regress, with normalisation of myelin [4, 51]. Others have a severe course and early mortality, such as HLD14 (UFM1), HLD17 (AIMP2), HLD20 (CNP) and HLD23 (RNF220), the latter with dilated cardiomyopathy [4]. In HLD12 (VPS11), six patients homozygous for p.(Cys846Gly) had diffuse hypomyelination and focal absence of the cerebellar cortex [49]. DEGS1 deficiency (HLD18), with about 20 patients described, ranges from isolated spastic paraparesis to disease with death at 18 months [50].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In the newborn, the combination of pendular or rotatory nystagmus, stridor and hypotonia should suggest connatal PMD [1, 83]. Saudubray's tables of signs associate the triad “nystagmus, dystonia and stridor” with PMD and list, among the causes of neonatal hypotonia with nystagmus and white matter abnormality, congenital PMD, TMEM106B-related disease and deficiency of the thyroid hormone transporter MCT8 [43]. In the infant and young child, the typical pattern is that of a child diagnosed with cerebral palsy or static encephalopathy who had nystagmus in the first two years and initial hypotonia, especially if there is a family history compatible with X-linked inheritance; absence of a family history does not exclude the diagnosis [1]. In males with developmental regression, the X-linked disorders should be considered, such as X-linked adrenoleukodystrophy and PMD, and in X-linked ID the neurological signs point towards L1CAM, PMD, SPG2 or Allan-Herndon-Dudley syndrome [90, 91].

In the older child, the adolescent and the adult, spastic paraparesis with or without CNS involvement, spastic bladder and a family history without male-to-male transmission suggest SPG2 [1]. In the adult, oculodentodigital dysplasia may present as spastic paraplegia, usually without nystagmus, and SPG44, the late forms of TUBB4A- and POLR3-related disease and spastic ataxia due to hypomorphic POLR3A fall within the same consideration [1, 2, 5, 68]. In women, adult-onset neurological signs in a family with SPG2, the null syndrome or HEMS should prompt testing for the familial variant [1, 66].

4.2. Clues pointing to the gene

4.3. Warning signs and emergencies

Stridor and dysphagia indicate a risk of aspiration; in the GLIA-PMD cohort, patients of the profound subtype required a feeding tube at a median of 0.8 years, before poor weight gain became apparent [15]. A sudden and persistent change in tone should prompt a search for intercurrent illness, pain or new CNS pathology [17]. Fever transiently worsens neurological signs in PMD, and minor infections may trigger deterioration in PMLD1 and POLR3-related leukodystrophy [1, 2, 41]. In HLD13 (HIKESHI), a febrile illness may precipitate heart failure [4]. In patients with an intrathecal baclofen pump, high fever, altered mental status, rebound spasticity and rigidity suggest interruption of the infusion and constitute an emergency, with a risk of rhabdomyolysis, multiorgan failure and death [93]. “Autonomic storms” and non-epileptic paroxysmal events (reflux with Sandifer posturing, dystonia, pain crises) must be distinguished from epileptic seizures [17].

4.4. Newborn screening

None of the hypomyelinating leukodystrophies is included in the newborn screening programmes described in the sources consulted. The GLIA diagnostic consensus recommends reviewing the newborn screening result as part of the rapid exclusion of treatable leukodystrophies [94]. In MCT8 deficiency, the thyroid signature may not be present at newborn screening and may be detected in the first two years [95].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and operational definition

No published consensus clinical diagnostic criteria exist for PLP1-related disorders or for TUBB4A-related leukodystrophy [1, 5]. In males, the diagnosis is established by a pathogenic or likely pathogenic hemizygous variant in PLP1; in females, generally, by neurological signs, family history and a heterozygous variant [1]. In the other entities, the diagnosis requires the suggestive picture and biallelic variants (GJC2, POLR3A, POLR3B, POLR1C, HYCC1) or a heterozygous variant (TUBB4A) classified as pathogenic or likely pathogenic; a VUS, alone or in combination with a pathogenic variant, neither establishes nor excludes the diagnosis [2, 3, 5, 6].

5.2. Magnetic resonance imaging: definition of hypomyelination

Brain MRI is the main investigation, with a minimum protocol of sagittal T1, axial T1, T2 and FLAIR, and with spinal MRI at least once in every patient with an undiagnosed leukodystrophy [94]. A single MRI, especially in the 1st year, does not distinguish delayed myelination, hypomyelination and the early phase of a leukodystrophy; the GLIA consensus defines hypomyelination as an unchanged pattern of deficient myelination on two MRI scans at least 6 months apart in a child older than 1 year, and recommends serial MRI 6–12 months apart, at least one after age 2 years [94]. The T1 sequence carries particular weight, because T1 shortening precedes T2 [94]. The Oxford Desk Reference adopts the same definition and considers T2 hyperintensity of the cerebral white matter abnormal after 18 months [83]. In the hypomyelinating pattern, the white matter is hyperintense, isointense or slightly hypointense on T1 relative to the cortex, and the T2 hyperintensity is less marked than in the demyelinating disorders [83, 96]. The 2026 Brazilian review, illustrated with genetically diagnosed patients aged 3 to 18 years followed in tertiary and quaternary centres in Brazil, summarises the decisive distinction: in hypomyelination, myelin never forms, and the white matter retains diffuse and persistent T2/FLAIR hyperintensity, relatively stable between scans, often with T1 hypointensity in the internal capsule, corona radiata and optic radiations, reduced volume and absence of contrast enhancement and of diffusion restriction; in demyelination, already formed myelin is destroyed, and the lesions are confluent, progressive and have a topography characteristic of each disease [97].

The normal newborn already has myelin signal on T1 and T2 in the pons and cerebellum, and at 3 months in the posterior limb of the internal capsule, the splenium of the corpus callosum and the optic radiations; the absence of these early landmarks suggests PMD or another hypomyelinating disorder, although myelination takes place mainly in the first two years and T2 may not be definitive in the young infant [1]. In a retrospective study of 112 patients with hypomyelination of known cause, blinded classification using a standardised list formed 10 groups; the most discriminating items were early cerebellar atrophy, homogeneity of the white matter T2 signal, abnormal signal of the basal ganglia, signal changes in the pons and additional T2 lesions in the deep white matter [98].

5.3. MRI patterns by entity

In the pons, PMD shows one of two patterns: global T2 hyperintensity, often with T1 hypointensity, or T2 hyperintensity and T1 hypointensity confined to the pyramidal tracts of the ventral pons; the corpus callosum is often thin [97]. In POLR3-related leukodystrophy, the same review adds to the relative preservation already described that of the perirolandic region and the T2 hypointensity of the optic radiations and of the anterolateral thalamus, without contrast enhancement [97].

In the Japanese series of 19 patients with PMD (0–29 years), clinical severity was greater when there was T2 hyperintensity of the whole brainstem or of the corticospinal tract in the internal capsule; a T1 myelination age equivalent to “before birth” was associated with a severe phenotype, and the 8 patients with T1 myelination beyond 4 months had a mild phenotype; corpus callosum atrophy was present in 17 of 19 [76]. In the French series of 35 patients, the myelination score increased up to age 12 years, and atrophy and anterior myelination were proposed as biomarkers of motor development [38]. Quantitative MRI of the myelin water fraction measured 0.0267 ± 0.021 in two patients with PMD against 0.1299 ± 0.039 in seven controls, with measurable myelin in the brainstem and projection fibres and almost none in the commissural and association fibres; it is a potential biomarker for trials, with a very small sample [100]. After genetic diagnosis, most patients do not need serial MRI outside trials [17]; GeneReviews suggests an MRI to assess severity, most useful from 9 months [1].

5.4. Spectroscopy and neurophysiology

MRS shows reduced white matter NAA, especially in the null syndrome; in duplications it may be increased, without systematic studies [1]. Low choline is a spectroscopic marker of hypomyelination, and MRS is diagnostic in only a few disorders, such as Canavan disease [43]. The 2026 Brazilian review describes another profile in PMD: a slight reduction of NAA with increased choline, especially in the frontal lobe and the centrum semiovale, and increased creatine, which it attributes to the increase in astrocytic processes positive for glial fibrillary acidic protein (GFAP), noting that increased NAA in the white matter has also been described [97]. The increased choline in this description diverges from the low choline proposed as a marker of hypomyelination, and none of the sources consulted compares the two observations in the same series [43, 97]. MRS and BAEP help to separate PMD from PMLD1: in PMLD1 BAEP are usually normal, whereas in PMD they are abnormal [46, 101]. Nerve conduction velocity identifies the null syndrome and is probably reliable from age 4 years [1]. In HCC, motor conduction velocity is mildly to markedly slow and sural nerve biopsy shows thin or absent myelin and small onion bulbs [6]. Visual evoked potentials help to detect early optic nerve involvement in the hypomyelinating disorders [43].

