Congenital Tetraplegia and Tetraparesis of Genetic Cause – Aetiological Approach

Literature and regulatory information updated: 31 October 2026.

Hereditary congenital spastic tetraplegia (CPSQ and AP-4 deficiency), genetic mimics of cerebral palsy, molybdenum cofactor deficiency and severe neonatal hypotonia of peripheral, spinal or malformative origin: recognition and testing algorithm.

0. Initial Reference Table

Congenital tetraplegia (or tetraparesis, when the motor deficit is partial) is not a disease but a sign that brings together entities with very different mechanisms, prognoses and recurrence risks. The core entities are as follows.

1. Introduction

1.1. Definitions and scope

Tetraplegia refers to loss of motor function in all four limbs; tetraparesis, or quadriparesis, to its partial form. In paediatric practice, the two words apply to two pictures with opposite physiological bases. In the first, the lesion affects the upper motor neuron or the corticospinal tract and spasticity arises, with hypertonia, brisk reflexes, pathological reflexes, clonus and weakness; when all four limbs are involved the term spastic quadriplegia or tetraparesis is used, as opposed to spastic diplegia or paraplegia, in which the lower limbs predominate, and to hemiplegia [22]. In the second, the lesion lies in the lower motor neuron, nerve, neuromuscular junction or muscle, and the neonate presents with flaccid tetraparesis, described in neonatal language as a floppy infant [23]. Between the two lies spinal cord injury, which produces initial flaccidity below the level of the lesion and may evolve into spasticity [21].

The distinction is clinically unstable in the first year of life. Cerebral palsy (CP) is a non-progressive disorder of movement and posture without an ongoing pathological process, but its signs change with brain maturation, and children who later develop spasticity may be very hypotonic in the neonatal period [24]. In hereditary congenital spastic tetraplegia, the Orphanet definition describes precisely this sequence: non-progressive spastic tetraparesis, variable across several members of a family, without factors complicating pregnancy or delivery, with congenital hypotonia, intellectual disability (ID) and developmental delay, and sometimes dysphagia, dysarthria, exotropia, nystagmus, seizures and cerebral atrophy with ventriculomegaly [3].

The sign "congenital tetraplegia/tetraparesis" serves here as the diagnostic starting point. The entities covered are the genetic disorders whose main phenotype is early-onset spastic tetraparesis (the CPSQ group, AP-4 deficiency, HPDL, molybdenum cofactor and sulphite oxidase deficiency, GAD1, COL4A1/COL4A2), the reasoning that separates acquired CP from its genetic mimics, and the algorithm for investigating neonatal flaccid tetraparesis. Spinal muscular atrophy (SMA), congenital myotonic dystrophy, congenital myopathies, myasthenic syndromes, congenital muscular dystrophies, arthrogryposis, later-onset hereditary spastic paraplegias, leukodystrophies, Prader-Willi syndrome and Zellweger spectrum disorders appear only in the differential diagnosis and the algorithm.

1.2. From "acquired" cerebral palsy to genetic forms

For decades, CP was attributed by default to perinatal asphyxia. The Oxford Desk Reference summarises the change: perinatal asphyxia is a major factor in fewer than 5% of cases, birth trauma is not a frequent cause, and the aetiology is unknown in most children [24]. A 2021 exome study recalls that recent studies attribute fewer than 10% of cases to asphyxia [25]. The first solid evidence of genetic risk came from family recurrence studies. Bundey and Griffiths, in 1977, showed that symmetry of spasticity and microcephaly were the main determinants of risk and estimated 9% recurrence for siblings of a child with symmetrical CP and a history of normal delivery, a figure obtained before magnetic resonance imaging (MRI) and which may overestimate current risk (cited by [24]).

The molecular genetics of "hereditary" CP began with consanguineous or multigenerational families. In 2005, Lerer and colleagues described a four-generation family in which nine children had congenital CP with quadriplegia and ID, all born to healthy related parents, and identified a 225 kb deletion at 9p24.3 containing a single gene, ANKRD15, now KANK1; the parent-of-origin-dependent pattern was interpreted as exclusive expression of the paternal allele [26]. In 2009, Verkerk and colleagues studied for more than 20 years a consanguineous sibship with tetraplegic CP, ID, white matter loss and cerebellar atrophy, whose course and imaging resembled hypoxic-ischaemic CP; they found a homozygous splicing variant in AP4M1 and named the entity "congenital spastic tetraplegia", proposing it as a genetic model of hypoxic-ischaemic white matter injury [27]. In 2013, Kruer and colleagues identified the ADD3 variant p.(Gly367Asp) in a consanguineous Jordanian family [28].

1.3. OMIM nomenclature and reclassifications

OMIM created the "cerebral palsy, spastic quadriplegic" (CPSQ) series, starting from a definition of CP as a non-progressive but not unchanging disorder of posture or movement, caused by a brain abnormality and evident during the phase of rapid brain development, in which the spastic form accounts for about 60% of cases [1]. CPSQ1 (603513) was provisionally assigned to GAD1 on the basis of a single family; CPSQ2 (612900) corresponds to the KANK1 deletion inherited on the paternal allele and CPSQ3 (617008) to ADD3 [1, 2]. The four genes of the AP-4 complex initially received the designations CPSQ3 to CPSQ6 and were later reclassified as autosomal recessive spastic paraplegias SPG50 (AP4M1, formerly CPSQ3), SPG51 (AP4E1, formerly CPSQ4), SPG47 (AP4B1, formerly CPSQ5) and SPG52 (AP4S1, formerly CPSQ6) [5, 29]. CPSQ1 underwent the most significant reclassification: when a new branch of the original family was ascertained, the GAD1 variant did not segregate with the disease, and linkage by autozygosity followed by exome sequencing identified the HPDL variant c.527T>C p.(Leu176Pro), which segregated in both branches; the authors concluded that HPDL-related disease can mimic spastic CP and that GAD1 should not be included in hereditary CP panels [30]. OMIM reclassified the former CPSQ1 as "neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities" (NEDSWMA, 619026) and created spastic paraplegia 83 (SPG83, 619027) for the pure juvenile forms, both related to HPDL [7, 8]. GAD1 retains a distinct association, a neonatal-onset developmental epileptic encephalopathy with spastic quadriparesis, described in 2020 [15]. The KANK1 deletion has also been re-evaluated: later reviews concluded that small deletions involving KANK1 are probably benign variants [31].

These reclassifications make the label "genetic CP" ambiguous. For ClinGen and part of the recent literature, "CP" with a monogenic cause is better described as a motor-predominant neurodevelopmental disorder, potentially progressive, and the genetic diagnosis removes from the child the presumption of perinatal injury [4, 32]. Throughout the text, "CP" designates the clinical phenotype, and "genetic cause" the demonstrated aetiology.

2. Molecular Genetics and Pathophysiology

2.1. Mechanisms converging on tetraparesis

The genetic causes of congenital tetraparesis are grouped by anatomical level. In the upper motor neuron, the lesion may be developmental (failure of formation or axonal migration of the corticospinal tract, cortical malformations), early-onset degenerative (retrograde degeneration of corticospinal axons, as in the hereditary spastic paraplegias), toxic-metabolic (sulphite accumulation in molybdenum cofactor deficiency), vascular (porencephaly due to prenatal haemorrhage in the collagen IV disorders) or synaptic (GABA deficiency in GAD1) [15, 16, 33, 34]. Almost all progressive neurometabolic diseases eventually produce some degree of spasticity, and Saudubray includes among those that can begin with isolated spastic paraparesis X-linked adrenoleukodystrophy, homocysteine remethylation defects, biotinidase deficiency, HHH syndrome, arginase deficiency, Segawa disease and defects of phospholipid synthesis and remodelling [22]. In the lower motor neuron and the motor unit, the mechanisms are anterior horn degeneration (5q SMA, SMARD1, X-linked SMA), neuromuscular junction dysfunction and the congenital myopathies and dystrophies [19, 23].

2.2. CPSQ group and HPDL

KANK1 (CPSQ2). KANK1 encodes an adaptor protein with KN domains and ankyrin repeats that links focal adhesions to cortical microtubule-stabilising complexes through talin and KIF21A [4]. In the original family, affected members did not express KANK1 in lymphoblasts, whereas carrier parents with the same deletion had normal expression, and the CpG islands near DMRT1 were hypermethylated in cis with the deletion in the parents [26]. The review by Wallis and colleagues found similar deletions at approximately equal frequency in cases and controls, no excess of neurological disease in carrier parents and, in some carriers, another genetic diagnosis explaining the picture; the authors recommend seeking an alternative explanation when a small KANK1 deletion is found [31]. A laboratory series of 28 carriers of KANK1 copy number variants (CNVs) found mainly autism spectrum disorder and only two cases of CP (according to GeneGuidance) [4].

