
==== Front
Curr Opin Neurol
Curr Opin Neurol
CONEU
Current Opinion in Neurology
1350-7540
1473-6551
Lippincott Williams & Wilkins Hagerstown, MD

39083076
WCO370512
10.1097/WCO.0000000000001307
00002
3
PERIPHERAL NERVE AND NEUROMUSCULAR JUNCTION DISEASE: Edited by Mary M. Reilly
The evolving spectrum of complex inherited neuropathies
Rossor Alexander M. a b
Haddad Saif a
Reilly Mary M. a
a Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square institute of Neurology and National Hospital for Neurology and Neurosurgery
b Department of Neurology, Guys and St Thomas’ Hospitals NHS Foundation Trust, UK
Correspondence to Alexander M. Rossor, UCL Institute of Neurology: University College London Queen Square Institute of Neurology, London WC1N 3BG, UK. E-mail: a.rossor@ucl.ac.uk
10 2024
31 7 2024
37 5 427444
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Purpose of review

Inherited peripheral neuropathies can be divided into those diseases in which peripheral neuropathy is the sole or main feature of the disease (Charcot-Marie-Tooth disease) and those in which peripheral neuropathy is just one feature of a more complex syndrome. In recent years there has been a substantial expansion in the number of genes associated with complex neuropathy syndromes.

Recent findings

This review will focus on emerging themes in this group of diseases, namely the increasing number of diseases due to repeat expansions; the emergence of both recessive and dominant negative alleles in the same gene producing a common phenotype and diseases in which there is selective loss of the allele from haematopoietic stem cells making genetic diagnosis on blood derived DNA problematic.

Summary

In this review we provide a practical approach to investigating and diagnosing patients with peripheral neuropathy as part of a complex syndrome and provide an updated table of the genes associated with this group of diseases.

Keywords

ataxia
peripheral neuropathy
repeat expansion
spasticity
National Institute for Health Research University College London Hospitals Biomedical Research CentreG104817 MMR and SHMedical Research CouncilMRC MR/S005021/1 National Institutes of Neurological Diseases and Stroke and office of Rare DiseasesU54NS065712 and 1UOINS109403-01 Muscular Dystrophy AssociationMDA510281 Charcot Marie Tooth Association (CMTA), Alnylam Pharmaceuticals and Applied TherapeuticsOPEN-ACCESSTRUE
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pmcINTRODUCTION

Healthcare professionals involved in the diagnosis of individuals with inherited peripheral neuropathy have traditionally tested genes associated with diseases in which peripheral neuropathy is the sole or major component of the phenotype. Testing has therefore focused on those genes that have been described in association with Charcot-Marie-Tooth disease (CMT) and the closely related diseases, hereditary sensory neuropathy and distal hereditary motor neuropathy. With the widespread adoption of next generation sequencing into routine clinical practice, it has now become apparent that many complex genetic diseases associated with peripheral neuropathy such as the Hereditary Spastic Paraplegias (HSP) and Spinocerebellar Ataxias can present with peripheral neuropathy. This is relevant as many of the genes responsible for such diseases are absent from inherited neuropathy gene panels. In 2017, we published a clinical approach to these complex neuropathy syndromes [1]. In this review, we revisit our approach and include an up-to-date table of more than 250 genes associated with complex neuropathy syndromes. 

Box 1 no caption available

APPROACH TO GENETIC TESTING IN COMPLEX NEUROPATHY SYNDROMES

There are more than 250 genes associated with complex neuropathy phenotypes, many of which are exceptionally rare and reported in only a handful of families. It is therefore unrealistic to expect to have a working knowledge of the phenotypes of all the causative genes. We propose an approach in which the clinician defines the major feature of the nonneuropathy phenotype. In the majority of patients this will be a neurological phenotype of either ataxia, spasticity or global developmental delay (Table 1) although rarer neurological features including optic atrophy, ophthalmoplegia, deafness, myopathy and movement disorders may also be associated with peripheral neuropathy (Table 2). Important nonneurological phenotypes are diverse and include cardiomyopathy, dermatological disease and liver and renal failure (Table 2). Once the predominant phenotype has been defined the neuropathy should then be characterised based on the nerve conduction velocities (NCV) into those with normal or slow conduction. Neuropathies with normal nerve conduction velocities should then be further classified into those which are predominantly sensory, those predominantly motor and those that are mixed (see Fig. 1). Using this approach, one is able to sub classify the many genes associated with complex phenotypes into a workable format (see Tables 1 and 2).