5.5. Biochemical tests

The GLIA consensus recommends rapid exclusion of the treatable leukodystrophies (X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy and cerebrotendinous xanthomatosis) with a minimum battery: very long-chain fatty acids (VLCFA), galactocerebrosidase, arylsulfatase A, cholestanol and review of newborn screening [94]. The Oxford Desk Reference extends the initial investigation to organic acids and amino acids, oligosaccharides and mucopolysaccharides, lactate, ammonia, biotinidase, leucocyte enzymes and cerebrospinal fluid (CSF; cells, protein, lactate, serine, glycine, interferon α and pterins), and recommends storing DNA [83]. In the hypomyelinating disorders, two biomarkers have diagnostic value: in MCT8 deficiency, raised T3 (usually free), low rT3, reduced or low-normal T4, a free T3/free T4 ratio above 0.75 (molar ratio) and normal or mildly raised TSH [92]. The 2020 French PNDS (French National Diagnosis and Care Protocol) on Allan-Herndon-Dudley syndrome describes the same profile (normal or subnormal TSH, low or low-normal free T4, raised or high-normal free T3) and proposes, based on the experience of the reference centres, a threshold of 0.75 for the free T3/free T4 ratio calculated in pmol/pmol; it adds that the profile is more suggestive in the young child than in the newborn, that it rarely appears normal and may vary with age in the same patient, and that, because many laboratories do not measure free T3 as a first-line test, the request must mention it explicitly [102]; and in DEGS1 deficiency, increased dihydrosphingolipids and dihydroceramide/ceramide ratio in blood, muscle and fibroblasts [50]. There is no blood biochemical assay for PMD.

5.6. Genetic testing in the PLP1 spectrum

GeneReviews proposes two options [1]. In the first, targeted deletion/duplication analysis is performed (MLPA, targeted array, quantitative PCR or FISH); if negative, PLP1 is sequenced (missense, nonsense, splicing variants and small indels), including intron 3, which should be sequenced when HEMS is suspected and no exon 3B variant is found; and, if negative, a multigene panel with PLP1 and the genes of the differential diagnosis is used. In the second, exome or genome is used when the phenotype is indistinguishable from other disorders with motor and cognitive impairment; these tests can detect CNVs by read depth or breakpoints, but possibly with lower sensitivity than targeted analysis [1]. MLPA is more accurate than interphase FISH for counting copies beyond duplication [34]. The study by Kevelam and colleagues recommends including intron 3 in all diagnostic sequencing [36]. In the Chinese family with three brothers with the classic form, the duplication was identified by exome with CNV analysis, and the authors recommend early CNV detection [74].

Source: GeneReviews PLP1, Table 1 [1]. The proportions refer to variants detected in the series of patients with a molecular diagnosis and are not equivalent to clinical sensitivity.

5.7. Genetic testing in the other entities of the class

In PMLD1, GJC2 is sequenced first, including non-coding exon 1, where c.-167A>G and c.-170A>G are located; if only one variant is found, deletion/duplication analysis is performed; panels should include the promoter region [2]. In the GeneReviews table, sequencing including the promoter identified variants in 53 of 79 probands and targeted deletion/duplication analysis in 26 of 79 [2]. In POLR3-related leukodystrophy, the order of genes depends on ancestry: in French Canadians, POLR3A first and then POLR3B; in Europeans, POLR3B first (with deletion analysis if only one variant is found) and then POLR3A; in other ancestries, either first; POLR1C is tested when both are negative [3]. The distribution by gene was POLR3A 41%, POLR3B 49%, POLR1C 5% and unknown cause 5%; sequencing detects about 100% of POLR3A and POLR1C variants and about 97% of POLR3B variants, in which multiexon deletions account for about 3% [3]. In TUBB4A-related leukodystrophy, single-gene testing is rarely useful and is not recommended; panel, exome or genome detect the coding variants, and no deletions or duplications have been described [5]. In HCC, HYCC1 sequencing identified variants in 16 of 17 patients, and a consanguineous Turkish family had a homozygous deletion [6]. In NKX6-2-related disease, an ataxia, paraparesis or hypomyelinating leukodystrophy panel is recommended [55].

5.8. Diagnostic yield and limits of testing

Yield has increased with next-generation sequencing (NGS). In 2015, even with complete investigation, 30–40% of the leukodystrophies and genetic leukoencephalopathies and 50% of hypomyelinating cases remained undiagnosed [94]. The 2021 review estimates that NGS provides a definitive diagnosis in 80–90% of patients with hypomyelination [26]. Published yields range between 40% and 94% depending on clinical and radiological expertise and the methods used: in a Chinese cohort of 119 patients there was a diagnosis in 112 (94%), and in a cohort of 26 infants with probable hypomyelinating leukodystrophy the sequential karyotype, microarray and exome strategy reached 58% [103]. In the Indian Manipal cohort (24 families and 25 patients recruited between 2019 and 2024, half of the families consanguineous, median age 2 years), a molecular diagnosis was obtained in 22 families (92%): in 4 of 9 with targeted testing (PLP1 MLPA in boys with diffuse hypomyelination without another distinguishing sign; Sanger sequencing of the RNASEH2C founder variant frequent in that population when calcifications were present) and in 18 of 23 with broader genomic testing, 14 of them in 17 by proband-only exome [103]. The 14 genes identified included PLP1, GJC2, POLR1C, TUBB4A, UFM1, NKX6-2 and DEGS1, and two boys with normal PLP1 MLPA had HLD2 and HLD11 on exome, illustrating the overlap with PMD [103]. The series is small, single-centre, without follow-up MRI and without genome sequencing in the 2 undiagnosed cases [103]. In the LeukoSEQ study (2017–2024), trio genome sequencing as a first-line test in under-18s with diffuse or tract white matter abnormalities gave a diagnostic result in 45 of 80 participants [104]. The Oxford Desk Reference cites a yield of 42% for panel, exome or genome in leukodystrophies [83]. About 20% of males with a picture compatible with PMD have no identifiable PLP1 variant [1].

A negative result does not exclude the diagnosis. Exome and capture-based panels detect PLP1 duplications and complex rearrangements irregularly, do not generally cover deep intronic variants or distal enhancers, and do not resolve insertions of the duplicated segment into other chromosomes [1, 64]. In the family with the 3′UTR CNV, clinical exome sequencing of four members was negative and only the genome gave the diagnosis [66]; in the family with the enhancer microdeletion, confirmation required long-read sequencing [65]. In TUBB4A-related leukodystrophy, parental mosaicism may not be detected in leucocytes [5]. Reanalysis of the exome with refined HPO terms and family information allowed the diagnosis of HLD19 after a negative trio exome [51]. The 2026 European consensus on NGS in rare neurological diseases (Delphi with 31 experts, external quality assessment scheme with the European Molecular Genetics Quality Network, EMQN) recommends that reports describe the composition and updating of panels, the technique-specific limitations and the minimum quality parameters [105].

5.9. Report, VUS and segregation

The report should identify the gene, the transcript with version (NM_000533.5 for PLP1), the variant in HGVS nomenclature, the zygosity (hemizygous, heterozygous or homozygous) and the class according to ACMG/AMP criteria, with confirmation of pathogenic or likely pathogenic variants by an orthogonal method [94]. For duplications, the report should state the copy number, and high-density array or junction sequencing characterise complex rearrangements [34, 64]. Classification of a novel variant depends on segregation and functional evidence: in the Brazilian case of p.(Ala21Val), the variant was classified as likely pathogenic with the criteria PM2, PP3 strong, PP2, PM1 and PP4, and maternal segregation and absence in unaffected uncles and cousins reinforced the interpretation [37]; in the Colombian family, p.(His66Leu) remained a VUS despite cosegregation [73]. For variants that may alter splicing, RNA (cDNA) studies demonstrate the effect, as with the AIMP1 variant c.603+1G>A [48].

5.10. Practical algorithm

The pathway starts from clinical suspicion (subsection 4.1). The first step is MRI with a minimum protocol, read by paediatric neuroradiology, before other tests; indiscriminate testing is generally of little use [83, 94]. The second is to recognise the hypomyelinating pattern and, if the child is under 1 year or there is doubt, to repeat the MRI 6–12 months later [94]. The third is to exclude the treatable leukodystrophies with the minimum battery and to request T3, rT3 and free T4 for hypotonia with nystagmus in a boy [92, 94]. The fourth, in the boy with early nystagmus and a homogeneous pattern, is PLP1 dosage analysis followed by sequencing including intron 3 or, alternatively, exome or genome with CNV analysis [1]. The fifth, in the other cases or after a negative result, is a broad panel, exome or trio genome, with periodic reanalysis and DNA storage [51, 83, 94]. The sixth is to study segregation and test the mother [1].

5.11. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible once the familial variant has been identified [1]. In PMD, the result does not accurately predict the clinical outcome, because phenotypes vary within the same family and women may be normal or have mild to moderate signs [1]. In 1995, in a family of Portuguese origin studied in Indianapolis, the maternal variant was detected by PCR in amniocytes from a male fetus [72]. Interphase FISH detects duplication carriers [33]. Without a molecular diagnosis, prenatal diagnosis is not possible [83].

