A summary of the complex inherited neuropathy syndromes with one of the three major core clinical phenotypes of ataxia, spasticity or global neurodevelopmental impairment
| Disease (Online Mendelian Inheritance in Man (OMIM)) | Inheritance | Gene | Clinical description |
| (a) Ataxia and neuropathy syndromes | |||
| Ataxia and sensory predominant axonal neuropathy | |||
| Friedreich’s ataxia/ FRDA-1 (229300) | AR | FXN (repeat) | Early-onset ataxia, cardiomyopathy, myelopathy, optic atrophy, sensory axonal neuropathy |
| EAOH (208920) | AR | APTX | Early-onset ataxia, sensory axonal neuropathy, oculomotor apraxia, hypoalbuminemia (EAOH) |
| SCAR1 (606002) | AR | SETX | Juvenile onset ataxia, increased α-fetoprotein, nystagmus, cerebellar and pontine atrophy, oculomotor apraxia, sensory axonal neuropathy |
| Ataxia-telangiectasia (208900) | AR | ATM | Childhood-onset progressive ataxia, conjunctival telangiectasia, sensory axonal neuropathy, chorea and dystonia, immunodeficiency and increased risk of malignancy, elevated α-fetoprotein |
| Abetalipoproteinemia (200100) | AR | MTP | Young onset; hypocholesterloaemia leading to malabsorption of fat-soluble vitamins (vitamin E), acanthocytes, retinitis pigmentosa, progressive sensory axonal neuropathy |
| Ataxia with isolated vitamin E deficiency (277460) | AR | TTPA | Early-onset ataxia and sensory axonal neuropathy similar to Friedreich’s ataxia, head titubation, normal fat absorption unlike abetalipoproteinemia, rarely retinitis pigmentosa |
| Fragile X tremor ataxia syndrome (300623) | AD | FXTAS(repeat) | Late-onset tremor, ataxia, parkinsonism, sensory axonal neuropathy, middle cerebellar peduncle changes on MRI |
| SCA27 (609307) | AD | FGF14 | Learning difficulties, cerebellar ataxia, sensory axonal neuropathy |
| Galactosialidosis (256540) | AR | CTSA | Coarse facies, dwarfism, hearing loss, cherry red macular spot, global developmental delay, ataxia, haemangiomas, vascular abnormalities, rarely sensory axonal neuropathy |
| CANVAS (614575) | Unknown | Unknown | Late-onset Cerebellar Ataxia, Sensory axonal neuropathy, Vestibular Areflexia Syndrome (CANVAS) |
| Ataxia and sensory-motor axonal neuropathy | |||
| Leukoencephalopathy with brainstem and spinal cord involvement (LBSL) (611105) | AR | DARS2 | Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings |
| Neuropathy, ataxia, retinitis pigmentosa (NARP) (551500) | m8618insTm8993T>G m8993T>C m9185T>C | MTATP6 | Ataxia, retinitis pigmentosa, cardiomyopathy, sensory-motor axonal neuropathy |
| SCAN1 (607250) | AR | TDP1 | Cerebellar ataxia and sensory-motor axonal neuropathy |
| Peroxisome biogenesis disorder 6A (214100) | AR | PEX10 | Failure to thrive, facial dimorphism, agenesis of the corpus callosum, death in first year of life, axonal motor neuropathy, progressive ataxia and sensory-motor axonal neuropathy in adulthood described |
| Microcephaly, seizures, and developmental delay (MCSZ) (613402) | AR | PNKP | Microcephaly, global developmental delay, progressive cerebellar ataxia and atrophy, sensory-motor axonal neuropathy |
| SCA1 (164400) | AD | ATXN1 (repeat) | Adult-onset, cerebellar ataxia, spasticity, sensory-motor axonal neuropathy in 40%, occasional choreiform movements |
| SCA3/MJD (109150) | AD | ATXN3 (repeat) | Adult-onset, cerebellar ataxia, external ophthalmoplegia, spasticity, extrapyramidal, sensory-motor axonal neuropathy in 50% |
| SCA7 (164500) | AD | ATXN7 (repeat) | Adult-onset, cerebellar ataxia, pigmentary macular degeneration, sensory-motor axonal neuropathy |
| SCA10 (603516) | AD |
ATXN10 (repeat) | Adult-onset cerebellar ataxia, sensory-motor axonal neuropathy |