Table 1 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 (OMIM)	Inheritance	Gene	Clinical description	
A. Ataxia and neuropathy syndromes	
Ataxia and sensory predominant axonal neuropathy	
Friedreich 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	
Abetalipoproteinaemia (200100)	AR	MTTP	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 ataxia, head titubation, normal fat absorption unlike abetalipoproteinaemia, 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	
SCA27A (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)	AR	RFC1 expansion	Late onset Cerebellar Ataxia, Sensory axonal neuropathy, Vestibular Areflexia Syndrome (CANVAS)	
SCA27B (620174)	AD	FGF14 GAA expansion	Ataxia, vestibular hypofunction, mild axonal neuropathy	
AOA3 (615217)	AR	PIK3R5	Oculomotor apraxia, ataxia and sensory axonal neuropathy	
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>Cm9185T>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%	
SCA5/SCAR14	AD/AR	SPTBN2	Cataracts, optic atrophy, cerebellar ataxia, sensory and motor axonal neuropathy PMID:33188499	
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	
SCA14 (605361)	AD	PRKCG	Usually adult onset isolated cerebellar ataxia. Missense mutation in catalytic domain of exon 11 associated with complex syndrome including cerebellar ataxia, sensory motor axonal neuropathy, parkinsonism, dystonia, myoclonus and pyramidal syndrome.	
SCA19 (607346)	AD	KCDN3	Prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy in the late onset forms	
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	
SCAR4 (607317)	AR	VPS13D	Saccadic intrusions, acanthocytosis, dyskinesias, psychiatric issues. Neuropathy not characterised.	
HLD7 (607694)	AR	POLR3A	Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications (hypodontia, severe peridontal disease. Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain. ‘Abnormal nerve conduction in 8 out of 14 cases.	
SCAN3 (618387)	AR	COA7	Cerebellar atrophy, leukoencephalopathy and spinal cord atrophy in some patients. Axonal sensory and motor neuropathy.	
AOA4 (616267)	AR	PNKP	CMT2, ataxia, microcephaly, seizures, developmental delay	
SCAR26 (617633)	AR	XRCC1	Ataxia, developmental delay, azoospermia and hypogonadism, myotonia, sensory and motor axonal neuropathy.	
SCAR32 (619862)	AR	PRDX3	Ataxia and sensory and motor neuropathy	
MITCH (618960)	De novo dominant	ACOX1	Ataxia, sensory motor neuropathy, leukodystrophy, cognitive impairment	
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	
OHS (304150)	XL	ATP7A	Early onset ataxia, spastic tetraparesis, dystonia and axonal motor neuropathy	
CMT2Z (616688)	AD	MORC2	Congenital onset SMA, cerebellar atrophy and diaphragmatic palsy	
CONDCA (618276)	AR	AGTPBP1	Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy	
CONDSIAS (618170)	AR	ADPRHL2	Ataxia, spasticity, cognitive impairment / psychosis, motor neuropathy	
SCAR8 (610743)	AR	SYNE1	Cerebellar atrophy, motor neuropathy in some patients	
Ataxia and slow nerve conduction velocity (SNCV)	
Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts (PHARC) (612674)	AR	ABHD12	Onset 2nd decade, neuropathy with SNCV, sensory neuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia	
ARSACS (270550)	AR	SACS	Complex neurodegenerative disorder characterized 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 Disease (266500)	AR	PHYH	Sensory-motor neuropathy with normal or SNCV, deafness, retinitis pigmentosa, ichthyosis, heart failure, ataxia, raised CSF protein.	