ADD3 (CPSQ3). ADD3 encodes γ-adducin, the ubiquitous subunit of the adducins, which cap the fast-growing end of actin filaments and promote assembly of the spectrin-actin network [4]. The variant NM_016824.5:c.1100G>A p.(Gly367Asp) lies in the critical oligomerisation region, impairs association with the α subunit and the actin-capping function, and alters fibroblast proliferation and migration; loss of function of the orthologue hts in Drosophila impairs locomotion [28, 35]. The same biallelic variant was found in a 16-year-old boy with spastic diplegia and normal neurometabolic studies, brain and spinal MRI and array [32]. The ClinGen CP expert panel classified the gene-disease relationship as moderate, autosomal recessive (2022); GenCC classifiers range from limited to strong (according to GeneGuidance) [4].

HPDL (formerly CPSQ1). HPDL is a single-exon gene, probably originating by retrotransposition at the base of the tetrapods, that encodes a 371-amino-acid mitochondrial protein similar to 4-hydroxyphenylpyruvate dioxygenase, whose function has not yet been clarified; unlike HPD, it does not alter tyrosine metabolites [30, 36]. Missense variants introduced into the orthologous HPPD impair conversion of 4-hydroxyphenylpyruvate to homogentisate, hpdl knockdown in zebrafish produces abnormal motor behaviour and knockout mice reproduce the disease with cortical apoptosis [10, 36]. Protein levels are reduced in fibroblasts from the most severely affected patients [9]. The variant of the CPSQ1 family is NM_032756.4:c.527T>C p.(Leu176Pro) (rs773333490) [30, 35].

2.3. AP-4 deficiency

The AP-4 adaptor complex is a heterotetramer formed by two large chains (AP4B1 and AP4E1), one medium (AP4M1) and one small (AP4S1); it exports transmembrane proteins, such as ATG9A, from the trans-Golgi network, and its absence retains the cargo and impairs autophagosome formation, according to the review included in a 2026 case report [37]. Biallelic loss-of-function variants in any of the four subunits produce the same clinical picture, with no genotype-phenotype correlation described [5]. The founder variant of Verkerk's congenital spastic tetraplegia, NM_004722.4:c.1137+1G>T in intron 14 of AP4M1, causes skipping of exon 14 and a premature stop codon in exon 15, with truncation of the C-terminal cargo-binding domain; in post-mortem brain, the glutamate receptor GluRδ2 was mislocalised and dendritic spine morphology was abnormal [27, 35]. Heterozygous AP4E1 variants have been described in persistent stuttering, without a motor phenotype [5].

2.4. Molybdenum cofactor deficiency and isolated sulphite oxidase deficiency

Molybdenum cofactor deficiency and isolated sulphite oxidase deficiency (MoCD and ISOD) enter the differential diagnosis. The molybdenum cofactor (MoCo) is synthesised in several steps: MOCS1 converts GTP to cyclic pyranopterin monophosphate (cPMP); molybdopterin synthase, encoded by MOCS2 and reactivated by the sulphurtransferase MOCS3, converts cPMP to molybdopterin; gephyrin (GPHN) adenylates molybdopterin and inserts molybdenum [34]. MoCo is required by sulphite oxidase, aldehyde oxidase, the mitochondrial amidoxime-reducing component and xanthine dehydrogenase. Sulphite accumulation is the probable cause of neurotoxicity and lens dislocation, through breakage of the cystine bridges of the suspensory ligament; xanthine dehydrogenase deficiency raises xanthine and hypoxanthine and lowers urate [34]. Sulphite is converted to thiosulphate and reacts with cysteine to form S-sulphocysteine, and secondary pyridoxal phosphate deficiency may contribute to the disease [34]. Classification by gene has therapeutic consequences: MOCS1 corresponds to type A (about 49% of cases), MOCS2 to type B (about 45%), GPHN to type C (about 4%; with a recurrent deleted region in exons 3–5 of the G domain) and MOCS3 to about 2%, with a mild form only [11]. A MOCS2 allele frequent in the Roma community is associated with a mild phenotype, and a heterozygous GPHN variant appears to have caused epileptic encephalopathy in a man, possibly owing to the role of gephyrin at inhibitory synapses [34]. Isolated sulphite oxidase deficiency results from biallelic variants in SUOX [14, 34]. There are no established genotype-phenotype correlations in MoCD [11].

2.5. GAD1

GAD1 encodes GAD67, a pyridoxal phosphate-dependent enzyme that decarboxylates glutamate to GABA and supplies up to about 90% of basal GABA in the central nervous system [4, 38]. Biallelic loss of function produces a developmental epileptic encephalopathy with an extraneurological component (cleft palate, contractures, omphalocele) that reproduces the Gad1 knockout mouse [15]. Missense variants appear to be less associated with cleft palate and omphalocele (according to GeneGuidance) [4]. There is no biochemical marker of GAD67 deficiency in blood, urine or cerebrospinal fluid (CSF) [38].

2.6. COL4A1 and COL4A2

Pathogenic COL4A1 variants cause cerebral small vessel disease, with porencephaly due to prenatal or perinatal parenchymal haemorrhage, periventricular leukoencephalopathy, microhaemorrhages, lacunar infarcts and calcifications, associated with ocular (congenital cataract, retinal arterial tortuosity, Axenfeld-Rieger anomaly) and systemic abnormalities (haematuria, renal cysts, cramps with raised CK, aneurysms, arrhythmia) [16]. Inheritance is autosomal dominant, with penetrance probably close to 100% and highly variable expressivity within the same family [16]. HANAC syndrome variants cluster in exons 24 and 25, and those associated with more severe cerebral disease are distributed mainly across exons 25 to 51 [16]. COL4A2 causes porencephaly 2 [39]. The GeneReviews chapter dates from 2016 and does not include COL4A2.

2.7. Genes of the neuromuscular branch

In 5q SMA, anterior horn degeneration results from lack of the SMN protein due to homozygous deletion of exon 7 of SMN1 in 94% of typical patients; SMN2 copy number modulates severity, and in type I neuronal death is detectable at 12 weeks of gestation [19]. SMARD1 results from biallelic variants in IGHMBP2 at 11q13.3, a gene that also causes a late-onset axonal neuropathy (CMT2S), and X-linked infantile SMA results from hemizygous variants in UBA1 [4, 18, 40]. The mechanisms of congenital myotonic dystrophy (DMPK CTG expansion, usually above 1000 repeats), myotubular myopathy (MTM1) and fetal akinesia syndromes due to defects of the fetal acetylcholine receptor (CHRNG and others) are specific to each entity [23, 41].

3. Clinical Spectrum and Manifestations by System

3.1. Cerebral palsy as the reference phenotype

CP affects about 1 in 400 births according to the Oxford Desk Reference and about 1 in 500 live births according to the early diagnosis review by Novak and colleagues [24, 42]. It is classified as spastic (hemiplegic, diplegic or quadriplegic), athetoid or dyskinetic (extrapyramidal, dystonic, choreoathetoid) and ataxic [24]. Recognised factors are prematurity (the lower the gestational age, the higher the risk), birth weight below 1500 g, multiple pregnancy, prenatal and postnatal infections and vascular events; CP is more frequent in the first child, from the fifth child onwards and in twins [24]. Seizures occur in 25–30% of children and 10% of adults with CP and may indicate a brain malformation or metabolic disease [24]. In high-income countries, two in three people with CP walk, three in four speak and one in two has normal intelligence [42]. In spastic CP, symmetry of spasticity and microcephaly are the main determinants of genetic risk, which gives the symmetrical quadriplegic form particular weight in aetiological investigation [24].

3.2. Hereditary congenital spastic tetraplegia (CPSQ group)

The original CPSQ2 family had nine children with congenital hypotonia that evolved into spastic tetraplegia in the first year of life, with ID and cerebral atrophy [26, 31]. In CPSQ3, the four siblings of the Jordanian family had a neurodevelopmental disorder with variable spasticity and cognitive impairment: three developed severe spastic tetraplegia in the first months or years, one had spastic diplegia with borderline intellectual function at 7 years, all had borderline microcephaly and poor speech, and MRI showed T2 hyperintensities in all [2, 28]. Goncalves and colleagues (2018) described five further patients from three families with microcephaly, ID, cataracts, partial agenesis of the corpus callosum, refractory epilepsy and skeletal abnormalities (short stature, short metatarsals), and Theunissen and colleagues (2018) a patient with encephalopathy, epilepsy and spastic tetraplegia (according to OMIM) [2]. Sanchez Marco's case began at 4 months as slowly progressive spastic diplegia, with walking at 3 years, Achilles tendon lengthening at 7 and a stiff crouch gait with knee contractures at 16 [2, 32]. Orphanet records 17 reported cases for the entity ORPHA:210141 [4].