6. Differential Diagnosis

6.1. Cerebral palsy, delayed myelination and other leukodystrophies

Patients with PLP1-related disease are often initially diagnosed with cerebral palsy or static encephalopathy [1]. Nystagmus in the first two years, initial hypotonia and abnormal signal in structures that should be myelinated at birth (posterior limb of the internal capsule, middle and superior cerebellar peduncles, medial and lateral lemnisci) separate PMD from cerebral palsy, especially when there is an X-linked family history [1]. The first discriminator on MRI is distinguishing hypomyelination from demyelination: in the demyelinating disorders there is loss of formed myelin, with more intense T2 hyperintensity and T1 hypointensity, and in the hypomyelinating disorders there is a production defect with relatively normal T1 signal [83, 96]. The second is distinguishing hypomyelination from delayed myelination, which requires serial MRI [94]. The demyelinating leukodystrophies, the other leukoencephalopathies and Alexander disease enter the differential diagnosis.

6.2. Comparative table

6.3. PMD and PMLD1

The clinical presentation and MRI are similar, and both may present as isolated spastic paraparesis [2]. Extensive brainstem involvement, especially of the pons, is more characteristic of PMLD1, and BAEP are usually normal in PMLD1 and abnormal in PMD [2, 46, 101]. Inheritance separates the two entities when there are affected sisters or consanguinity (PMLD1, AR) or transmission through the maternal line to several males (PMD) [1, 2]. The overall prognosis is better in PMLD1 [46].

6.4. PMD, POLR3-related leukodystrophy and TUBB4A-related leukodystrophy

POLR3-related leukodystrophy is the most frequent hypomyelinating disorder after PMD; it is generally distinguished by the absence of nystagmus, prominent ataxia and mild or absent spasticity, together with abnormal dentition, myopia and hypogonadism [1, 2]. On MRI, relative preservation of the ventrolateral thalamus, optic radiations, globus pallidus, dentate nucleus and pyramidal tracts in the internal capsule is the most useful clue [3, 12]. TUBB4A-related leukodystrophy usually presents as a simplex case, with prominent extrapyramidal signs and progressive atrophy of the putamen and cerebellum; some children have pure hypomyelination similar to that of PMD, and nystagmus, typical of PMD, is described but not typical in TUBB4A-related disease [1, 5]. The tubulinopathies (TUBA1A, TUBB, TUBB2A, TUBB2B, TUBB3, TUBG1) enter the differential diagnosis of TUBB4A-related disease, but have cortical malformations, agenesis of the corpus callosum and generally normal myelination [5].

6.5. Allan-Herndon-Dudley syndrome (MCT8 deficiency)

MCT8 deficiency mimics PMD in the boy with neonatal hypotonia, nystagmus and severe delay, and MRI before age 5 years shows a severe delay of myelination that is confused with hypomyelination and improves over time [92]. In one study, SLC16A2 variants were found in 11% of 53 families with severe PMLD and unusual improvement of myelin with age [92]. The Oxford Desk Reference states that the MRI is normal; the 2020 GeneReviews chapter restricts that observation to older reports of older patients and describes delayed myelination in young children, which is the relevant finding for the differential diagnosis [92, 95]. The discriminator is biochemical: raised T3, low rT3 and a free T3/free T4 ratio above 0.75 [92]. About 25% of heterozygous females have raised T3 without neurological signs [92]. The diagnosis has therapeutic consequences, because tiratricol (Emcitate®) is approved in the EU and the USA (subsection 7.14) [107, 108]. Levothyroxine or liothyronine alone may aggravate the raised T3 and hypermetabolism [92]. Non-goitrous congenital hypothyroidism 6 (THRA, AD) also presents with a raised free T3/free T4 ratio, but has normal MRI and improves with levothyroxine [92]. The 2020 French PNDS describes MRI in MCT8 deficiency as sometimes normal, but with frequent hypomyelination in early childhood, partial correction on successive MRI scans without corresponding clinical improvement, and cerebral and sometimes callosal atrophy; in the hypomyelinating leukodystrophies (PMD and PMLD), by contrast, hypomyelination changes little with age and the thyroid profile is normal, which makes the free T3/free T4 ratio the test that guides the diagnosis [102]. The same protocol completes the picture of THRA deficiency with short stature, delayed bone age, a tendency to anaemia and macrocephaly, and considers it a differential diagnosis mainly of the moderate forms of MCT8 deficiency [102]. MECP2 duplication syndrome, also X-linked, shares with PMD and MCT8 deficiency early hypotonia in a boy, severe intellectual disability, frequent absence of speech, progressive spasticity and epilepsy, and may show white matter abnormalities on MRI, but the thyroid profile is normal [102]. Confirmation of MCT8 deficiency rests on SLC16A2 sequencing (Sanger, intellectual disability, leukodystrophy or movement disorder panel, exome or genome) and on the search for large rearrangements by MLPA [102].

6.6. SPG2 and other spastic paraplegias

More than 80 genetic types of hereditary spastic paraplegia have been defined [1]. SPG2 is distinguished by X-linked inheritance, nystagmus and the white matter abnormality in the complicated form; in the pure form, MRI may be normal [1, 3]. SPG44 (GJC2), SPG84 (PI4KA), spastic ataxia due to hypomorphic POLR3A, POLR1A-related paraplegia, TUBB4A-related paraplegia with mild white matter changes and adult oculodentodigital dysplasia should be considered in the same context [1, 2, 5, 54, 56, 68].

6.7. DYT-TUBB4A

DYT-TUBB4A, with normal MRI, enters the differential diagnosis with the isolated dystonias DYT-KMT2B, DYT-GNAL, DYT-TOR1A and DYT-THAP1 [5]. Juvenile-onset spasmodic dysphonia and a “hobby horse” gait point towards TUBB4A, but TUBB4A screening in isolated dystonias has a very low yield [89].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

No disease-modifying therapy is approved for PMD or for any hypomyelinating leukodystrophy [1, 16]. There are no published clinical practice guidelines for PLP1-related disorders, and the GeneReviews recommendations are based on the authors' experience [1]. The reference document is the revised GLIA consensus (Adang 2017), which replaced the 2015 consensus on preventive and symptomatic care in the leukodystrophies; it is based on existing studies, consensus opinion and extrapolation from other neurological disorders, especially cerebral palsy, without formal grades of evidence [17, 109]. Its principle is that all leukodystrophies are treatable in the sense of comprehensive care, and that lack of a definitive diagnosis should not delay preventive and symptomatic care [17]. The team includes genetics and genetic counselling, neurology, complex care paediatrics, respiratory medicine, gastroenterology, speech and language therapy, endocrinology, physical and rehabilitation medicine (PRM), orthopaedics, physiotherapy and occupational therapy, palliative care and social work [1, 17]. In POLR3-related leukodystrophy, dentistry, ophthalmology, otorhinolaryngology and neuropsychology are added [3], and in TUBB4A-related leukodystrophy cardiology and mental health [5]. All the symptomatic drugs mentioned are used off-label in these disorders, with doses extrapolated from the labels or from analogous conditions, especially the spasticity and dystonia of cerebral palsy.

7.2. Initial assessment after diagnosis

7.3. Spasticity

Assessment should be carried out by a physiotherapist with standardised scales, repeated over time: the Hypertonia Assessment Tool distinguishes dystonia, spasticity and rigidity; the Modified Ashworth Scale (6 points) and the Modified Tardieu (which takes velocity into account) grade spasticity; none is validated in the leukodystrophies [17]. Treatment is stepwise. In mild spasticity without major axial hypotonia, oral baclofen or diazepam are used with physiotherapy and daily stretching [17]. In focal spasticity that impedes tasks (adductors for hygiene, gastrocnemius for walking), botulinum toxin or phenol neurolysis is administered by a trained professional [17]. In case of failure or intolerance, intrathecal baclofen is considered, which allows higher doses with fewer systemic effects, at the cost of a risk of infection and mechanical failure with withdrawal syndrome, and, in selected cases, tendon lengthening or release surgery or nerve pathway surgery, weighing the anaesthetic risk [17]. GeneReviews adds tizanidine and stresses that antispasticity drugs are most useful combined with physiotherapy, exercise and orthoses, and that surgery releases severe contractures [1]. In cerebral palsy, the 2010 American Academy of Neurology (AAN) practice parameter concluded that the data were insufficient to support or refute oral baclofen, dantrolene and intrathecal baclofen (level U), that diazepam should be considered in the short term for generalised spasticity (level B), that tizanidine may be considered (level C) and that botulinum toxin A should be offered for focal or segmental spasticity (level A), with conflicting evidence on functional improvement [110].