DEE32 (616366)	AD	KCNA2	Childhood onset spasticity, intellectual disability, ataxia, seizures, sensory and motor SNCV in one family	
ATXPC (159550)	AD	SAMD9L	Ataxia pancytopenia syndrome, demyelinating neuropathy. Variant may be clonally selected against in blood	
CMT1I (619742)	AD	POLR3B	De-novo dominant. Ataxia, developmental delay, spasticity and demyelinating neuropathy	
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	
SPG23 (270750)	AR	DSTYK	Childhood onset spastic paraplegia, prominent skin pigment abnormalities (vitiligo, hyperpigmentation, diffuse lentigines), premature greying of hair, sensory predominant axonal neuropathy (mild).	
SPG35 (612319)	AR	FA2H	Childhood onset spasticity, cognitive decline and leukodystrophy. Mild sensory axonal neuropathy on NCS. Epilepsy, dysphagia, dysarthria and dystonia also observed.	
SPG79A (620221)/SPG79B (615491)	AD and AR	UCHL1	Spasticity, optic atrophy, ataxia, cognitive impairment, sensory axonal neuropathy	
SCA25 (608703)	AD	PNPT1	Cerebellar ataxia and sensory 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	
SPG15PEX10 (270700)	AR	ZFYVE26	As SPG11, but with pigmentary maculopathy	
SPG23 (270750)	AR	DSTYK	Spastic paraplegia, pigmentary abnormalities, axonal sensory and motor neuropathy	
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	
SPG43 (615043)	AR	C19orf12	Childhood onset spastic paraplegia and sensory-motor axonal neuropathy, NBIA with optic atrophy, extrapyramidal signs	
SPG48 (613647)	AR	AP5Z1	Late onset spastic paraplegia and axonal neuropathy (ataxia, dystonia, parkinsonism reported). Thin corpus callosum	
SPG54 (615033)	AR	DDHD2	Spasticity, developmental delay, ataxia, abnormal eye movements, thin corpus callosum, periventricular white matter lesions, Peripheral neuropathy in some	
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 1st 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	
SPAX5 (614487)	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	
HLD7 (607694)	AR	POLR3A	See 1A	
SPG76 (616907)	AR	CAPN1	Onset 3rd decade, spasticity, dysarthria and ataxia. ‘Peripheral neuropathy’ reported in some individuals	
CMT2Z (616688)	AD	MORC2	Early onset, pyramidal signs and axonal neuropathy, nonlength dependent weakness, retinitis pigmentosa, developmental delay, deafness, scoliosis, seizures, cataracts, dysmorphisms, nocturnal hypoventilation also reported.	
SPAX2 (611302)	AR	KIF1C	Onset 1st decade, spasticity, ataxia, cervical dystonia, neuropathy. Variable developmental delay/ occipital/ posterior white matter change.	
SPG78 (617225)	AR	ATP13A2	Kufor-Rakeb syndrome. Juvenile onset Parkinson's disease, neuronal ceroid lipofuscinosis, cerebellar atrophy, sensory and motor axonal neuropathy.	
SPG6 (600363)	AD	NIPA1	Spastic paraplegia. Neuropathy infrequently reported	
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 and adult onset spastic paraplegia, motor axonal neuropathy in some patients	
SPG9A (601162) / SPG9B (616586)	AD/AR	ALDH18A1	Adolescent 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	
SPG30 (610357)	AR	KIF1A	HSP with sensory motor axonal neuropathy +/- cerebellar signs	
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	
Adrenoleukodys-trophy (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	
SPG81 (618768)	AR	SELENOI	Infantile onset, global developmental delay, spasticity, periventricular white mater signal change on MRI, peripheral neuropathy with SNCV. Seizures and bifid uvula in some affected individuals	