| SCA12 (604326) | AD | PPP2R2B (repeat) | Adult-onset cerebellar ataxia, tremor of head and arms, subclinical sensory-motor axonal neuropathy |
| SCA23 (610245) | AD | PDYN | Cerebellar ataxia, sensory-motor axonal neuropathy |
| Spinocerebellar ataxia, autosomal-recessive 21 (SCAR21) (607982) | AR | SCYL1 | Early-onset ataxia (<1 year) with recurrent episodes of liver failure, sensory-motor axonal neuropathy, cerebellar atrophy |
| Ataxia and motor predominant axonal neuropathy | |||
| SCA2 (183090) | AD | ATXN2 (repeat) | Adult-onset, slow saccades, ataxia, tremor, parkinsonism, motor>sensory axonal neuropathy in 80% |
| SCA36 (614153) | AD | NOP56 | Late-adult-onset gait ataxia, tongue atrophy and fasciculation, distal motor neuropathy |
| Ataxia and slow nerve conduction velocity (SNCV) | |||
| Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts (PHARC) (612674) | AR | ABHD12 | Onset second decade, neuropathy with SNCV, sensory neuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia |
| ARSACS (270550) | AR | SACS | Complex neurodegenerative disorder characterised by ataxia, spasticity, neuropathy with SNCV |
| Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus ACPHD (616192) | AR | DNAJC3 | Cerebellar ataxia, neuropathy with SNCV, hearing loss, diabetes mellitus |
| Cerebrotendinous xanthomatosis (213700) | AR | CRP27A1 | Adolescent-onset progressive ataxia, myelopathy and dementia, cataracts, low cholesterol, atherosclerosis, xanthomas, soft palate myoclonus, intractable infantile-onset diarrhoea, cerebral white matter lesions on MRI, sensory>motor axonal neuropathy, SNCV described in a minority of patients |
| Refsum’s disease (266500) | AR | PHYH | Sensory-motor neuropathy with normal or SNCV, deafness, retinitis pigmentosa, ichthyosis, heart failure, ataxia, raised CSF protein |
| (b) Spasticity and neuropathy syndromes | |||
| Spasticity and sensory-predominant axonal neuropathy | |||
| HSN with spastic paraplegia (256840) | AR | CCT5 | Severe mutilating sensory neuropathy with spastic paraplegia |
| SPG61 (615685) | AR | ARL6IP1 | Childhood-onset spastic paraplegia with mutilating, sensory>motor axonal neuropathy |
| Spasticity and sensory-motor axonal neuropathy | |||
| SPOAN (609541) | AR | KLC2 | Early-onset spastic paraplegia, congenital optic atrophy and axonal sensory-motor neuropathy |
| SPG3A (182600) | AD | ATL1 | Early-onset spastic paraplegia, axonal sensory-motor neuropathy in some patients |
| SPG7 (607259) | AR | PGN | Spastic paraplegia, optic atrophy, ataxia and sensory-motor axonal neuropathy in some patients |
| SPG10 (604187) | AD | KIF5A | Adult onset; spastic paraplegia, axonal sensory-motor neuropathy, rarely parkinsonism and cognitive decline |
| SPG11 (604360) | AR | SPG11 | Onset second decade, spastic paraplegia, intellectual disability and cognitive decline, thin corpus callosum, mild cerebellar eye signs, axonal sensory-motor neuropathy, parkinsonism and dystonia, pseudobulbar involvement |
| SPG15 (270700) | AR | ZFYVE26 | As SPG11, but with pigmentary maculopathy |
| SPG26 (609195) | AR | B4GALNT1 | Spastic paraplegia, intellectual disability, ataxia, dystonia, axonal sensory-motor neuropathy |
| SPG28 (09340) | AR | DDHD1 | Spastic paraplegia, occasionally cerebellar eye signs and subclinical axonal neuropathy |
| SPG30 (610357 | AR | KIF1A | HSP with sensory-motor axonal neuropathy ± cerebellar signs |
| SPG43 (615043) | AR | C19orf12 | Childhood-onset spastic paraplegia and sensory-motor axonal neuropathy, NBIA with optic atrophy, extrapyramidal signs |