7.4. Dystonia and other movement disorders

Dystonia is underdiagnosed in the leukodystrophies [17]. The GLIA consensus considers trihexyphenidyl one of the most effective treatments for generalised dystonia, generally well tolerated in this population with monitoring for constipation; the alternatives are levodopa and tetrabenazine, and oral baclofen and benzodiazepines are effective at doses higher than those used for spasticity; in focal dystonia, botulinum toxin is preferable to oral drugs, and the invasive methods are intrathecal baclofen and, rarely, deep brain stimulation (DBS) [17]. In PMLD1, trihexyphenidyl and tetrabenazine are potentially useful, but dystonia is often refractory [2]. In TUBB4A-related leukodystrophy, GeneReviews lists botulinum toxin, baclofen, trihexyphenidyl, tetrabenazine and high-dose levodopa/carbidopa, and DBS has been used successfully in several cases, with improvement of laryngeal dystonia and the “hobby horse” gait in at least one [5]. In a 35-month-old Japanese boy with H-ABC and hemidystonia, levodopa/carbidopa improved the dystonia and halted its progression, with final doses of 200 mg/day levodopa and 20 mg/day carbidopa [111]. In DYT-TUBB4A, bipallidal DBS reduced the Burke-Fahn-Marsden scale score by 55% six months after surgery in a 44-year-old patient [112], and in the systematic review four cases treated with globus pallidus internus DBS had good improvement, greater in the motor than in the laryngeal component, whereas medical treatment was generally of little effect, with some benefit from propranolol, tetrabenazine and alcohol intake [89].

The evidence for trihexyphenidyl comes from dystonic cerebral palsy and is inconsistent. In an open-label trial of 23 children (4–15 years), titration up to 0.75 mg/kg/day improved upper limb function at 15 weeks (p=0.045), but not at 9 weeks, and the hyperkinetic subgroup worsened [113]. In a retrospective series of 101 children, the mean starting dose was 0.095 mg/kg/day and the mean maximum dose 0.55 mg/kg/day, with adverse effects in 69% and benefit for upper limb dystonia in 59.4% and for sialorrhoea in 60.4% [114]. In a randomised, double-blind, crossover trial of 16 children, there was no significant effect on the Barry-Albright scale and adverse effects were frequent [115]. In a retrospective Chinese cohort, adding levodopa/benserazide to trihexyphenidyl reduced the dystonia score more than trihexyphenidyl alone (−5.25 vs −2.52; p<0.001), in a non-randomised study [116]. D2 receptor blockers should be avoided (subsection 7.17) [3, 17].

7.5. Dosing of drugs for spasticity and dystonia

None of these drugs has an approved indication in PMD or in the hypomyelinating leukodystrophies. The recommended dose is that of the consensus, the guideline or, failing these, the trial or published series in the closest indication, usually spasticity or dystonia of cerebral origin; the official label (FDA, EMA or national SmPC) is given alongside for comparison, with the difference explained, and is the main dose only when none of those sources gives a dose, with the extrapolation stated.

In Brazil, ANVISA open data list Baclon®, Baclofen®, Valium®, Sirdalud®, Artane®, Botox®, Dysport®, Parkidopa® and Prolopa® as active; oral Lioresal® is inactive, there is no active registration of tetrabenazine (only of deutetrabenazine, Austedo®) or of oral glycopyrronium, and the Brazilian package inserts were not read because the ANVISA package insert database returned a server error on 26/10/2026 [138]. In Portugal, Sirdalud® (Sandoz) has been authorised since 31/01/1992 and Valium® (Atnahs) since 01/04/1964 [120, 123].

7.6. Epilepsy and paroxysmal events

Seizures occur in almost half of patients with leukodystrophies as a whole, in 14.0% in the GLIA-PMD cohort and typically only in the connatal phenotype according to the PLP1 GeneReviews chapter [1, 15, 17]. The GLIA consensus finds no evidence for prophylactic antiseizure medication before the first seizure; after a seizure, provoking factors should be sought (fever, electrolytes, drug withdrawal, infection, particularly urinary tract infection), and provoked seizures rarely require daily prophylaxis [17]. Many episodes with seizure semiology are mimics: reflux with Sandifer posturing, breath-holding spells, syncope or dysautonomia, dystonias, tics, pain crises, parasomnias, hypoglycaemia and staring episodes; in TUBB4A-related disease, movement disorders are mistaken for seizures [5, 17]. PMD seizures generally respond to standard antiseizure medications, such as carbamazepine [1]; in TUBB4A-related leukodystrophy and in HCC no antiseizure medication has shown specific efficacy [5, 6]. Phenobarbital, phenytoin, carbamazepine and valproate impair bone mineralisation [17].

The GLIA consensus mentions rectal diazepam and buccal or intranasal midazolam as rescue medication for prolonged or clustered seizures [17]; the doses in the table are those of the labels.

7.7. Feeding, nutrition, sialorrhoea and the digestive system

Feeding and nutritional assessment (dysphagia, reflux, constipation, dentition) is performed at diagnosis and every 3–6 months; when aspiration is suspected, instrumental studies are used (videofluoroscopy, modified barium swallow, fibreoptic endoscopic evaluation of swallowing) and, if normal, reassessment takes place in 3–6 months [17]. Feeding therapy includes thickening or cooling foods; a nasogastric tube or gastrostomy is indicated in severe dysfunction [1]. The consensus advises considering gastrostomy for persistent poor weight gain or oromotor dysfunction, notes that it is often referred late, when the risk is greater, that it can coexist with oral feeding and that, without significant reflux, there is no evidence for adding a Nissen fundoplication; the nasogastric tube is more often associated with vomiting in children under 1 year, aversions and difficulty in transition [17]. In POLR3-related leukodystrophy, dysphagia varies greatly, even over the same day, because of cerebellar incoordination with fatigue [3]; in TUBB4A-related leukodystrophy, swallowing patterns may change abruptly, and high-risk foods should be avoided (round sweets, popcorn, hard nuts, grapes, large pieces of bread, whole sausages) [5]. Gastro-oesophageal reflux (GOR) is a clinical diagnosis, treated with proton pump inhibitors (PPIs) such as lansoprazole or omeprazole; prolonged PPI use increases the risk of fractures and requires monitoring of calcium, magnesium, iron and vitamin B12, and fundoplication is reserved for medical failure [17]. Constipation (two or fewer bowel movements per week) is treated with hydration, fibre, polyethylene glycol or lactulose, sodium phosphate enemas, senna or bisacodyl [17].

In sialorrhoea, the first step is oromotor and behavioural therapy, positioning, review of sialogogue drugs and treatment of constipation, scoliosis and reflux; anticholinergics are used with caution, because of thickening of secretions and central sedation (oral or transdermal hyoscine, trihexyphenidyl, 1% atropine eye drops given sublingually); glycopyrronium reduces saliva with fewer central effects; and in refractory cases botulinum toxin A into the salivary glands or surgery is used [3, 17]. The surgery described in POLR3-related leukodystrophy is rerouting of the parotid and submandibular ducts, with or without excision of the sublingual glands [3].

The two labels use different units: Cuvposa® doses the salt (glycopyrronium bromide, in mg) and Sialanar® the base (glycopyrronium, in µg); 12.8 µg/kg of base is equivalent to about 16 µg/kg of bromide [144, 145]. The GLIA consensus notes that glycopyrronium was approved above 3 years [17].

7.8. Respiratory system and sleep

The dystonic dysphonia of H-ABC and 4H leukodystrophy and obstruction due to hypotonia cause intermittent obstructive apnoea [17]. Swallowing is reassessed every 3–12 months depending on progression, more often if there is sialorrhoea, previous pneumonia or coughing at meals [17]. Prevention includes annual influenza and pneumococcal vaccination, positioning, hand hygiene, palivizumab in selected cases, chest physiotherapy, vibration vest, assisted cough and home suctioning; salivary botulinum toxin may reduce aspiration pneumonia, without studies [2, 17]. For RSV prevention, palivizumab (Synagis®), 15 mg/kg monthly during the season, is authorised in the EU for infants born at 35 weeks or less, bronchopulmonary dysplasia and haemodynamically significant congenital heart disease [146]. Nirsevimab (Beyfortus®) has been authorised in the EU since 31 October 2022 for all newborns and infants in their first season (50 mg below 5 kg and 100 mg from 5 kg, as a single IM dose) and, since 1 August 2024, for children up to 24 months who remain vulnerable in their second season (200 mg) [147]. Clesrovimab (Enflonsia®), as a single 105 mg IM dose, was approved by the FDA on 9 June 2025 and authorised in the EU on 15 April 2026, for the first season only [148, 149]. The hypomyelinating leukodystrophies do not appear as a named indication; inclusion in the second season depends on respiratory vulnerability and national guidelines. Early discussion of ventilation options (invasive, continuous or bilevel positive pressure, oxygen) with respiratory medicine should form part of the goals of care [17]. In the GLIA-PMD cohort, 24.3% of patients with data had artificial ventilation [15]. In NKX6-2-related disease, sleep studies are recommended for apnoea [55], and in TUBB4A-related disease a sleep study if there is snoring [5]. For sleep, the consensus recommends sleep hygiene and a sleep diary, notes that there are no FDA-approved drugs for paediatric insomnia and that clonidine, tricyclics and benzodiazepines are used off-label, and that melatonin is used in practice [17].