3.3. HPDL-related disease

The family of the former CPSQ1 was of Pakistani origin and consanguineous: four siblings presented in childhood with a picture compatible with spastic CP, with moderate to severe ID and spasticity predominantly in the lower limbs (two with mild hypertonia and ataxia of the upper limbs), without seizures; in the follow-up by Morgan and colleagues, with three additional affected members, the disease proved progressive and most became wheelchair-dependent in the second or third decade (according to OMIM) [7]. The spectrum is broad. In the series of Husain and colleagues (17 individuals from 13 families), presentation ranged from severe neonatal-onset delay, with imaging similar to mitochondrial encephalopathy, to isolated spastic paraplegia with onset in adolescence, and all developed spasticity predominantly in the lower limbs [9]; the two most severely affected siblings, of unrelated Algerian parents, had hypotonia and poor feeding from birth and developed spastic tetraparesis, axial dystonia, progressive microcephaly (−5 SD), seizures and contractures, whereas the juvenile forms began between 14 and 15 years with unsteady gait, cramps and myalgia (SPG83) [7, 8]. In the series of Wiessner and colleagues (34 individuals from 25 families), the spectrum ranged from pure juvenile hereditary spastic paraplegia to infantile-onset spastic tetraplegia with global delay, sometimes with episodes of neurological and respiratory decompensation [10]. Ghosh and colleagues described eight families with an infantile neurodegenerative condition with a mitochondrial pattern [36].

3.4. AP-4 deficiency

The GeneReviews synthesis integrates 156 individuals from 101 families and data from a natural history study with 303 individuals from 289 families [5]. Mild global hypotonia in infancy is present in 92% (244/264). Progressive spastic paraparesis typically begins between 4 and 6 years (85%, 256/301); lower limb spasticity is present in 60% (47/78) of children under 4 years and in 96% (216/226) of those aged 4 years or older, begins at the ankles and progresses proximally [5]. Motor delay is almost universal (99%, 277/281), with median ages of 12 months for sitting (interquartile range 9–18), 18 for crawling, 24 for standing unsupported and 25 for walking with support; about 45% (110/243) achieve unsupported walking (median 30 months), an ability that is often lost [5]. Speech is absent or severely impaired in 97% (269/276), microcephaly appears in 67% (73/109), usually between −2 and −3 standard deviations, and about 60% (96/160) have epilepsy; 70% (94/134) have seizures with fever, and status epilepticus occurred in a subgroup [5]. Urinary (81%) and faecal (72%) incontinence, clubfoot or other foot deformities (50%), stereotyped laughter (46%), reduced pain sensitivity (38%), short stature (34%), extrapyramidal signs (28%; dystonia 14%, ataxia 7%), dysphagia in advanced stages (24%, with gastrostomy in 5% of 88) and dysarthria (21%) complete the picture [5]. Upper limb spasticity may appear in adolescence or adulthood, generally less disabling, and the oldest known individual is 55 years old [5]. No pure form has been described [5].

In Verkerk's sibship, initial hypotonia gave way, by the end of the first year, to spasticity of all four limbs with generalised hypertonia, brisk reflexes and Babinski sign, without seizures and with a slowly progressive course over about 20 years [27]. The difference from the current synthesis (in which spasticity is concentrated in the lower limbs and begins later) illustrates the variability of AP-4 deficiency and explains why it was initially classified as tetraplegic CP.

3.5. Molybdenum cofactor deficiency and isolated sulphite oxidase deficiency

In the early-onset form of MoCD, presentation occurs in the first days of life (median 1 day; range 1–50) with severe encephalopathy, refractory seizures, opisthotonus, axial hypotonia with appendicular hypertonia, feeding difficulties and apnoea [11]. Pregnancy and delivery are generally normal, although up to 40% of patients have an Apgar score below 7 at one minute, with improvement at 5 and 10 minutes [11]. The frequencies described are: encephalopathy and delay/ID in 100%, neonatal seizures in 93% (spasms in about 4%), feeding difficulties in 66%, craniofacial dysmorphism in 61% (enophthalmos, prominent cheeks, coarse facies, bitemporal narrowing), appendicular hypertonia in 59%, acquired microcephaly in 45%, axial hypotonia in 41%, lens dislocation in 16% (late) and hyperekplexia in 9% [11]. Over the first months, spastic tetraplegia and extrapyramidal rigidity become established; the brainstem is relatively preserved, and the peripheral nervous system is not affected [11]. Renal xanthine stones may appear later [34]. In late-onset forms, delay, pyramidal or extrapyramidal signs (sometimes sudden after infection), seizures, lens dislocation or a marfanoid habitus appear, with episodic decompensations that may improve after the infection [11, 34].

Isolated sulphite oxidase deficiency reproduces the clinical picture and imaging of MoCD, without renal stones: most patients present in the first 3 days with seizures, poor feeding and axial hypotonia, followed by spasticity (including spastic tetraplegia), microcephaly and severe psychomotor impairment, and death usually occurs in the first months in the classic form [14, 34]. The late-onset form appears between 6 and 18 months with variable lens dislocation, delay or regression, dystonia, choreoathetosis, ataxia and, rarely, acute hemiplegia due to metabolic stroke, with a progressive or episodic course [14].

3.6. GAD1 encephalopathy

In the 11 patients of the founding series, all seizures began in the first 2 months, and in the 10 with early history available in the first month, mainly as epileptic spasms or myoclonic seizures, with burst-suppression, burst attenuation or hypsarrhythmia on the electroencephalogram (EEG); eight had contractures and/or talipes equinovarus, seven cleft palate, two omphalocele, and four died before 4 years [15]. Axial hypotonia coexists with appendicular quadriparesis, spasticity, abnormal eye movements, dystonia and hyperkinesias; imaging shows cerebral and cerebellar atrophy and hypoplasia of the corpus callosum; the oldest patient was 11 years old [38]. A second series assembled six individuals from six families with the same pattern (according to GeneGuidance) [4].

3.7. Collagen IV disorders

COL4A1-related familial porencephaly has been described in more than 50 individuals and manifests as infantile hemiparesis, seizures, ID, dystonia, stroke and migraine, with great intrafamilial heterogeneity; the first manifestation, including intracerebral haemorrhage, may occur in asymptomatic adults, and MRI abnormalities may be clinically silent [16]. Bilateral lesions produce pictures of tetraparesis that, without MRI and ophthalmological examination, are confused with acquired CP [24].

3.8. Neonatal flaccid tetraparesis

In SMA type I, severe weakness and hypotonia begin in the first months; the child never sits, and fatal respiratory failure usually occurs by 2 years and often before 6 months in natural history; one third of mothers report abnormal fetal movements [19]. Type 0 presents at birth with arthrogryposis multiplex congenita and respiratory compromise [19]. The infant with SMA type I lies in a "frog-leg" posture, retains eye movements and small finger movements without large limb movements, has facial involvement but with preserved expression, may have tongue fasciculations and usually has absent reflexes [19]. A study of 33 infants with SMA type I treated conventionally showed that none acquired a major motor milestone, which set the baseline for disease-modifying therapies (cited by [19]).

In SMARD1, the series of Grohmann and colleagues (29 infants) showed that the first signs are intrauterine growth restriction, weak cry and foot deformities, and that most present between 1 and 6 months with respiratory distress due to diaphragmatic paralysis and progressive weakness predominantly distal in the lower limbs, with sensory and autonomic involvement [40]. Respiratory distress from the first day is not typical; in a natural history analysis of 11 cases, loss of spontaneous breathing and weakness set in between 2 and 9 months, all patients needed mechanical ventilation by 9 months and the mean age at death without ventilation was 9 months (data from Eckart and colleagues summarised by Saladini 2020, according to GeneGuidance) [4, 43]. X-linked infantile SMA manifests as congenital hypotonia, areflexia, congenital contractures and/or fractures and progressive ventilatory failure, with normal intellect [18].

Congenital myotonic dystrophy is the most common neuromuscular cause of neonatal hypotonia: pregnancy is often complicated by polyhydramnios, and at birth the neonate is hypotonic, with respiratory problems due to diaphragmatic hypoplasia and need for ventilation, in a mixture of central and peripheral hypotonia [23]. Severe nemaline myopathy and X-linked myotubular myopathy present at birth with generalised weakness and respiratory failure, and myotubular myopathy is usually fatal in the neonatal period in boys, although there are families with a mild phenotype [23]. The congenital muscular dystrophies manifest at birth or in the first 6 months with weakness, hypotonia and progressive contractures, with or without brain malformation [23].