| SPG46 (614409) | AR | GBA2 | Spastic paraplegia, cognitive decline, thin corpus callosum, ataxia, cataracts, bulbar dysfunction, axonal sensory-motor neuropathy |
| SPG55 (615035) | AR | C12ORF65 | Early-onset spastic paraplegia, optic atrophy, intellectual impairment, axonal sensory-motor neuropathy |
| SPG56 (615030) | AR | CYP2U1 | Onset first decade, spastic paraplegia, rarely dystonia and cognitive impairment, subclinical sensory-motor axonal neuropathy |
| SPG57 (615658) | AR | TFG | Childhood-onset spastic paraplegia, sensory-motor axonal neuropathy, optic atrophy |
| Spastic ataxia 5 | AR | AFG3L2 | Early-onset spastic paraplegia, later myoclonic epilepsy, sensory-motor axonal neuropathy, ataxia, dystonia |
| Adult polyglucosan body disease (263570) | AR | GBE1 | Late-onset, cognitive impairment, spasticity, sensory-motor axonal neuropathy, bladder dysfunction, cerebellar and extrapyramidal signs also seen, periventricular white matter abnormalities on MRI |
| Spasticity and motor predominant axonal neuropathy | |||
| Spinal muscular atrophy, distal (DSMA2) (605726) | AR | SIGMAR1 | Spastic paraplegia, motor neuronopathy predominantly affecting the extensor muscles of the upper limbs |
| SPG4 (182601) | AD | SPAST | Infantile-onset and adult-onset spastic paraplegia, motor axonal neuropathy in some patients |
| SPG9A (601162)/ SPG9B (616586) | AD/AR | ALDH18A1 | Adolescent-onset and adult-onset spastic paraplegia, dysarthria and motor neuronopathy, cataracts, skeletal abnormalities |
| SPG12 (604805) | AD | RTN2 | Spastic paraplegia, motor neuropathy seen with homozygous, recessive mutations (MMR, AMR, personal observation) |
| SPG17 (270685) | AD | BSCL2 | Silver syndrome, spasticity, motor neuropathy in arms > legs |
| SPG20/Troyer syndrome (275900) | AR | SPG20 | Spasticity, short stature, mental retardation, facial dysmorphism, distal amyotrophy/motor neuropathy |
| SPG39 (612020) | AR | PNPLA6 | Childhood onset of slowly progressive spastic paraplegia; progressive distal motor neuropathy beginning in early through late adolescence |
| Spasticity and SNCV | |||
| SPG5A (270800) | AR | CYP7B1 | Childhood to adult-onset spastic paraplegia and bladder dysfunction, periventricular white matter abnormalities on MRI, one patient described with SNCV |
| Adrenoleukodystrophy (300100) | X-linked | ABCD1 | Adrenomyeloneuropathy, spastic paraparesis, adrenal insufficiency, axonal sensory-motor neuropathy, sphincter disturbance |
| Alpha-methylacyl-CoA racemase deficiency (AMACRD) 614307) | AR | AMACR | Retinopathy, myelopathy, axonal or SNCV neuropathy, elevated phytanic and pristanic acids |
| (c) Global neurodevelopmental impairment and neuropathy syndromes | |||
| Global neurodevelopmental impairment and sensory predominant axonal neuropathy | |||
| Congenital insensitivity to pain | AR | CLTCL1 | Congenital insensitivity to pain and severe global developmental delay, dysmorphic, delayed myelination on brain MRI |
| Familial dysautonomia, hereditary, sensory autonomic neuropathy, with intellectual disability | AR | TECPR2 | Global developmental delay, sensory axonal neuropathy, autonomic features, central apnoea/chronic respiratory disease, seizures, encephalopathy |
| MTDPS7 (271245) | AR | C10ORF2 | Infantile-onset ataxia, PEO, encephalopathy, deafness, seizures and sensory axonal neuropathy |
| Global neurodevelopmental impairment and sensory-motor axonal neuropathy | |||
| Giant axonal neuropathy-1 (256850) | AR | GAN | Progressive neurodegenerative disorder characterised by spasticity ataxia and sensory-motor axonal neuropathy, kinky/curly hair |