7.9. Bone health and vitamin D

The risk of low bone mass and fractures is high because of immobility, little sun exposure, nutritional deficits and antiseizure medications, and POLR3-related leukodystrophy adds endocrine dysfunction and secondary osteoporosis [17]. Raised parathyroid hormone (PTH) is the initial marker of insufficient calcium intake or absorption, because serum calcium alone is not sensitive; 25-hydroxyvitamin D is measured at least once a year; and densitometry (DXA) of the lumbar spine and total body less head is performed at around 5 years, the minimum age with reference data, repeated according to the result; plain radiography is not a screening tool, but a lateral spine radiograph looks for vertebral fractures in immobilised patients or those with previous fractures, and the forearm or lateral distal femur replace standard DXA when contractures or scoliosis prevent it [17]. In PMLD1, GeneReviews recommends regular monitoring of vitamin D and calcium [2].

Source: GLIA consensus, Table 4, reproducing the Endocrine Society guideline; deficiency defined as 25(OH)D <20 ng/mL (50 nmol/L), insufficiency 21–29 ng/mL (52.5–72.5 nmol/L) and sufficiency 30–100 ng/mL [17].

7.10. Orthopaedics: hip, scoliosis and walking

Hip surveillance follows that of cerebral palsy: physical examination every 6 months and annual radiograph from 2 years until skeletal maturity [17]. Dislocation warrants surgery if it is painful, limits mobility or brings other risks; below 5 years conservative measures are preferred (adductor tenotomy, tone control), and above 6 years reconstructive surgery may be considered [17]. The spine is examined at every visit, with anteroposterior and lateral radiographs if suspected; orthoses optimise sitting position and chest expansion but do not alter progression, and surgery is usually considered with a Cobb angle greater than 40–50° [17]. The PLP1 GeneReviews chapter indicates corrective surgery if there is pulmonary compromise or discomfort and notes that appropriate seating and physiotherapy may reduce or avoid surgery [1]. In TUBB4A-related leukodystrophy, serial hip and spine radiographs are recommended when weight-bearing is limited [5]. Walking, or at least weight-bearing, should be maintained with orthoses, walkers and standers, and the skin inspected daily by the caregiver and at every visit, with attention to orthoses and the nappy area [17].

7.11. Urinary system, autonomic dysfunction and pain

Spastic bladder is followed by urology [1]. In urinary tract infection, the urine culture threshold is more than 100,000 colony-forming units/mL, and neurological patients may have hypo- or hyperthermia; referral to urology is made with two or more infections per year in girls or one or more in boys, and retention is treated with catheterisation guided by urology [17]. In TUBB4A-related leukodystrophy, recurrent urinary tract infection should raise the possibility of abnormal bladder emptying [5]. For “autonomic storms”, prevention uses gabapentin, cyproheptadine, baclofen, beta-blockers or clonidine, and acute crises diphenhydramine, paracetamol or ibuprofen [17]. Pain is assessed with the CRIES or FLACC scales in young children and Wong-Baker FACES, looking for hidden causes (dental abscess, constipation, fracture, dislocation, urinary tract infection, pancreatitis, skin lesions) and following World Health Organization principles [17]. Gabapentin is used for neuroirritability and neuropathic pain, without studies in the leukodystrophies [17]. For irritability, the GLIA consensus proposes starting 15–20 mg/kg/day in 2–3 doses and escalating up to 60 mg/kg/day, the recommended dose [17]. The Neurontin® label (FDA), cited for comparison, has a paediatric indication only as adjunctive therapy in focal epilepsy from 3 years: start 10–15 mg/kg/day in three doses, titrated over about 3 days, maintenance 40 mg/kg/day from 3 to 4 years and 25–35 mg/kg/day from 5 to 11 years, with doses up to 50 mg/kg/day in a long-term study; neuropathic pain is an indication only in adults (post-herpetic neuralgia, up to 1800 mg/day); the consensus maximum is above the maximum studied in the label and outside the label conditions [150].

7.12. Communication, development and education

Speech and language therapy assessment should include augmentative and alternative communication (AAC) whenever communication does not meet daily needs; AAC ranges from picture exchange to voice-output devices and does not hinder verbal development [1, 17]. GeneReviews describes early intervention from 0 to 3 years, preschool education with an individualised education plan and occupational therapy for fine motor skills [1]. In PMLD1, dysarthria often requires AAC [2]. In POLR3-related leukodystrophy, learning difficulties progress slowly and cognitive involvement is less severe than motor involvement [3]. In TUBB4A-related leukodystrophy, assessment for ASD, ADHD and aggression guides behavioural interventions and medication [5].

7.13. Entity-specific measures

In POLR3-related leukodystrophy, endocrinology follows the patient regularly, and the decision to treat sex hormone and GH deficiency is individualised [3]. The GLIA consensus proposes screening for growth failure at diagnosis and then annually, measuring testosterone or oestradiol, LH and FSH at the expected age of puberty (13 years in girls and 14 in boys), measuring TSH and T4 with replacement as needed, and discussing the benefits and risks of sex steroid replacement; these recommendations are opinion-based, without clinical evidence [17]. The study of 150 patients concluded that there was insufficient evidence for evidence-based recommendations and that a prospective study is needed [13]. When GH deficiency is documented, the somatropin label (Genotropin®) generally recommends 0.16–0.24 mg/kg/week, divided into 6 or 7 subcutaneous injections [151]. In hypogonadotropic hypogonadism, the label for intramuscular testosterone enanthate indicates replacement with 50–400 mg every 2–4 weeks and, in delayed puberty, low starting doses with progressive increases weighing chronological and bone age, with hand and wrist radiographs every 6 months [152]. The sources consulted do not include the pubertal induction regimens of the paediatric endocrinology guidelines, nor oestrogen doses for girls; these indications fall within the remit of paediatric endocrinology. Myopia progresses over several years before stabilising and requires regular ophthalmology, with attention to retinal detachment, and dental anomalies (delayed eruption, natal teeth, hypodontia) require dentistry, ideally paediatric special care dentistry [3, 17].

In HCC, the cataract is usually extracted in the first months, and some patients have febrile seizures [6]. In TUBB4A-related leukodystrophy, a baseline echocardiogram is recommended because of aortic arch and valvular anomalies, with cardiac surveillance as advised by cardiology [5]. In PI4KA-related disease, the atresias and inflammatory bowel disease are treated by surgery and gastroenterology and the immunodeficiency by immunology; leflunomide has been proposed on the basis of laboratory data from TTC7A deficiency, without efficacy data in PI4KA-related disease [56]. In HLD13 (HIKESHI), the possibility of heart failure during febrile illness advises cardiac surveillance during intercurrent illness [4].

In MCT8 deficiency, an entity in the differential diagnosis, tiratricol (Emcitate®, 350 µg dispersible tablets) is indicated for peripheral thyrotoxicosis from birth in the EU and in adults and children in the USA [107, 108]. The starting dose is 350 µg/day from 10 kg and 175 µg/day below 10 kg, with increases of the same magnitude every 2 weeks, in 1–3 doses, until serum T3 falls below the midpoint of the normal range for age; the maxima are 100 µg/kg below 10 kg, 80 µg/kg between 10 and 40 kg, 60 µg/kg between 40 and 60 kg and 50 µg/kg above 60 kg [107, 108]. T3 must be measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS), because tiratricol cross-reacts with immunoassays; the drug is contraindicated in hyperthyroidism of other causes and in pregnancy, and the US label has a boxed warning against use in obesity or for weight loss and suggests periodic visual assessment below 8 years [107, 108]. The most frequent adverse effects in the EU are hyperhidrosis (7%) and diarrhoea (6%), generally transient [107].

7.14. Regulatory status

7.15. Trials and investigational therapies

The trials do not allow indirect comparison: populations, designs and outcomes differ, and the stem cell and curcumin studies are open-label, uncontrolled and with nine patients or fewer. The randomised withdrawal trial of tiratricol has 15 randomised patients and a confidence interval whose lower limit is 1.0. The trihexyphenidyl and tizanidine studies come from cerebral palsy and serve only to support doses; the only randomised trial of trihexyphenidyl was negative [115]. For deferiprone, which rescued oligodendrocyte survival and allowed myelination in the jimpy mouse [61], GeneReviews mentions clinical evaluation, but a ClinicalTrials.gov search on 26/10/2026 found no registered trial in PMD, the leukodystrophies or hypomyelination [1, 163]. A phase 1 study of umbilical cord blood-derived oligodendrocyte-like cells (DUOC-01), given intrathecally after cord blood transplantation, is recruiting patients with inherited metabolic disorders and is not specific to PMD [164].

7.16. Developments in the last 12 months

On the regulatory front, tiratricol was approved by the FDA on 28/09/2026 for MCT8 deficiency, an entity in the differential diagnosis, following the European authorisation of 12/02/2025 [107, 108]. No results announcement, marketing authorisation application, Committee for Medicinal Products for Human Use (CHMP) opinion or authorisation was found for any disease-modifying therapy for PMD or HLDs up to 26/10/2026, in a search of ClinicalTrials.gov, the EMA list of orphan designations, the Ionis pipeline and Europe PMC; a negative search does not prove non-existence [160, 163]. On the trials front, ION356 remains recruiting (last update 12/12/2025), and the second single-patient ASO for TUBB4A started in September 2025 [16, 19].