In a 22-year Portuguese series (Coimbra) of 91 hypotonic neonates admitted to intensive care, 46.2% had abnormal prenatal history (polyhydramnios 28.6%, intrauterine growth restriction 21.4%, breech presentation 19.0%), 58.2% required resuscitation at birth, and a final diagnosis was obtained in 64 (70.3%), of whom 81.3% had central hypotonia and 18.7% peripheral hypotonia; mortality was 8.8%, 58.3% in the peripheral group and 1.3% in the central group [44].

3.9. Spinal cord injury at birth and malformations

In a Canadian series of 22 neonates with spinal cord injury diagnosed in life, the lesions were above C4 in 14, between C4 and T4 in 6 and in the thoracolumbar region in 2; all 14 high cervical cases had cephalic presentation and all 6 cervicothoracic cases breech presentation [21]. High cervical injury manifests as flaccid tetraplegia with apnoea, and absence of respiratory movements on the first day with little motor recovery in the first 3 months was associated with permanent ventilator dependence and severe quadriplegia [21]. Malformations of the spinal cord and craniovertebral junction (dysraphism, Klippel-Feil syndrome) and genetic hydrocephalus enter the differential diagnosis.

3.10. Forms with arthrogryposis

Arthrogryposis affects about 1 in 3000 live births and results, in about 90% of cases, from a neurological cause and, in 5–10%, from a muscular cause [41]. About 50% of cases of the arthrogryposis-SMA association are homozygous for SMN deletions, and larger 5q deletions are associated with contractures [41]. Schaaf-Yang syndrome (MAGEL2, paternally expressed 15q11-q13 region) overlaps with Prader-Willi syndrome and is associated, in most cases, with contractures ranging from fetal akinesia to contractures of the small finger joints [23].

4. Clinical Recognition and Warning Signs

4.1. Signs pointing to a genetic cause in a child with "CP"

The Oxford Desk Reference lists the features described in familial cases of CP: microcephaly, marked and symmetrical spasticity, progression of symptoms, seizures, ID, other congenital anomalies, a positive family history and consanguinity, absence of significant perinatal asphyxia and other environmental factors, and dysmorphic features [24]. Children without an abnormal pregnancy, delivery or perinatal period should be investigated exhaustively for metabolic and genetic diseases, and regression is, by definition, incompatible with CP [24]. The history includes birth order, paternal age (associated with athetoid CP in one study), first-trimester haemorrhage and loss of a twin (vascular events), invasive tests, infections and drugs in pregnancy, and serial head circumference [24]. Ichthyosis suggests Sjögren-Larsson syndrome, and cutaneous pigmentary changes suggest chromosomal mosaicism [24].

Genomic yield patterns confirm these signs. In the Moreno-De-Luca laboratory referral cohort, exome yield rose from 11.2% in patients without ID, epilepsy or autism spectrum disorder to 32.9% in those with all three comorbidities [25]. In the Srivastava meta-analysis, the yield was 35% in cryptogenic CP (without risk factors) and 7% in cohorts with known risk factors [45]. The presence of risk factors does not exclude a genetic cause: metabolic or genetic diseases tolerate labour poorly, and hypoxic-ischaemic encephalopathy (HIE) can coexist with them [46].

4.2. Neonate with encephalopathy that looks like HIE

MoCD and sulphite oxidase deficiency are the entities in which diagnostic error has immediate therapeutic consequences. Absence of a perinatal sentinel event and an interval between birth and onset of symptoms distinguish MoCD from neonatal hypoxic-ischaemic injury [11]. Other warning signs are hyperekplexia (excessive startle to noise, touch or movement, with tonic spasms that can cause apnoea without an electrographic seizure), opisthotonus, mild facial dysmorphism and refractoriness of seizures [11]. Babies who are born normal, feed well and then deteriorate are more likely to have a metabolic cause, and organic acidaemias and urea cycle defects typically manifest on the 2nd–3rd day, with the protein load [46]. In neonatal encephalopathy in a neonate of more than 36 weeks, the definition of HIE requires, in addition to abnormal tone, altered wakefulness, weak reflexes and feeding difficulties, at least three of: late decelerations or meconium, delayed onset of breathing, cord arterial pH below 7.1, Apgar score below 7 at 5 minutes and multiorgan failure [46]. The suspicion of HIE should be reassessed if these features and the typical MRI findings are lacking [46].

4.3. Hypotonic infant: central, peripheral or mixed

Central hypotonia is much more frequent than peripheral neuromuscular disease [23]. A peripheral cause is more likely if the baby is alert and responsive and the hypotonia remains stable over hours or days; a central or metabolic cause is more likely if the baby is lethargic, and progression over hours or days suggests a metabolic cause [23]. In central axial hypotonia there is relative sparing of the face and limbs: the baby seems very floppy when held, with marked head lag, but kicks vigorously when supine [23]. Facial involvement is common in congenital myopathies and congenital myotonic dystrophy, but not in SMA; a markedly myopathic face suggests myotonic dystrophy or myotubular myopathy [23]. Respiratory distress soon after birth is rare in SMA type I and common in congenital myotonic dystrophy, severe nemaline myopathy and myotubular myopathy; early diaphragmatic weakness suggests SMARD [23]. Absent reflexes suggest a peripheral cause, but their presence does not exclude SMA, and they may be reduced in Prader-Willi syndrome [23]. Contractures and clubfoot indicate reduced fetal movements; polyhydramnios indicates poor fetal swallowing [23]. The mother should be examined for myotonic dystrophy (facies, sternocleidomastoid weakness, grip myotonia) and myasthenia gravis [23].

The clinical distinction is reliable for central hypotonia and less so for peripheral hypotonia: in the Coimbra series, the positive predictive value of the initial clinical classification was 97.9% for central hypotonia and 66.7% for peripheral hypotonia [44].

4.4. Spinal cord injury and other diagnoses not to be missed

A neonate with flaccid tetraplegia and apnoea after a difficult delivery should prompt consideration of high cervical spinal cord injury, especially with cephalic presentation and extraction manoeuvres; breech presentation is associated with cervicothoracic injury [21]. In a child with spastic paraparesis or tetraparesis without sensory signs, a therapeutic trial of levodopa should be performed to exclude dopa-responsive dystonia, whose response is marked and sustained; in a family without male-to-male transmission, adrenomyeloneuropathy should be considered, and a normal brain MRI does not exclude it [33]. Non-genetic causes of myelopathy (space-occupying lesions, vitamin B12, vitamin E or copper deficiency, syphilis, HTLV-1, HIV) enter the differential at older ages [33].

4.5. Emergency signs

Emergency signs are worsening hypotonia over hours, which requires investigation and consideration of transfer to intensive care [23]; persistent hypoglycaemia, metabolic acidosis and hyperammonaemia [46]; refractory neonatal seizures, in which a pyridoxine trial is justified in all cases of early-onset intractable seizures [46]; and suspected MoCD type A, because treatment must begin within a very short window after the onset of symptoms and, in most successfully treated patients, within the first 24 hours [11, 34]. In SMARD1 and SMA, respiratory compromise determines survival [19, 40]. Newborn screening for SMA and early therapy alter the natural history.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal published criteria for hereditary congenital spastic tetraplegia beyond the Orphanet definition (non-progressive congenital spastic tetraparesis in several members of a family, without pregnancy or delivery factors) [3]. For the monogenic entities in this article, the diagnosis is established by identification of biallelic (AP4B1, AP4E1, AP4M1, AP4S1, MOCS1, MOCS2, GPHN, MOCS3, SUOX, HPDL, GAD1, ADD3), heterozygous (COL4A1, COL4A2) or hemizygous (UBA1) pathogenic or likely pathogenic variants in a patient with a compatible phenotype [5, 11, 14, 16, 18]. In AP-4 deficiency, GeneReviews defines the suggestive findings: infantile hypotonia, postnatal microcephaly, seizures (including febrile), incontinence; on MRI, thinning or absence of the anterior commissure, thin corpus callosum with posterior predominance, reduced periventricular white matter with colpocephaly, global volume reduction and the "grizzly bear ears" sign; less frequently delayed myelination, bilateral perisylvian polymicrogyria, hippocampal malrotation and iron deposition in the globus pallidus and substantia nigra [5]. About half of patients with AP-4 deficiency come from consanguineous families (46%, 142/311) [5].

5.2. Early diagnosis of CP

Before 5 months of corrected age, the most predictive tools for CP risk are MRI at term-equivalent age (sensitivity 86–89%), Prechtl's qualitative assessment of general movements (98%) and the Hammersmith Infant Neurological Examination (HINE; 90%); after 5 months, MRI, HINE and the DAYC scale (C index 83%) [42]. Topography and severity are harder to determine in infancy [42]. MRI is necessary before counselling to assess signs of hypoxic-ischaemic injury and exclude other causes, and its reading requires an expert, because findings vary with gestational age, the severity and duration of the insult and the timing of the examination [24].