| Neurodegeneration with brain iron accumulation 2A/ infantile neuroaxonal dystrophy (256600) | AR | PLA2G6 | Infantile-onset, progressive neurodegeneration (tetraplegia, dementia, visual loss) and axonal sensory-motor neuropathy, globus pallidus iron deposition on MRI |
| CEDNIK syndrome (609528) | AR | SNAP29 | Cerebral Dysgenesis and severe psychomotor retardation, axonal sensory-motor Neuropathy, Ichthyosis, palmoplantar Keratoderma, fatal by second decade of life |
| Pyruvate dehydrogenase E1-alpha deficiency (PDHAD/312170) | X-linked | PDHA1 | Episodic lactic acidosis, cerebellar ataxia, neurodevelopmental delay and clinical features resembling Leigh syndrome, neuropathy reported (NCV not reported) |
| Congenital disorder of deglycosylation (615273) | AR | NGLY1 | Developmental delay, choreoathetosis, alacrimia, seizures, microcephaly, transaminitis, neuropathy |
| Hypomyelinating leukodystrophy 6 (HLD6/612438) | AD | TUBB4A | Early-onset, delayed motor development, extrapyramidal movement disorder, spasticity, ataxia, rarely seizures and sensory-motor axonal neuropathy |
| Mental retardation 9 (601255) | AD | KIF1A | Developmental delay, microcephaly, seizures, extrapyramidal disorder, spasticity, cerebellar atrophy, sensory-motor axonal neuropathy |
| Harel-Yoon syndrome (HAYOS) (617183) | AD | ATAD3A | Global developmental delay, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy |
| PBD9B (614879) | AR | PEX7 | Infantile (more severe) variant of Refsum’s disease, skeletal and facial dysmorphism, global developmental delay |
| MTDPS5 (612073) | AR | SUCLA2 | ‘Leigh’-like syndrome, deafness, progressive dystonia, mild methylmaolnic acidaemia |
| Global neurodevelopmental impairment and motor predominant axonal neuropathy | |||
| Hexosaminidase A deficiency (272800) | AR | HEXA | Usually infantile-onset, developmental delay and cognitive decline, visual loss (‘cherry red spot’), motor>sensory neuronopathy, hypometric saccades, adult-onset (second decade) cases described |
| Sandhoff disease (268800) | AR | HEXB | Indistinguishable from HEXA deficiency |
| Pontocerebellar hypoplasia type 1B (614678) | AR | EXOSC3 | Severe disease often with death in first five years, developmental delay, pontocerebellar hypoplasia on MRI, motor neuronopathy |
| Pontocerebellar hypoplasia (PCH9) (615809) | AR | AMPD2 | Global developmental delay, spasticity, seizures, dysmorphic facies, axonal neuropathy, agenesis of the corpus callosum and cerebellar hypoplasia on MRI |
| Spinal muscular atrophy, lower extremity predominant (SMALED1) (158600) | AD | DYNC1H1 | Congenital-onset lower-limb motor neuronopathy with contractures, global developmental delay and cerebral dysgenesis in some patients |
| Spinal muscular atrophy, lower extremity predominant (SMALED2) (615290) | AD | BICD2 | Congenital-onset lower-limb motor neuronopathy with contractures, global developmental delay and cerebral dysgenesis in some patients |
| AAAS (231550) | AR | AAAS | Achalasia, addisonianism, alacrima, mental retardation, spastic tetraparesis, bulbospinal motor neuropathy, autonomic neuropathy |
| Spinal muscular atrophy with progressive myoclonic epilepsy (159950) | AR | ASAHI | Onset first and second decade Neurodevelopmental delay after onset of seizures Motor neuronopathy |
| Global neurodevelopmental impairment and SNCV | |||
| Infantile-onset multisystem neurological, endocrine and pancreatic disease | AR | PTRH2 | Infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, sensory neuronal hearing loss, hepatomegaly, pancreatic insufficiency, proximal placement of thumb, SNCV neuropathy |