On the natural history front, the GLIA-PMD cohort (2026) proposed subtypes by stridor and head control at 12 months to stratify trials [15]. On the genetic front, PIKFYVE and BLOC1S1 were described as new hypomyelinating leukodystrophy genes, along with the first AR form of HLD22 due to CLDN11, polyneuropathy due to monoallelic POLR3A variants and new families with HLD19, SPG2 and HLD27 [9, 51, 53, 54, 57, 58, 73]. On the preclinical front, without human data: inhibition of the integrated stress response (PERK inactivation; eIF2B activators 2BAct and ISRIB) increased oligodendrocyte survival and doubled the lifespan of the jimpy mouse [165]; concentrated adenine base editors (cABE-2.0, compatible with AAV vectors) corrected the PLP1 p.A243V variant in oligodendrocytes [166]; a Citrus unshiu peel extract improved differentiation and myelin proteins in cells and in a PLP1 transgenic mouse [167]; a spontaneous canine model of connatal PMD was described in the English Cocker Spaniel [168]; proteasome inhibitors rescued hypomyelination in iPSC-derived oligodendrocytes with HIKESHI variants [169]; restoration of ER calcium corrected ER–Golgi trafficking [62]; and rapamycin attenuated vacuolisation in the PIKFYVE zebrafish [57]. The 2024 and 2025 reviews describe as strategies in development PLP1 suppression by ASO or by gene therapy with artificial miRNA, cell transplantation, iron chelation and modulation of intracellular stress [60, 170].

7.17. Agents to avoid, pregnancy, perioperative care and transition

D2 receptor blockers, such as haloperidol, risperidone and metoclopramide, should be avoided because of the risk of worsening extrapyramidal signs and of tardive dyskinesia [3, 17]. Fever should be treated early, because it transiently worsens neurological manifestations [1]. In ataxia, GeneReviews advises avoiding excessive alcohol consumption [1]. In MCT8 deficiency, levothyroxine or liothyronine alone may aggravate hypermetabolism [92]. Baclofen should not be stopped abruptly by any route, and the intrathecal pump requires attention to programming, refills and alarms, especially in those with communication difficulties [93, 117]. Carbamazepine requires HLA-B*15:02 testing in at-risk Asian ancestries [139, 140].

In pregnancy, decisions concern mainly carriers and women with mild forms. Oral baclofen used up to delivery may cause neonatal withdrawal [118]; glycopyrronium (Sialanar®) and tiratricol are contraindicated in pregnancy [107, 144]; and the TUBB4A GeneReviews chapter refers questions of drug exposure to the MotherToBaby service [5]. Perioperatively, orthopaedic and gastrostomy surgery require weighing of the anaesthetic risk, and gastrostomy performed late, when malnutrition and aspiration are already present, carries greater risk [17]. Preparation for transition to adult care should begin at around 10 years in TUBB4A-related leukodystrophy and in adolescence in the PLP1 spectrum [1, 5], and the GLIA consensus recommends early palliative care, distinct from end-of-life care, a written care plan with warning signs and the opportunity to take part in natural history studies [17].

7.18. Recommendations and divergences between sources

The recommendations come from three types of source: the GeneReviews chapters for each entity, based on the authors' experience; the 2017 GLIA consensus, which replaced that of 2015 and relies on extrapolations from cerebral palsy; and the drug labels [1, 17, 109]. When doses diverge, the reference is the dose of the consensus, guideline or study, and the official label (FDA, EMA or national SmPC) is cited for comparison; a dose that departs from it falls outside the label conditions, which is stated for information. The divergences that change practice are as follows. The US label does not recommend oral baclofen in cerebral palsy or below 12 years, whereas the Portuguese SmPC has a paediatric indication in cerebral spasticity, with weight-based dosing [117, 118]. Botox® has a paediatric indication in both limbs in the USA and only in the ankle and foot of ambulant children in Portugal, and Dysport® has in the Portuguese SmPC a bilateral upper limb maximum that the US label does not mention [127–130]. Tetrabenazine starts at 12.5 mg/day and has a maximum of 100 mg/day with genotyping in the USA, and starts at 75 mg/day and has a maximum of 200 mg/day in Portugal [136, 137]. Tizanidine has an indication in the spasticity of cerebral palsy in the Portuguese SmPC, but is not recommended below 18 years, and the published paediatric doses, which are those recommended in children, fall outside the label conditions [123, 125]. The recommended gabapentin dose of the GLIA consensus (up to 60 mg/kg/day) exceeds the maximum studied in the paediatric epilepsy label (50 mg/kg/day) [17, 150]. The PLP1 GeneReviews chapter mentions deferiprone under clinical evaluation, with no registered trial found [1, 163]. The TUBB4A GeneReviews chapter refers to the Gavazzi study (2025) as standards of care, but it is a natural history study [5, 14]. The 2017 GeneReviews chapter on POLR3 does not include POLR3K, WRS, hypomorphic spastic ataxia or the dominant forms, and its management covers only classic leukodystrophy [3, 4, 8, 68]. The ERN-RND network provides standards of care, diagnostic flowcharts and minimum MRI requirements for the leukodystrophies, whose individual content was not read [20]. In MCT8 deficiency, an entity in the differential diagnosis, the 2020 French PNDS considers treatment only symptomatic and predates the authorisations of tiratricol in the EU (12/02/2025) and the USA (28/09/2026), which now become the therapeutic reference; regarding MRI, the PNDS describes frequent hypomyelination in early childhood, GeneReviews delayed myelination and the Oxford Desk Reference a normal MRI, a divergence explained by the age of the patients described in each source [92, 95, 102, 107, 108].

8. Reproductive Options and Family Counselling

8.1. PLP1 spectrum: recurrence risks

Inheritance is X-linked [1]. The father of an affected male does not have the disease and is not hemizygous and need not be tested; in most families, including simplex cases, the mother is heterozygous, and she is an obligate heterozygote when there is more than one affected individual in the family [1]. A heterozygous mother transmits the variant in 50% of pregnancies: sons who inherit it are affected, and daughters are heterozygous, asymptomatic or with mild to moderate signs [1]. Marked intrafamilial variability is uncommon, but families with a mild phenotype may have more severely affected children, and PMD and SPG2 have coexisted in the same family [1]. Males with classic PMD do not reproduce; males with SPG2 transmit the variant to all their daughters and to none of their sons [1]. Maternal aunts and their offspring are at risk and should be informed [1].

8.2. Maternal testing, de novo variants and mosaicism

Testing of the mother is recommended [1]. In a simplex case, the mother may be heterozygous, the variant may be de novo in the proband, or there may be maternal somatic or gonadal mosaicism; a minority of affected males have a de novo variant [1]. A mother with more than one affected son and without the variant in leucocytes probably has gonadal mosaicism, and even with a single affected son and a negative maternal test the recurrence risk is higher than that of the population [1]. Testing of other female relatives may identify the generation in which the variant arose [1]. Some duplications result from an interchromosomal rearrangement of maternal origin [33]. Duplications inserted at a distance, for example at 19qter or on the Y chromosome, are rare, but complicate counselling because transmission may not follow the X-linked pattern [1].

8.3. Counselling of heterozygous females

Counselling of carriers should include the severity of the disease in the affected males of the family, because the risk of signs is highest in families with null, nonsense or small indel variants, intermediate with missense variants and lowest with duplications [77]. Heterozygous sisters are more likely to have signs when the male phenotype is mild, and manifestations may appear at 30–40 years [1, 66]. Detection of heterozygotes requires prior identification of the familial variant [1]; the X-inactivation pattern cannot replace it [78]. Interphase FISH detects duplication carriers, and MLPA and array quantify the copy number better [33, 34].

8.4. Autosomal recessive hypomyelinating leukodystrophies

In PMLD1, POLR3-related leukodystrophy, HCC, NKX6-2-related disease, PI4KA-related disease and the other AR types, the parents are obligate heterozygotes and asymptomatic, and each sibling has a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of not being a carrier; the parents' siblings have a 50% chance of being carriers [2, 3, 6, 55, 56]. In HCC, GeneReviews recommends testing both parents, because de novo variants occur at a low but appreciable frequency in AR disorders [6]. In POLR3-related leukodystrophy, the phenotype is similar among relatives, but severity and age at onset vary; predictive testing of at-risk asymptomatic adults is possible once the variants have been identified, and storing DNA from probands without a molecular diagnosis is recommended [3]. The offspring of a patient with POLR3-related leukodystrophy are obligate heterozygotes [3]. In an undiagnosed leukodystrophy, consanguinity or an affected sibling point to a 25% risk, and, even without these data, it should be explained that the risk may be as high as 25% [83]. In HLD22, inheritance may be AD (de novo stop-loss variants) or AR (homozygous loss of the initiation codon), and counselling depends on the variant type [53].