CDCBM5 (615763)	AD	TUBB2A	Progressive infantile onset spasticity, ataxia and sensory and motor neuropathy. Superior cerebellar vermis atrophy and thin corpus callosum.	
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	
HSAN9 (615031)	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	
EMPF1 (614388)	AD	DNM1L	Developmental delay, global hypotonia and severe ataxia due to axonal sensory neuropathy. Optic atrophy.	
Phosphoserine phosphatase deficiency (614023)	AR	PSPH	Hereditary sensory neuropathy, osteomyelitis, epilepsy, global developmental delay, responsive to serine.	
Global neurodevelopmental impairment and sensory-motor axonal neuropathy	
Giant axonal neuropathy-1 (256850)	AR	GAN	Progressive neurodegenerative disorder characterized by spasticity ataxia and sensory-motor axonal neuropathy, kinky/curly hair	
Neurodegeneration with brain iron accumulation 2A (NBI2A)/ infantile neuroaxonal dystrophy (INAD) (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 2nd 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 disease, skeletal and facial dysmorphism, global developmental delay	
MTDPS5 (612073)	AR	SUCLA2	‘Leigh’ like syndrome, deafness, progressive dystonia, mild methylmalonic acidaemia.	
PNRIID (618124)	AR	MCM3AP	Severe, early onset sensory and motor axonal neuropathy with loss of independent ambulation by the second decade. Mild to moderate intellectual disability	
CMT4B3 (615284)	AR	SBF1	Infantile onset CMT2, ophthalmoplegia, developmental delay, pyramidal signs, ataxia and cerebellar atrophy.	
CMT2Z (616688)	AD	MORC2	See 1A and 1B	
Phosphoglycerate Kinase 1 Deficiency (300653)	XL	PGK	Axonal sensorimotor polyneuropathy, mental retardation, microcephaly, ophthalmoplegia, pes cavus, retinitis pigmentosa, seizures, stroke, parkinsonism, nonspherocytic haemolytic anaemia.	
MC4DN11 (619054)	AR	COX20	Axonal peripheral neuropathy and static encephalopathy.	
DEE80 (618580)	AR	PIGB	DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Peripheral neuropathy.	
DEE44 (617132)	AR	UBA5	Severe congenital neuropathy with death in infancy. Epilepsy, movement disorder.	
IDDSAPN (619099)	AR	NEMF	Speech difficulties, abnormal eye movement, scoliosis intellectual disability and peripheral axonal neuropathy	
NEDNMS (619833)	AR	NRCAM	Developmental delay, peripheral neuropathy, spasticity. PMID 35108495	
CONDMIM (620089)	AR	LETM1	Global developmental delay, optic atrophy, sensorineural hearing loss, and cerebellar ataxia, epilepsy, spasticity, myopathy, neuropathy (not characterised) PMID 36055214	
PCH10 (615803)	AR	CLP1	Failure to develop motor skills, absent/delayed speech, progressive spasticity, epilepsy, sensory and motor axonal neuropathy	
WARBM3 (614222)	AR	RAB18	Microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. Sensory and motor axonal neuropathy	
PCH2D (613811)	AR	SEPSECS	Microcephaly, cortical and cerebellar atrophy, spasticity, seizures, axonal neuropathy.	
	De novo	DHX9	Cerebellar atrophy, thin corpus callosum, neurodevelopmental delay	
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 (2nd decade) cases described	
Sandhoff disease (268800)	AR	HEXB	Indistinguishable from HEXA deficiency	
Pontocerebellar hypoplasia type 1B (PCH1B) (614678)	AR	EXOSC3	Severe disease often with death in first 5 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 (SMAPME) (159950)	AR	ASAHI	Onset first and second decade. Neurodevelopmental delay after onset of seizures. Motor neuronopathy.	