5.3. MRI: acquired injury or genetic disease

Suggestive of acute perinatal insult are cerebral oedema, cortical enhancement, focal or global loss of grey-white matter differentiation, abnormal signal in the basal ganglia and thalami (posterior putamen and ventrolateral thalamic nucleus), loss of the normal signal of the posterior limb of the internal capsule, haemorrhages and arterial, parasagittal or watershed infarction [46]. In the first 24 hours MRI may be falsely normal; diffusion changes in the first 5 days, conventional imaging is best between days 5 and 14, and atrophy due to perinatal insult appears only at least 2 weeks after birth, so earlier atrophy suggests a prenatal cause [46]. In a series of 261 term neonates with neonatal encephalopathy referred to tertiary intensive care (not population-based, with referral bias), 80% had acute lesions compatible with hypoxic-ischaemic insult, 16% a normal MRI and the rest other diagnoses, such as agenesis of the corpus callosum in non-ketotic hyperglycinaemia, basal ganglia cysts in mitochondrial disease or cerebellar hypoplasia in Walker-Warburg syndrome; in 90 neonates with seizures in the first 72 hours without encephalopathy, 31% had a metabolic, neurocutaneous, vascular or developmental disease of genetic or congenital origin (study by Cowan and colleagues, 2003, cited by [46]).

In MoCD, acute MRI closely resembles hypoxic-ischaemic injury, with loss of grey-white differentiation, gyral oedema, sulcal injury, diffusely raised T2 and panlobar diffusion restriction in the forebrain and midbrain with relative sparing of the brainstem; spectroscopy shows a lactate doublet and a glutamine-glutamate peak [11]. Within weeks, severe cortical atrophy, cystic leukomalacia and basal ganglia degeneration appear, and, unlike hypoxic-ischaemic injury, diffusion restriction persists in the remaining parenchyma in the chronic phase [11]. Favouring MoCD are mega cisterna magna or Dandy-Walker malformation, a hypoplastic or atrophic corpus callosum or cerebellum and evidence of prenatal degeneration already present at birth; their absence does not exclude the diagnosis [11]. COL4A1 porencephaly has findings that overlap with those of HIE [24].

5.4. Biochemical and ophthalmological investigation

In the child with CP, the Oxford Desk Reference list includes ophthalmological examination (lens dislocation in molybdenum cofactor deficiency; retinal arterial tortuosity and cataract in COL4A1), creatine kinase (CK, for muscle-eye-brain disease), plasma urate, free thyroxine, free triiodothyronine and TSH, urinary amino acids and organic acids, sulphite in fresh and frozen urine, purine metabolites, testing for microscopic haematuria (COL4A1), thrombophilia study and factor V Leiden if the CP resulted from perinatal stroke and, if relevant, maternal lupus and phenylketonuria [24]. Organic acidaemias can present as spastic diplegia [24].

In the neonate with encephalopathy, second-line investigation includes ammonia, plasma and urinary amino acids, organic acids, dried blood spot acylcarnitines, the dinitrophenylhydrazine test for α-keto acids (maple syrup urine disease), sulphite test, ketone bodies with lactate and pyruvate, CSF glycine and lactate (CSF lactate may be raised after asphyxia and seizures), and, if there are dysmorphic features or seizures, biotinidase, very long-chain fatty acids (VLCFA), transferrin isoelectric focusing, cholesterol and 7-dehydrocholesterol, lysosomal enzymes, CSF pipecolate and urinary α-aminoadipic semialdehyde, CSF pyridoxal phosphate and a pyridoxine trial [46]. The tests that discriminate the metabolic diseases most relevant to neonatal spastic tetraparesis are as follows.

The urinary sulphite dipstick test is unreliable because urine rarely reaches the laboratory fresh; quantitative sulphite requires plasma or urine frozen at −80 °C within about 30 minutes, and S-sulphocysteine is the stable biomarker [34]. None of the metabolites is on its own specific for MoCD, and the diagnosis must be confirmed [11].

5.5. Neuromuscular tests

In hypotonia of peripheral appearance, CK is raised in most congenital muscular dystrophies and normal or slightly raised in SMA and the congenital myopathies; electromyography (EMG) and nerve conduction studies show fibrillation in SMA, and a myopathic pattern leads to muscle biopsy with histology and immunohistochemistry; echocardiography excludes cardiomyopathy (Pompe disease) [23]. In hypotonia of central appearance, CK should be normal; if it is raised, a congenital muscular dystrophy with brain involvement, with mixed hypotonia, should be considered [23]. The first genetic test when SMA is suspected is SMN1 and SMN2 dosage (exon 7 deletion); if normal, next-generation sequencing follows, and X-linked SMA should be considered in boys with an SMA picture, normal SMN MLPA and compatible inheritance [19, 41]. The DMPK CTG expansion is tested mainly when there is a myopathic face and a suggestive mother; rarely the mother appears normal [23]. SNRPN methylation (Prader-Willi syndrome) is tested in central hypotonia with poor suck without another cause [23].

5.6. Genomic strategy

Genomic array was indicated, in the Oxford Desk Reference (2017), in all children with CP with any atypical sign, except in uncomplicated CP without ID and with typical MRI, followed by a panel, exome or genome [24]. Subsequent evidence shifts the first test to sequencing. In the laboratory referral cohort (1345 patients, median 8.8 years), the yield of exome sequencing with CNV detection was 32.7% (95% CI 30.2–35.2), and in a predominantly adult health system cohort (181 patients) 10.5% (6.0–15.0); pathogenic variants were found in 229 genes [25]. Meta-analyses estimated yields of 23% (95% CI 15–34) for exome and 5% (2–12) for array [45], and 31.1% (24.2–38.6) for exome or genome, with 34.8% in paediatric cohorts and 42.1% when there were criteria excluding acquired causes [48]. In a Canadian trio genome study in 327 children with CP, 11.3% had pathogenic or likely pathogenic variants (SNVs/indels 6.7%, CNVs 3.4%, mitochondrial 1.5%) and 17.7% variants of uncertain significance (VUS); COL4A1 was the gene with the most pathogenic variants [17]. The authors of these studies propose sequencing as part of first-line investigation: exome followed by array in cryptogenic CP [45], inclusion of CP in the recommendation of first-line exome for neurodevelopmental disorders [48] and genome in all CP and related phenotypes [17]. The American College of Medical Genetics and Genomics (ACMG) guideline strongly recommends considering exome or genome as a first- or second-tier test in children with congenital anomalies with onset before 1 year or with developmental delay or ID, but does not explicitly mention CP [48, 49].

In the hypotonic neonate in intensive care, an international study of 147 infants with unexplained hypotonia obtained a molecular diagnosis in 72 of the 121 (60%) who underwent rapid exome or genome sequencing, with no significant difference between isolated (66%) and multisystem (54%) hypotonia; two additional diagnoses required mitochondrial genome sequencing after a negative exome, and a short repeat expansion missed by the genome was found by targeted testing [50]. The diagnosis changed management in 57 of 66 diagnosed infants [50].

5.7. Limits of the tests and content of the report

A negative exome does not exclude a genetic cause. Exome sequencing detects missense, nonsense, splicing and small indel variants, but usually does not detect deletions or duplications of whole exons [11]. Repeat expansions (DMPK) and the SMN1 exon 7 deletion, which requires distinguishing SMN1 from SMN2, require targeted tests; genome sequencing may miss expansions, and the mitochondrial genome may not be covered by the exome [19, 50]. In the spastic paraplegias, a significant proportion of SPAST variants are exon deletions that require MLPA [33]. In MoCD, sequencing detects more than 95% of described variants, and the detection rate of targeted deletion/duplication analysis is unknown [11]. The proportion of variants detectable by a method is not the clinical sensitivity of the test. CPSQ2 illustrates the risk of interpreting a rare CNV as causal: small KANK1 deletions are probably benign [31]. The CPSQ1 case illustrates the risk of accepting a candidate variant in a single family without complete segregation [30].

The report should state the gene, the reference transcript with version (for example, AP4M1 NM_004722.4, ADD3 NM_016824.5, HPDL NM_032756.4), the HGVS c. and p. nomenclature, zygosity, the ACMG/AMP classification and, in recessive forms, confirmation of phase (parental testing) [11, 35]. Biallelic VUS, or one pathogenic variant with one VUS, neither establish nor exclude the diagnosis [11].

5.8. Algorithm

The step-by-step investigation sequence is as follows.

6. Differential Diagnosis

The differential is organised along three axes: genetic mimics of spastic CP, disorders with neonatal flaccid tetraparesis, and structural or acquired causes.