8.5. TUBB4A-related leukodystrophy and other dominant types

In TUBB4A-related leukodystrophy, most cases are simplex, due to a de novo variant or one inherited from an apparently asymptomatic mosaic parent [5, 70]. DYT-TUBB4A is generally inherited from a parent, affected or not, because of reduced penetrance [5]. Transmission from an affected parent to a child with complicated spastic paraplegia and hypomyelination, and from a mosaic parent to a child with epileptic encephalopathy and hypomyelination, have been described [5]. In a simplex case both parents should be tested, and the variant is considered de novo only if both are negative; leucocytes may not reveal somatic or gonadal mosaicism [5]. Siblings have a 50% risk if a parent is a carrier and a risk slightly above that of the population if the variant is not detected in the parents; recurrence in siblings with an asymptomatic mosaic mother has been described [5, 70]. The offspring of an affected individual have a 50% risk [5]. The same rules apply to the AD types of the series (HLD16, HLD19, HLD24, HLD25 and the dominant form of HLD22) [4].

8.6. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and preimplantation genetic testing are possible in all entities once the familial variant or variants have been identified [1–3, 5, 6]. In the PLP1 spectrum, the result identifies the affected or carrier fetus, but does not predict the phenotype, and views on the use of these tests differ between professionals and families; in most centres the decision is personal [1]. The ideal time for counselling is before pregnancy, and it should be offered to young adults who are affected, heterozygous or at risk [1]. Without a molecular diagnosis there is no carrier detection or prenatal diagnosis, and periodic review of the case (new MRI, new phenotypes, genomic reanalysis) may bring the diagnosis [83].

8.7. Carrier screening

An estimate of the relative frequency of 30 leukodystrophies (55 genes) in more than 49,000 exomes showed a relatively high frequency of disorders previously considered very rare, including POLR3-related leukodystrophy, TUBB4A-related leukodystrophy and PMD; carrier screening laboratories were then testing only 20 of the 55 genes, and the authors proposed extending screening to the AR genes [171]. PMD, which is X-linked, and TUBB4A-related leukodystrophy, almost always de novo, are not captured in the same way by couple screening of AR genes.

8.8. Counselling of minors and family impact

Heterozygosity testing in asymptomatic girls raises the question of benefit in childhood; GeneReviews places the ideal time for reproductive information before pregnancy and recommends offering counselling to young adults [1]. Predictive testing in POLR3-related leukodystrophy is described for at-risk asymptomatic adults [3]. Two international qualitative studies on POLR3-related leukodystrophy, with 24 parents and 9 siblings, described barriers to access, limited knowledge among professionals, parents as experts and advocates, better perceived care in leukodystrophy clinics, caregiver burden, emotional impact on siblings and limited knowledge of the disease among them [172, 173]. Social work support, respite care and home nursing are part of the plan [1, 17].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each estimate measures

Estimates based on the PMD phenotype underestimate the frequency of PLP1-related disorders, because the SPG2 end of the spectrum is not counted, and the Czech figure suggests a higher frequency than recognised [1]. The figure of 0.13 per 100,000 live births for PMD does not appear in the abstract of the German survey and is cited by GeneReviews and Orphanet from the full text [1, 11, 174]. The original Czech study (Seeman 2003) is not indexed in PubMed or Crossref, and the figure enters by attribution from GeneReviews [1]. For PMLD1, POLR3-related leukodystrophy, TUBB4A-related leukodystrophy and HCC there is no published prevalence; case counts are not rates [2, 3, 5, 6].

9.2. Geography, ancestry and founder populations

POLR3-related leukodystrophy shows a distribution by ancestry. TACH was mapped to 10q22.3–23.1 in French-Canadian families, and the POLR3A variant c.2015G>A p.(Gly672Glu) was homozygous in 3 of the 4 TACH families from the same region of Quebec [67]. Except in French Canadians, patients of European origin are more likely to have POLR3B variants, and most had the common variant c.1568T>A on one allele [12]. These observations underpin the ordering of tests by ancestry [3]. Homozygous PI4KA p.(Tyr1623Asp) has only been described in the Amish community [56]. HLD3 was defined in a consanguineous Israeli Bedouin family, with a variant absent in 250 Bedouin controls [47], and the homozygous HYCC1 deletion in a consanguineous Turkish family [6]. NKX6-2-related disease has been described in Northern European, Arab, North African and Asian families [55].

The GLIA-PMD cohort was 65.8% white, 9.0% Asian, 7.2% Black and 3.6% Hispanic, with 60.4% of patients outside the USA; this composition reflects recruitment and not the distribution of the disease [15]. In the US paediatric hospital database (Pediatric Health Information System, PHIS, 2016–2024; 613 patients with 15 leukodystrophies), there were 32 deaths (5.2%), mainly from Krabbe disease, adrenoleukodystrophy, metachromatic leukodystrophy and vanishing white matter disease, without PMD among the main ones; mortality was numerically higher in females and in Black, Asian and multiracial patients, without statistical significance, and lower in hospitals with more admissions [175]. The sources consulted do not provide frequency estimates by country beyond those for the USA, Germany and the Czech Republic [1, 11].

The sources consulted include cases from Portugal and Brazil, without this constituting systematic geographical coverage. In Portugal: a family of Portuguese origin with PMD studied in the USA, with prenatal diagnosis by PCR in amniocytes [72]; a case of HEMS published in 2026 by neuroradiology and paediatric neurology in Porto and Almada with the Centre for Predictive and Preventive Genetics of IBMC (University of Porto) [176]; a 2-year-old girl from Centro Hospitalar Universitário de São João (Porto) with HLD3 due to a novel homozygous AIMP1 variant c.603+1G>A, with skipping of the last 24 nucleotides of exon 5 (p.Val194_Gln201del) demonstrated in cDNA, the first AIMP1 splicing variant described [48]; and the participation of the neuroradiology department of Centro Hospitalar do Porto in the multinational 4H study [12]. In Brazil: the classic PMD case from Brasília (section 10) [37]; a case of PMLD1 due to GJC2 in Santa Maria (Rio Grande do Sul) [46]; a clinical image from Campinas [177]; and the DYT-TUBB4A series with patients and authors from Belo Horizonte and São Paulo [88]. The MRI review of the leukodystrophies published in 2026 by radiologists from Porto Alegre, São Paulo and Campinas uses images of genetically diagnosed Brazilian patients aged 3 to 18 years, including cases of POLR3-related leukodystrophy, without stating the number of patients per entity [97]. In Latin America, the first Colombian family with SPG2 was described in 2026 [73].

9.3. Special populations

Heterozygous females constitute a population of their own, with late manifestations that may be mistaken for other diseases (subsection 3.7) [1, 66]. Adults with SPG2, late forms of POLR3- and TUBB4A-related disease or oculodentodigital dysplasia reach adult neurology without a previous diagnosis [1, 3, 87]. Patients with cognitive impairment and those who are non-verbal require adapted assessment of pain and communication (subsections 7.11 and 7.12) [17].

9.4. Reference networks and patient associations

ERN-RND (European Reference Network on Rare Neurological Diseases) covers the leukodystrophies and provides, on the leukodystrophies page of its Disease Knowledge Hub, centres, standards of care in several languages, diagnostic flowcharts, minimum MRI requirements, the GMFC-MLD scale, a standard operating procedure for nerve conduction studies, patient organisations, trials and registries (https://www.ern-rnd.eu/disease-knowledge-hub/leukodystrophies/) [20]. MetabERN (https://metab.ern-net.eu/) is the network for metabolic diseases, relevant to the metabolic leukodystrophies in the differential diagnosis [178]. The Global Leukodystrophy Initiative (GLIA, https://theglia.org/), founded in 2013, brings together experts and associations [179]. Patient associations include the PMD Foundation (USA; PMD and PMLD, with a family registry, a natural history study and a network of centres; https://www.pmdfoundation.org/), the United Leukodystrophy Foundation (https://ulf.org/), ELA — Association Européenne contre les Leucodystrophies (France, with a list of centres; https://ela-asso.com/; also recommended by the French PNDS on Allan-Herndon-Dudley syndrome, prepared by the reference centre for rare leukodystrophies and leukoencephalopathies of the BRAIN-TEAM network and by the reference centre for intellectual disabilities of rare causes of the DéfiScience network [102]) and the Foundation to Fight H-ABC (https://www.h-abc.org/) [180–183]. GeneReviews also lists Leukodystrophy Australia, the Leukodystrophy Foundation (Canada), the Myelin Disorders Bioregistry Project, the Dystonia Medical Research Foundation, Dystonia Europe and the Dystonia Coalition [1, 3, 5]. In the United Kingdom, the Oxford Desk Reference mentions Climb and Contact a Family [83].

10. Illustrative Clinical Case

The case was published in 2025 by Manzke and colleagues, from the movement disorders clinic of Hospital de Base do Distrito Federal, in Brasília [37]. A 29-year-old Brazilian man had had cervical hypotonia since early childhood, followed by horizontal nystagmus and convergent strabismus; he acquired head control at 9 months and sitting without support at 1 year, never walked without support and developed incomplete speech [37]. He had had dysphagia since age 5 years, ID with attendance at a special school, irritability, aggressiveness and emotional lability, and over the previous 3 years a progressive horizontal head tremor [37]. He was classified as form 3 on the Cailloux scale, which corresponds to classic PMD [37].