| MEDNIK (609313) | AR | AP1S1 | Congenital-onset, Mental retardation, Enteropathy (severe congenital diarrhoea), Deafness, sensory-motor Neuropathy with intermediate conduction velocities, Ichthyosis, Keratoderma |
| Cockayne syndrome (216400/133540) | AR | ERCC6/ ERCC8 | Dwarfism, optic atrophy, mental retardation, cutaneous photosensitivity, pigmentary retinopathy, deafness, neuropathy with slow conduction velocities |
| Leigh syndrome variant (256000) | AR | SURF1 | Leigh syndrome (early-onset progressive neurodegeneration of the brain stem, basal ganglia and spinal cord), neuropathy with SNCV |
| Encephalopathy due to defective mitochondrial and peroxisomal fission 2 (EMPF2) (617086) | AR | MFF | Leigh-like syndrome, developmental delay, optic atrophy, seizures, sensory-motor neuropathy with SNCV, Leigh syndrome-like MRI brain (T2 high signal of basal ganglia and subthalamic nucleus) |
| Agenesis of the corpus callosum with peripheral neuropathy (218000) | AR | SLC12A6 | Mental retardation and progressive neurodegeneration, dysmorphic facies and facial diplegia, agenesis of the corpus callosum, neuropathy with intermediate conduction velocities |
| Aicardi-Goutieres syndrome | TREX1 (606609, AD/AR) RNASEH2A (606034), RNASEH2B (AR, 610326), RNASEH2C (AR, 610330), SAMHD1 (AR, 606754), ADAR1 (AR, 146920), IFH1 (AD, 606951) | Inflammatory syndrome, encephalopathy and psychomotor regression of utero or infantile onset, bilateral striatal necrosis, leukodystrophy, intracranial calcifications, CSF lymphocytosis, spastic paraparesis, rarely neuropathy with SNCV | |
| Leukodystrophy hypomyelination and congenital cataract (HLD5 HCC) (610532) | AR | FAM126A | Congenital cataracts, global developmental delay from 1 year, diffuse cerebral hypomyelination on MRI, neuropathy with SNCV |
| Congenital disorder of glycosylation type 1A (212065) | AR | PMM2 | Neonatal-onset, leukodystrophy, abnormal serum glycoproteins, mental retardation, hypotonia, ataxia, retinitis pigmentosa, seizures, slowly progressive neuropathy with SNCV, severe infections, hepatic insufficiency and cardiomyopathy |
| Metachromatic leukodystrophy (250100) | AR | ARSA | Severe late infantile form with mental retardation and severe course. Regression before 30 months; adult-onset, psychiatric symptoms, leukodystrophy on MRI, progressive neuropathy with SNCV, optic atrophy |
| Globoid cell leukodystrophy/Krabbe (245200) | AR | GALC | Spastic paraplegia, developmental delay, optic atrophy; adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy |
| Pelizaeus-Merzbacher disease (312080) SPG2 (312920) | X-linked | PLP1 | Infantile-onset, nystagmus, cognitive impairment, spasticity and ataxia, leukodystrophy on MRI, mild multifocal SNCV neuropathy seen with null mutations and more mild phenotype of mild spasticity and ataxia |
For the sake of brevity, some conditions, for example, ARSACS, that could be classified in more than one major phenotypic category, only appear once in this table with the additional core features outlined in the clinical description. Number in parenthesis is the OMIM phenotype number.
AD, autosomal dominant; AR, autosomal recessive; ARSACS, autosomal-recessive spastic ataxia of Charlevoix-Saguenay; CSF, cerebrospinal fluid; EAO, Early age of onset; FLAIR, Fluid-Attenuated Inversion Recovery; MTDPS, mitochondrial DNA depletion syndrome; NBIA, neurodegeneration with brain iron accumulation; OMIM, Online Mendelian Inheritance in Man; PEO, progressive external ophthalmoplegia; SCAN1, spinocerebellar ataxia autosomal recessive with axonal neuropathy; SCAR1, spinocerebellar ataxia autosomal-recessive 1; SNCV, slow nerve conduction velocities.