Three differentials require comment. The first is the separation between HIE and MoCD, because treatment of type A is time-dependent and because up to 40% of patients with MoCD have a low Apgar score at one minute [11]; the combination of low urate, very low total homocysteine and raised S-sulphocysteine should be requested in all neonates with "hypoxic-ischaemic" encephalopathy without a sentinel event or with a symptom-free interval [11, 34]. Therapeutic hypothermia, the standard of care in HIE, has no demonstrated benefit or harm in non-hypoxic-ischaemic causes, and the Oxford Desk Reference considers it reasonable to rewarm before 72 hours when the diagnosis of HIE has been excluded [46].

The second is the separation between "static" spastic CP and early-onset complex hereditary spastic paraplegias. AP-4 deficiency was initially classified as tetraplegic CP [27], HPDL-related disease mimics spastic CP [30] and ADD3 presented as spastic diplegia with normal imaging [32]. Progression, postnatal microcephaly, febrile seizures and the MRI findings described in AP-4 deficiency are the most useful clues [5].

The third is the overlap between central and peripheral hypotonia. Congenital myotonic dystrophy combines both, congenital muscular dystrophies with brain involvement produce mixed hypotonia with raised CK, and the forms with arthrogryposis (SMA type 0, X-linked SMA, Schaaf-Yang syndrome) require simultaneous consideration of the anterior horn and the central nervous system [23, 41]. Non-genetic causes of myelopathy (compression, vitamin and copper deficiencies, infections) and primary lateral sclerosis are differentials of spastic paraparesis at older ages [33].

7. Treatments and Risk Management Strategies

7.1. Principles

For most entities in this article, treatment is supportive and multidisciplinary, with paediatric neurology, orthopaedics and physical and rehabilitation medicine, physiotherapy, occupational therapy, developmental paediatrics, speech and language therapy and clinical genetics [5]. Children with CP should be followed by a multidisciplinary neurodevelopmental team [24], and early diagnosis should lead to immediate referral for specific early intervention, to exploit motor and cognitive plasticity, prevent secondary complications and support carers [42]. Physiotherapy seeks to maximise function and prevent contractures, and antispasticity drugs may benefit some patients under neurological supervision [33]. In arthrogryposis, passive stretching is useful in most forms and surgery complements it in many children with amyoplasia [41].

The genetic diagnosis has therapeutic consequences in a subgroup. In a systematic review with Delphi consensus on 1841 sequenced patients with CP, 27% had pathogenic or likely pathogenic variants related to the phenotype and 8% (140) had an actionable aetiology, that is, one that changed clinical management; of the 243 genes, 58 had actionable options (16 directed at the primary mechanism, 16 with specific prevention strategies and 26 with specific symptomatic treatment), although 45 of 101 interventions had class D evidence or lower by ClinGen criteria [55]. In the hypotonic neonate, the molecular diagnosis changed management in 57 of 66 diagnosed infants, compared with 14 of 33 without a diagnosis [50].

7.2. Treatments that depend on the diagnosis

The situations in which a rapid diagnosis changes treatment are: MoCD type A (fosdenopterin), pyridoxine-, pyridoxal phosphate- and folinic acid-dependent seizures, biotinidase and holocarboxylase synthetase deficiency (biotin), congenital hypomagnesaemia (magnesium) [46], dopa-responsive dystonia (levodopa) [24, 33] and 5q SMA (disease-modifying therapies). In Brown-Vialetto-Van Laere syndrome, a differential of SMA type 0 due to variants in the riboflavin transporters SLC52A3 and SLC52A2, there may be a partial response to riboflavin [19]. Doses and regimens of pyridoxine, pyridoxal phosphate, biotin and levodopa follow the recommendations for pyridoxine-dependent epilepsies, biotinidase and holocarboxylase synthetase deficiencies and dopa-responsive dystonia.

7.3. Molybdenum cofactor deficiency type A: fosdenopterin

Fosdenopterin (NULIBRY® in the USA, the EU and Portugal) is a synthetic form of cPMP, the product that MOCS1 cannot form; its administration allows the subsequent steps of cofactor synthesis to proceed and reactivates sulphite oxidase, reducing sulphite accumulation [11, 13]. It has no effect in types B and C or in the MOCS3-related form, in which the block is downstream [11, 34]. The FDA label states that the drug should be started on a diagnosis or presumptive diagnosis of MoCD type A, that the diagnosis should be confirmed immediately after initiation and that it should be discontinued if genetic testing does not confirm type A [12]. GeneReviews emphasises that maximum benefit requires initiation within a very short window after the manifestations [11], and Saudubray indicates that, to avoid irreversible damage, treatment generally has to begin within the first 24 hours of life [34].

The dosage is that of the label, because there is no guideline with a different dose; GeneReviews refers to weight and age without setting values [11]. Presentation: vial of lyophilised powder containing 9.5 mg, reconstituted with 5 mL of water for injections (1.9 mg/mL), stored frozen and warmed to room temperature before reconstitution, without shaking [12].

The FDA label sets 0.9 mg/kg/day as the maximum recommended human dose, for all ages; in study 1 the dose was titrated over 5 months up to 0.9 mg/kg once daily, and in study 2 one patient received up to 0.98 mg/kg once daily (1.1 times the maximum approved dose) [12].

The dose is calculated on actual body weight and given by intravenous infusion once daily; for volumes below 2 mL a slow intravenous bolus with a syringe may be used [12]. A missed dose is given as soon as possible, with the next dose at least 6 hours later [12]. Home administration by the carer is possible if the physician considers it appropriate, through a long-term venous catheter [11, 12]. Treatment is lifelong when type A is genetically confirmed, and should be initiated and supervised by a physician experienced in inherited metabolic diseases [13].

In studies 1 and 2 (9 patients, median exposure 4.3 years), the most frequent adverse reactions were catheter complications (89%), fever (78%), viral infection (56%), pneumonia, otitis media, vomiting and cough or sneezing (44% each) and viral upper respiratory tract infection (33%) [12]. Fosdenopterin has phototoxic potential in animal studies: exposure to direct sunlight and artificial ultraviolet light, including UVA or UVB phototherapy, should be avoided or reduced, with protective clothing, a hat, broad-spectrum high-protection sunscreen from 6 months of age and sunglasses; in the event of photosensitivity, the patient should seek medical care and dermatological assessment [11, 12].

7.4. Other measures in MoCD and sulphite oxidase deficiency

In all MoCD subtypes, GeneReviews describes a cysteine-restricted diet, achieved by a low-protein diet with restriction of natural protein (for example, 1.75 g/kg/day of protein in the neonate, gradually reduced with age, and a protein-free formula), with monitoring of essential amino acids; the evidence is limited, and in severe forms the diet may reduce irritability without altering the course, whereas in mild forms it may favour development and reduce decompensations [11, 34]. Thiamine is supplemented in case of deficiency (1.2 mg/day in infants; from 50 mg once daily to 100 mg twice daily in children and adolescents), and headaches are treated with magnesium and usual migraine prophylaxis [11]. Valproate should be avoided whenever possible, because sulphite intoxication impairs mitochondrial function in vitro [11]. There is no effective treatment for severe types B and C [34]. In isolated sulphite oxidase deficiency there is no treatment for the metabolic defect; treatment includes antiseizure medications, antispasticity drugs, early gastrostomy for swallowing safety and caloric intake, and chest physiotherapy; a diet low in cysteine and methionine may help in mild forms [14, 34].

7.5. AP-4 deficiency, HPDL, GAD1 and the CPSQ group

In AP-4 deficiency, treatment is multidisciplinary and symptomatic: spasticity, contractures and foot deformities, epilepsy (usually controlled with standard antiseizure medications, except when there is polymicrogyria), bladder and bowel dysfunction, dysphagia, communication and behaviour [5]. In GAD1 encephalopathy there is no targeted therapy; patients often need several antiseizure medications, and five of seven responded well to vigabatrin, especially those with epileptic spasms [38]. A review that pooled the published cases found no drug common to the controlled patients, and pyridoxine is not an established treatment, because the disease is not a pyridoxine-dependent epilepsy (according to GeneGuidance) [4]. Cleft palate, contractures and talipes equinovarus are treated surgically according to the usual indications [4]. For HPDL, KANK1 and ADD3 there is no targeted treatment in the sources consulted.

7.6. COL4A1 and COL4A2

Treatment is supportive, and arterial hypertension should be treated to reduce the overall risk of stroke [16]. Smoking, sustained head pressure during delivery, activities with a risk of head trauma and anticoagulants should be avoided [16]. Caesarean section is recommended in pregnancies in which the fetus is at risk, to prevent cerebrovascular injury from birth trauma (a recommendation based on an experimental study cited by GeneReviews) [16].