NEDHND (617519)	AR	SPTBN4	Global developmental delay, congenital myopathy, myopathic facies, axonal motor neuropathy, central deafness.	
PEAMO (617207)	AR	TBCE	Onset at birth or first year of life. Distal amyotrophy, ataxia, spasticity, optic atrophy, developmental delay.	
NMIHBA (617481)	AR	PRUNE1	Manitoba Cree population. Microcephaly, brain malformations, infantile contractures, progressive lower and upper motor neuron degeneration.	
BIBARS (612292)	AD (maternal imprinting)	KCNK9	Birk Barel syndrome. Dysmorphic face. Congenital hypotonia (motor neuropathy). Mild to moderate intellectual disability	
D-bifunctional protein (DBP) deficiency (261515)	AR	HSD17B4	Peroxisomal disorder. Global developmental delay, seizures, sensorineural hearing loss, cerebellar atrophy, Basal ganglia signal change, leukodystrophy, adrenal insufficiency.	
CMT2DD (618036)	AD	ATP1A1	Motor axonal neuropathy, spasticity, hypomagnesemia with seizures and intellectual disability	
SPG64 (615683)	AR	ENTPD1	Global developmental delay, spasticity, motor axonal neuropathy, thin corpus callosum, cerebellar atrophy, signal abnormality posterior limb of the internal capsule	
COMNB (619903)	AR	SLC5A6	Can present as isolated motor neuropathy, upper limb predominant. Failure to thrive, microcephaly, spasticity, immunodeficiency, osteopenia.	
NEDHSCA (616917)	AR	PIGG	Mild intellectual disability, cerebellar atrophy, motor neuropathy with conduction block	
CONDCA (618276)	AR	AGTBP1	Global developmental delay, impaired intellectual development, poor/absent speech, and motor abnormalities, cerebellar atrophy	
Martsolf syndrome (212720)	AR	RAB3GAP2	Global developmental delay and growth retardation. Spasticity, motor predominant distal neuropathy with SNCV. Microphthalmia, microcornea, cataracts, cryptorchidism, micropenis.	
NEDBA (618443)	AD (de-novo)/AR	MAPK8IP3	Neurodevelopmental delay and motor axonal neuropathy (PMID:37462082/ 30945334)	
Global neurodevelopmental impairment and SNCV	
IMNEPD1 (616263)	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 and AP1B1	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 sub thalamic nucleus)	
Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) (218000)	AR/AD	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 (CDG1A) (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 (PMD) (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.	
HLD2	AR	GJC2	Infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Leukodystrophy	
Cowden syndrome 1 (158350)	AD	PTEN	Childhood onset, asymmetric progressive multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas	
SPG81 (618768)	AR	SELENOI	See 1B.	
HLD18 (618404)	AR	DEGS1	Motor developmental delay, spasticity, cerebellar atrophy and microcephaly, hypomyelination on MRI, scoliosis, neurogenic bladder, enteral nutrition.	
NEDMILG (619091)	AR or de-novo dominant	NARS1	Microcephaly, epilepsy, developmental delay, demyelinating neuropathy	
PNSED (616539)	AR	TRMT5	Global developmental delay, cerebellar abnormalities, severe demyelinating neuropathy	
NEDSDV (615075)	AD	CTNNB1	Spastic paraplegia, exotropia, ataxia and sensory demyelinating neuropathy	
NEDSWMA (619026)	AR	HPDL	Severe, neonatal-onset neurodevelopmental delay with neuroimaging resembling mitochondrial encephalopathy; allelic to SPG83. Slow NCV	
IDDPN (619844)	AR	NUDT2	Infantile onset sensory and motor neuropathy, thin corpus callosum, intellectual impairment. Muscle hypotonia and weakness	
AD, Autosomal dominant; AR, Autosomal recessive.