On examination he had a small café-au-lait spot on the left thigh, convergent strabismus due to lateral rectus palsy, inconsistent upward vertical gaze, pendular nystagmus, appendicular ataxia and dysdiadochokinesia in all four limbs, marked spastic paraparesis, bilateral Babinski sign and ankle clonus, with normal sensation; vision was subnormal due to optic atrophy and hearing was normal, and video endoscopy of swallowing showed involuntary vocal cord movements [37]. MRI at 1.5 T showed loss of brain volume, atrophy of the corpus callosum and cerebellum and diffuse T2/FLAIR hyperintensity of the periventricular, deep and subcortical white matter, the internal capsules and the corpus callosum, with preservation of signal in most of the brainstem; spectroscopy of the right parietal white matter showed a reduced NAA/creatine ratio and an increased myo-inositol/creatine ratio [37]. Figure 1 of the article (axial T2, FLAIR, sagittal T1 and spectroscopy) is at https://pmc.ncbi.nlm.nih.gov/articles/PMC11704000/figure/Fig1/ [37].

A panel of about 4000 genes (clinical exome with a mean coverage of 104×) identified the hemizygous variant NM_000533.5:c.62C>T, NP_000524.3:p.(Ala21Val), in the first transmembrane domain of PLP1 (residues 12–40), a region where 23 of 31 described variants are pathogenic or likely pathogenic [37]. The variant was confirmed by Sanger sequencing, was absent from gnomAD, ExAC and ABraOM (database of variants in the Brazilian population), had a REVEL score of 0.96 and was classified as likely pathogenic by ACMG/AMP criteria (PM2, PP3 strong, PP2, PM1 and PP4) [37]. It was inherited from the heterozygous mother, who had head and upper limb tremor resembling essential tremor, and was absent in a maternal aunt, a maternal uncle and two maternal cousins [37]. Figure 2 (Sanger electropherogram and alignment of the conserved Ala21) is at https://pmc.ncbi.nlm.nih.gov/articles/PMC11704000/figure/Fig2/ [37]. The article does not describe treatment or subsequent course [37].

The case, assessed at 29 years, illustrates that the molecular diagnosis of classic PMD may come in adulthood, as in the GLIA-PMD cohort, in which age at diagnosis reached 32 years [15]; it also illustrates diagnosis of a point variant by an extensive panel, when the recommended first line in a boy with a typical picture would be dosage analysis followed by sequencing [1]; the classification of a novel missense variant based on ACMG/AMP criteria and segregation; and the possibility of mild manifestations in the heterozygous mother, reported without demonstration of causality [1, 37]. The loss of brain volume and atrophy of the corpus callosum correspond to the pattern of progression described in the MRI series [38, 76].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis in the PLP1 spectrum

Survival depends on the form: in connatal PMD, death occurs from childhood to the 3rd decade, usually from aspiration; in the classic form, between the 3rd and 7th decades; in the null syndrome, between the 5th and 7th decades; in complicated SPG2 and HEMS, between the 4th and 7th decades; and in pure SPG2 life expectancy is normal [1]. These ranges describe patients under supportive care, and with attentive care survival in the connatal form may exceed the 3rd decade [1]. The typical course of PMD is slowly progressive, with a static motor phase in adulthood and late deterioration [83], and MRI shows slowly progressive volume loss, whereas the myelination score increases up to age 12 years [38]. The 2021 review describes, for the hypomyelinating disorders as a whole, slow clinical decline after a long phase of stability [26].

The most useful early predictors come from the GLIA-PMD cohort: stridor at presentation, present in about 18%, defines the profoundly affected subtype, with a feeding tube at around 7–8 months (median 0.8 years) and scoliosis at 9 years; without stridor, absence of head control at 12 months defines the severe subtype; and genotype alone does not predict milestone acquisition [15]. In the French series, forms PMD0–1 had more atrophy and a smaller corpus callosum area than PMD2 and PMD3–4 [38]. Mortality was not estimated in the GLIA-PMD cohort [15], and no life-table survival study has been published in the sources consulted.

11.2. Prognosis in the other entities

In PMLD1, most patients are wheelchair-dependent in the 1st decade and cognition is relatively preserved [2]. In POLR3-related leukodystrophy, the course is invariably progressive; early onset is associated with a greater risk of death in young adulthood, and late-onset forms may survive into the 4th–5th decade [3]. In TUBB4A-related leukodystrophy, sitting without support at 9 months and genotype predict walking at 3 years, carriers of p.Asp249Asn decline faster, and loss of walking with this variant typically occurs after 8–10 years; in the 2014 cohort of 42 patients there were 3 deaths and the oldest living patient was 29 years old [5, 14, 71]. In HCC, most are in a wheelchair between 8 and 9 years and the oldest living patient described was 34 years old [6]. In the severe form of NKX6-2-related disease, death occurs in early childhood [55]. HLD19 and HLD25 have a favourable course, with normalisation or improvement, and HLD14, HLD17, HLD20 and HLD23 are associated with death in childhood or adolescence [4]. Across the leukodystrophies as a whole, one-third of children die from the disease or its complications by age 8 years, according to the GLIA consensus [17].

11.3. Measurement of severity

The scales used in the PLP1 spectrum are the Cailloux scale (forms 0–4) and the Sarret motor scale (PMD0–PMD4) [37, 38]; intervention studies used the Gross Motor Function Measure (GMFM) and the PMD Functional Disability Score (PMD-FDS) [159], and a series of duplications used a 31-point functional disability scale [84]. In TUBB4A-related leukodystrophy, the GMFC-MLD and the Communication Function Classification System (CFCS) are used [14]. ERN-RND provides the GMFC-MLD [20]. The myelin water fraction on quantitative MRI is a potential biomarker [100].

11.4. Surveillance table

In POLR3-related leukodystrophy, GeneReviews does not define surveillance guidelines and recommends individualised monitoring [3]; the annual growth intervals and the ages for pubertal assessment come from the GLIA consensus and are opinion-based [17].

11.5. Palliative care and advance care planning

The GLIA consensus recommends introducing palliative care early, as an approach distinct from end-of-life care, with a written care plan, warning signs, early discussion of respiratory options and preparation of transitions [17]. In severe NKX6-2-related disease, palliative care is part of the team from diagnosis [55], and in PI4KA-related disease with extensive intestinal atresia the Amish newborns were managed with palliative care [56].

12. Summary and Final Considerations

Pelizaeus-Merzbacher disease is the most frequent hypomyelinating leukodystrophy and the reference disorder of the class [1, 60]. It results from variants of PLP1, at Xq22.2, which act through four mechanisms: duplications, the most frequent, through an excess of normal protein; missense variants, through toxicity of the misfolded protein in the endoplasmic reticulum; null variants, through axonal degeneration with little-affected myelin; and variants of exon 3B and intron 3, through imbalance between PLP1 and DM20 [1, 35, 36, 60]. The clinical spectrum is continuous, from the connatal form with stridor and no motor acquisitions to pure SPG2 with normal life expectancy, and heterozygous females manifest mainly in families with mild forms [1, 77]. The estimated prevalence in the USA is 1:200,000 to 1:500,000, Orphanet estimates 0.25 per 100,000 in Europe and the Czech figure of 1:90,000 births suggests underestimation [1, 11].

Diagnosis starts from MRI: hypomyelination is an unchanged pattern of deficient myelin on two MRI scans at least 6 months apart after the 1st year, and the pattern points to the gene [94, 98]. In the boy with early nystagmus, PLP1 dosage analysis precedes sequencing, which must include intron 3; the exome may miss duplications, complex rearrangements, deep intronic variants and enhancer alterations, which require genome or long-read sequencing [1, 65, 66]. MCT8 deficiency must be excluded with T3 and rT3, because it has an approved treatment [92, 107, 108]. The class has 28 types numbered by OMIM as of October 2026, of which POLR3-related leukodystrophy, TUBB4A-related leukodystrophy, PMLD1 and HCC are the most frequent or best characterised, each with clinical clues (teeth, puberty and myopia; dystonia and putaminal atrophy; brainstem involvement; congenital cataract) that guide testing [2–6].

There is no approved disease-modifying therapy. Treatment follows the 2017 GLIA consensus, with a multidisciplinary approach to spasticity, dystonia, feeding, sialorrhoea, bone health, hip and spine, breathing, communication and pain, with off-label drugs and doses extrapolated from cerebral palsy and from the labels, which differ between the USA and Portugal [17, 117, 118]. The anti-PLP1 ASO ION356 is in a phase 1b trial in duplications, personalised ASOs for TUBB4A are in single-patient trials, and the stem cell and curcumin studies have not shown benefit [16, 18, 19, 157, 159]. Counselling depends on the inheritance (X-linked, AR or de novo AD with parental mosaicism), and prenatal diagnosis, possible after identification of the familial variant, does not predict severity in the PLP1 spectrum [1, 3, 5].

13. References

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