7.7. Neuromuscular branch and spinal cord injury

The therapies for 5q SMA, congenital myotonic dystrophy, congenital myopathies and dystrophies and myasthenic syndromes are specific to each entity. In SMARD1 there is no approved disease-modifying treatment; the mainstay of management is permanent supportive mechanical ventilation after diaphragmatic paralysis, and gene therapy has preclinical results [4, 43]. In X-linked SMA, management includes caloric supplementation or gastrostomy, management of constipation, rigorous airway clearance and secretion management techniques, ideally non-invasive ventilation (tracheostomy with permanent ventilation may be considered), advance discussion with the family of a do-not-resuscitate decision, orthopaedics and physiotherapy for contractures and scoliosis, and treatment of gastro-oesophageal reflux [18]. In spinal cord injury at birth, ventilation and rehabilitation depend on the level and on respiratory and motor recovery in the first months [21].

7.8. Regulatory status

7.9. Trials and evidence

The fosdenopterin data come from open-label, single-arm studies with comparison to historical controls; the confidence interval for survival of treated patients is wide, and improved survival does not equate to normal development. The EPAR states that early treatment, before extensive brain injury, preserves oral feeding and improves growth and motor and cognitive development (according to GeneGuidance, which summarises the EPAR) [4]; Saudubray describes type A patients without seizures and with almost normal development after more than 6 years [34]. The reduction in urinary S-sulphocysteine is maintained with prolonged treatment: from 89.8 µmol/mmol creatinine in one patient before treatment to means of 11 (±8.5) to 7 (±2.4) µmol/mmol between months 3 and 48 [12]. The gene therapy data in AP-4 deficiency are from a single uncontrolled patient.

7.10. Developments in the last 12 months

Between November 2025 and October 2026, the changes identified in the sources consulted were: FDA approval of a labelling change for fosdenopterin on 26/05/2026, with no change of indication or dose in the text read [12]; the Melpida trial remaining in recruitment, with last update in 07/2026 and no published results [6]; and the publication of new reports of AP-4 variants, such as an AP4M1 frameshift variant in an Iranian case [37]. The GeneReviews chapter on AP-4 deficiency was updated in February 2025, with data from the registry of 311 individuals and information on expanded access to gene therapy in Canada and Spain [5]. The search found no clinical trials with results for HPDL, GAD1, KANK1 or ADD3, which does not prove that none exist.

7.11. Special populations

Pregnancy and delivery. In families with COL4A1, caesarean section is recommended for the at-risk fetus [16]. Women with SMA type II have had successful pregnancies, with stable lung function during pregnancy and transient deterioration after delivery [19]. Anaesthesia. In primary muscle disease, anaesthesia requires caution, and there is a form of multiple pterygium with malignant hyperthermia [41]. Newborn siblings at risk of MoCD without prenatal diagnosis should start metabolic treatment at birth, maintained until the diagnosis is excluded by molecular testing or, if the variants are not known, by serum uric acid and urinary sulphite, S-sulphocysteine, xanthine, hypoxanthine and uric acid [11]. Transition. In AP-4 deficiency, upper limb spasticity may appear in adolescence and dysphagia in advanced stages, which requires continuity between paediatric and adult teams [5].

8. Reproductive Options and Family Counselling

8.1. With a molecular diagnosis

With an established diagnosis, counselling follows the inheritance of the entity. In the autosomal recessive forms (AP-4 deficiency, MoCD, sulphite oxidase deficiency, HPDL, GAD1, ADD3, 5q SMA, SMARD1), each sibling of an affected individual has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier, and the parents are obligate heterozygotes with no risk of disease [5, 11, 14]. In 5q SMA, about 1.7% of patients have a de novo deletion, so parental testing is necessary; the carrier frequency is about 1 in 50, and the existence of alleles with two copies of SMN1 on one chromosome ("2+0") complicates carrier detection by dosage: with two copies, the residual risk of being a carrier falls to about 1 in 820 in a person without a family history and from 2/3 to 1/13 in an unaffected sibling [19]. In the collagen IV disorders (autosomal dominant), each child of a carrier has a 50% risk; at least 50% of probands have an affected parent and at least 27% result from a de novo variant, so parental assessment includes variant testing, brain MRI and ophthalmological examination [16]. In X-linked SMA, a heterozygous woman transmits the variant in 50% of pregnancies; boys who inherit it are affected and girls are usually unaffected carriers [18]. In the single family with a KANK1 deletion, the disease affected only the children of carrier men [26], but the current interpretation is that small KANK1 deletions are not causal in general [31].

With the variants known, carrier testing in relatives, prenatal diagnosis and preimplantation genetic diagnosis are possible [5, 11, 14]. In SMA, chorionic villus sampling can be performed at 11 weeks if the familial molecular basis is known, with prior genotyping of both parents [19]. In MoCD, sulphite oxidase activity can be measured in chorionic villi, although molecular diagnosis is the usual method [34, 46]. Predictive testing for adult-onset spastic paraplegias is reserved for adults able to participate fully in the decision [33].

8.2. Without a molecular diagnosis: empirical risks

In CP without a diagnosis, the available figures are empirical and predate the genomic era. If there is consanguinity, or two affected children, a recurrence risk of 25% for siblings may be given [24]. For symmetrical spastic CP with a history of normal delivery, the 1977 study estimated 9% for siblings, a figure that may overestimate current risk because it was obtained before MRI [24]. In athetoid CP, the risks described range from 1% (Amor and colleagues, 2001) to 10%, and many geneticists consider 1% too low; in ataxic CP, most authors counsel up to 10%, and high-resolution MRI is mandatory before counselling [24]. In CP with dysmorphic features without a diagnosis, in the absence of high-risk factors, a risk of about 5% for siblings of a female proband and 5–10% for siblings of a male proband is considered reasonable [24]. In neonatal encephalopathy without a diagnosis, genetic disease with a recurrence risk of up to 25% should be considered, and if HIE is certain the risk is low, with management of the next pregnancy guided by fetal medicine [46]. In arthrogryposis with central nervous system involvement, many cases are autosomal recessive, with a risk of 10–15% after one affected child, and classic amyoplasia has no appreciable recurrence risk [41].

Without an identified cause, carrier detection and prenatal diagnosis are not possible [24]. In arthrogryposis, prenatal diagnosis by real-time ultrasound of fetal movement can be made with scans at 16, 20, 24 and 32 weeks, discussing the limits of ultrasound with the family [41]. In lethal forms without a diagnosis, autopsy with neuropathology, muscle biopsy and DNA banking give the best chance of a specific diagnosis; in the neonate who will probably not survive, storage of DNA, blood on filter paper, frozen plasma, urine and CSF, a skin biopsy for fibroblast culture, muscle and liver biopsies frozen at −70 °C, photographs and radiographs is recommended [41, 46].

8.3. Particular points

In autosomal dominant spastic paraplegias, 10–20% of carriers are asymptomatic, so the risk of symptomatic disease in the children of a carrier is 40–45%, and the parents of apparently sporadic cases should be examined [33]. In newborn siblings of a child with MoCD without prenatal diagnosis, metabolic treatment begins at birth and continues until the diagnosis is excluded, which makes testing of the neonate an urgent diagnostic test [11]. Predictive testing for adult-onset forms, such as dominant spastic paraplegias, is restricted to adults [33].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Cerebral palsy

A systematic analysis of CP registers and population studies from 41 regions in 27 countries across five continents (births since 1995) showed a significant decrease in the birth prevalence of CP of prenatal or perinatal origin in Europe and Australia (11 of 14 regions), with no change in post-neonatal CP; in high-income countries, the estimated birth prevalence for those born since 2010 was 1.5 per 1000 live births (95% CI 1.4–1.6) for pre/perinatal CP and 1.6 per 1000 (1.5–1.7) including post-neonatal CP, and in regions of low- or middle-income countries it reached 3.4 per 1000 (3.0–3.9) for pre/perinatal CP [59]. The older figures of 1 in 400 births [24] and 1 in 500 live births [42] reflect different periods and methods. These estimates measure CP of all causes; the monogenic fraction depends on the cohort, between 10.5% in a predominantly adult health system cohort and 32.7% in a paediatric laboratory referral cohort [25], and should not be applied as a population prevalence of genetic disease.

9.2. Rare entities

Hereditary congenital spastic tetraplegia (ORPHA:210141) has a prevalence below 1 per 1,000,000, with 17 reported cases [3, 4]. AP-4 deficiency counts more than 300 known individuals, with families in North and South America, Europe, the Middle East, China and the Indian subcontinent; consanguinity is 46% in the current registry, lower than the initial proportions, which reflected ascertainment bias in populations with high consanguinity [5]. The global incidence of MoCD is estimated at between 1:100,000 and 1:200,000 live births, probably underdiagnosed; the MOCS2 allele frequent in the Roma community is associated with a mild phenotype [11, 34]. Isolated sulphite oxidase deficiency has about 50 patients described, possibly with a higher incidence in populations with high consanguinity [14]. For COL4A1 disorders there is no established prevalence; variants have been described in people of Dutch, Italian, French, German, American, Chinese, Spanish and Japanese origin [16]. SMA has a birth incidence of about 1 in 10,000 and a carrier frequency of about 1 in 50 [19]; SMARD1 has a prevalence below 1 per 1,000,000, with 128 cases or families registered in Orphanet [4, 20]; X-linked SMA counts 14 multigenerational families in North America, Europe, Mexico and Thailand [18]. Non-ketotic hyperglycinaemia, a differential of neonatal encephalopathy, has an incidence of 1/50,000 to 1/100,000, higher in Finland owing to a founder effect [46].

9.3. Portugal and Brazil

The Coimbra series of 91 hypotonic neonates in intensive care (22 years) is the only Portuguese datum identified in the sources consulted and shows a predominance of central hypotonia (81.3% of those diagnosed) and a mortality of 58.3% in peripheral hypotonia [44]. In Portugal, fosdenopterin has a marketing authorisation, with exclusively hospital dispensing, but no registered presentation or price [56]; in Brazil it has no ANVISA registration [57]. The sources consulted do not describe Brazilian data on genetic CP, MoCD or AP-4 deficiency.

9.4. European networks and associations

The European Reference Network for rare neurological diseases (ERN-RND, https://www.ern-rnd.eu) covers the hereditary spastic paraplegias, ataxias and leukodystrophies; EURO-NMD (https://ern-euro-nmd.eu) covers neuromuscular diseases; MetabERN (https://metab.ern-net.eu) covers inherited metabolic diseases, including MoCD. Associations: Scope (United Kingdom, https://www.scope.org.uk) and the Cerebral Palsy Foundation (USA, https://yourcpf.org), listed by the Oxford Desk Reference [24]; Associação Portuguesa de Paralisia Cerebral (https://www.appc.pt); Climb for metabolic diseases in the United Kingdom (https://www.climb.org.uk) [46]; The Arthrogryposis Group and AMC Support for arthrogryposis [41]; SMA Support UK for SMA [19]. The registry and natural history study of early-onset spastic paraplegias (NCT04712812, Boston Children's Hospital) recruits up to 30 years of age, with 700 estimated participants [60].

10. Illustrative Clinical Case

10.1. Congenital spastic tetraplegia in a consanguineous sibship, interpreted for years as CP

Verkerk and colleagues described five siblings (two girls and three boys) from a sibship of eleven, children of consanguineous parents of Moroccan origin, followed for about 20 years [27]. All had hypotonia in infancy, psychomotor delay, strabismus and severe ID (full-scale IQ of about 20); by the end of the first year, progressive spasticity of all four limbs set in, with generalised hypertonia, brisk reflexes and Babinski sign. None achieved independent walking; speech was absent or limited to dysarthric monosyllables; there were pseudobulbar signs (drooling, stereotyped laughter, exaggerated jaw jerk), absence of sphincter control and no seizures. The course was slowly progressive, with little or no regression [27].

The individual details show the resemblance to acquired CP. One of the boys, a dizygotic twin, was born at 38 weeks hypotonic, with a low Apgar score and clubfeet, had a diaphragmatic hernia and reflux and died at 17 months from aspiration pneumonia after fundoplication; at autopsy, the brain weighed 750 g (normal for age about 1050 g), with enlarged ventricles, a very thin corpus callosum, an atrophic pons, neuronal loss in the dentate nucleus and reduced myelin with gliosis, without active demyelination [27]. The twin had shown, on the 20-week ultrasound, ventriculomegaly and an occipital porencephalic cystic change; he was born with a normal Apgar score and head circumference at −2 standard deviations, stood with support at 7 years and lost this ability, and at 21 years spoke only monosyllables [27]. On MRI, the white matter was reduced but with normal T2 signal, the lateral ventricles enlarged with occipital predominance, the corpus callosum thin and the cerebellum atrophic to a variable degree, with little change between 13 and 21 years [27]. Four of the five also had arterial tortuosity syndrome due to an independent homozygous SLC2A10 variant.

Homozygosity mapping identified a single region at 7q22 (maximum LOD 4.35), and expression analysis selected AP4M1 among 203 genes. The five affected members were homozygous for NM_004722.4:c.1137+1G>T, which causes skipping of exon 14 and C-terminal truncation; the parents and four unaffected siblings were heterozygous, and the variant was absent in 224 Moroccan controls [27, 35]. The imaging is in figure 2 of the article (MRI, MR angiography and diffusion tractography; https://pmc.ncbi.nlm.nih.gov/articles/PMC2706965/figure/fig2/), the pedigree in figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC2706965/figure/fig1/) and the molecular analysis in figure 3 (https://pmc.ncbi.nlm.nih.gov/articles/PMC2706965/figure/fig3/).

The case illustrates three points of this article. The combination of consanguinity, affected siblings of both sexes, symmetry of spasticity and microcephaly corresponds to the warning signs of genetic CP [24]. The presence of a perinatal factor (low Apgar score in one of the twins) and of a prenatal lesion resembling porencephaly did not exclude the monogenic cause. And the entity, described as "congenital spastic tetraplegia", is now classified as SPG50, a form of AP-4 deficiency whose recent natural history shows predominance of spasticity in the lower limbs and epilepsy in about 60% [5], unlike the absence of seizures in this sibship. The management in the report (orthopaedic surgery, fundoplication) was individual and does not constitute a protocol.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

In CP, in high-income countries, two in three people walk, three in four speak and one in two has normal intelligence, figures that include all topographical forms [42]. In AP-4 deficiency, about 45% achieve unsupported walking, often with later loss, most communicate without verbal language and the oldest known individual is 55 years old [5]. In untreated early-onset MoCD, about 75% die in childhood from complications of neurological disability, mainly pneumonia [11]; in the genotype-matched type A natural history cohort, survival was 67% at 1 year and 55% at 3 years, compared with 92% and 84% in patients treated with fosdenopterin or rcPMP [12]. In the classic form of isolated sulphite oxidase deficiency, death usually occurs in the first months [14]. In GAD1 encephalopathy, four of eleven patients died before 4 years [15]. In SMA type I without disease-modifying therapy, fatal respiratory failure usually occurred by 2 years [19]; the prognosis has improved with disease-modifying therapies. In SMARD1 without ventilation, the mean age at death is 9 months [4]. In high cervical spinal cord injury at birth, respiratory movements on the first day were associated with mild disability, and their absence with little motor recovery in the first 3 months with permanent ventilator dependence and severe quadriplegia [21]. In COL4A1-related disease, the first haemorrhage may occur in adulthood in asymptomatic carriers [16]. In neonatal hypotonia, mortality in the Coimbra series was 58.3% in peripheral hypotonia and 1.3% in central hypotonia [44].

11.2. Surveillance

In progressive forms, follow-up also serves to review the diagnosis: a child labelled with CP who loses abilities or develops new signs should be reassessed, because CP is, by definition, non-progressive [24].

12. Summary and Final Considerations

Congenital tetraplegia or tetraparesis is a sign with two pathways of investigation. In the spastic pathway, the central problem is to separate acquired CP from its genetic mimics; perinatal asphyxia explains a minority of cases, and symmetry, microcephaly, progression, consanguinity and absence of perinatal insult increase the likelihood of a monogenic cause [24]. Exome or genome sequencing has yields of 23–31% in meta-analyses and about 35% in cryptogenic CP, and 8% of sequenced patients with CP have a diagnosis that changes management [45, 48, 55]. The OMIM "spastic quadriplegic CP" series illustrates the evolution of knowledge: AP-4 deficiency was reclassified as complex spastic paraplegia, CPSQ1 moved from GAD1 to HPDL and the KANK1 deletion is now considered probably benign [27, 30, 31].

MoCD type A is the entity in which recognition has the greatest immediate consequence: it mimics HIE, but has a symptom-free interval and simple markers (low urate and homocysteine, raised S-sulphocysteine), and fosdenopterin, started on suspicion and continued only with genetic confirmation, reduced the risk of death compared with historical controls [11, 12]. In the flaccid pathway, central hypotonia is the most frequent, congenital myotonic dystrophy is the most common neuromuscular cause and SMA requires SMN1 dosage from the outset; rapid exome or genome sequencing diagnosed 60% of unexplained hypotonic infants in an international consortium, with known limits for expansions, CNVs and mitochondrial DNA [23, 50]. Without a diagnosis, counselling relies on empirical risks, and sample storage in severely ill neonates preserves the possibility of future diagnosis [24, 46].

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