Table 2 A summary of the complex inherited neuropathy syndromes with one of the minor 10 clinical phenotypes associated with neuropathy

Disease (OMIM)	Inheritance	Gene	Clinical description	
A. Extrapyramidal disease and neuropathy syndromes	
Leukoencephalopathy with dystonia and motor neuropathy (613724)	AR	SCP2	Dystonia, hyposmia, azoospermia, motor predominant axonal neuropathy, bilateral thalamic T2 high signal on MRI	
MTDPS4B (613662)	AR	POLG	SANDO: Sensory Axonal Neuropathy, Dysarthria, Ophthalmoplegia, also parkinsonism and deafness. Also caused by recessive C10orf2 mutations.	
Chorea acanthocytosis (200150)	AR	VPS13A	Onset 3rd to 5th decade, red cell acanthocytosis and progressive neurodegeneration, seizures, dysarthria, chorea, orofacial dyskinesia, psychiatric disturbance, axonal sensory-motor neuropathy, raised CK	
McLeod syndrome (300842)	XL	XK	Onset 25–60, acanthocytes and Huntington-like syndrome, also epilepsy, cardiomyopathy, axonal motor neuropathy	
CMT2P (614436)	AD/AR	LRSAM1	Onset 3rd to 8th decade. Late onset parkinsonism described	
DSMA 5 (614881)	AR	HSJ1	Onset 2nd decade, motor predominant axonal neuropathy, rarely late onset parkinsonism	
Mitochondrial disease	m1095T>C	MTRNR1 (561000)	Parkinsonism, deafness, and sensory-motor axonal neuropathy	
	AD	NOTCH2NLC (repeat expansion)	Essential tremor, cognitive decline, leukodystrophy? axonal sensory and motor neuropathy	
SPG10 (604187)	AD	KIF5A	See Table 1B	
MTDPS5 (612073)	AR	SUCLA2	See Table 1C	
Siddiqi syndrome (618635)	AR	FITM2	Deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.	
Parkinsonism with polyneuropathy (619279)	AD	UQCRC1	Levodopa responsive parkinsonism and axonal sensory and motor peripheral neuropathy	
B. Ophthalmological and neuropathy syndromes	
Optic atrophy and neuropathy syndromes	
Syndromic optic atrophy (125250)	AD	OPA1	Optic neuropathy, PEO, deafness, myelopathy, sensory-motor axonal neuropathy	
Costeff syndrome or OPA3-related 3-methylglutaconic aciduria (258501) Optic atrophy and cataracts (165300)	AR/AD	OPA3	Infantile optic atrophy, additionally, extra pyramidal disorder (chorea), ataxia, cognitive defects, axonal sensory neuropathy, autonomic neuropathy, pseudo-obstruction	
Leber optic atrophy (53500)	Mitochondrial	MT-ND1, ND4, ND6	Optic atrophy, rarely neuropathy, spasticity, ataxia and extrapyramidal signs.	
HMSN6B (616505)	AR	SLC25A46	Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy	
BVVLS2 (614707)	AR	SLC52A2	Facial and bulbar weakness, sensory ataxia, sensory-motor axonal neuropathy, optic atrophy, sensory neuronal hearing loss	
SPOAN (609541)	AR	KLC2	See Table 1B	
SPG7 (607259)	AR	PGN	See Table 1B	
SPG43 (615043)	AR	C19orf12	See Table 1B	
SPG55 (615035)	AR	C12ORF65	See Table 1B	
SPG57 (615658)	AR	TFG	See Table 1B	
Metachromatic leukodystrophy (250100)	AR	ARSA	See Table 1C	
Krabbe disease (245200)	AR	GALC	See Table 1C	
EMPF2 (617086)	AR	MFF	Leigh-like syndrome, see Table 1C	
Cockayne syndrome (216400/133540)	AR	ERCC6/ERCC8	See Table 1C	
Hexosaminidase A deficiency (272800)	AR	HEXA	See Table 1C	
Sandhoff disease (268800)	AR	HEXB	See Table 1C	
HAYOS (617183)	AD	ATAD3A	See Table 1C.	
HMSN6C (618511)	AR	PDXK	Axonal sensory and motor peripheral neuropathy with optic atrophy (31187503). Vitamin B6 responsive.	
ANOA (617717)	AR	FDXR	Optic and auditory neuropathies. Sensory axonal neuropathy, psychosis, renal tubular acidosis.	
MC1DN1 (252010)	AR	NDUFS6	Axonal sensory and motor neuropathy, optic atrophy, borderline intellectual disability	
Retinitis pigmentosa and neuropathy syndromes	
CMTX5 (311070)	X-linked	PRPS1	Hearing loss, retinal dystrophy (optic atrophy), sensory-motor axonal neuropathy	
Methylmalonic aciduria and homocystinuria type Cb1c (MMACHC) (277400)	AR	MMACHC	Onset infancy to adulthood; thrombotic thrombocytopenia with encephalopathy, myelopathy, renal and pulmonary complications (can be life threatening), retinitis pigmentosa, axonal motor neuropathy; treat with high dose B12	
Kearns-Sayre syndrome (530000)	Mitochondrial		Ophthalmoplegia, retinitis pigmentosa, heart block, ptosis	
Posterior column ataxia & Retinitis pigmentosa (PCARP / 609033)	AR	FLVCR1	Retinitis pigmentosa, sensory ganglionopathy and abnormal posterior columns on MRI	
NARP (551500)	Mitochondrial	MTATP6	See Table 1A	
Refsum Disease (266500)	AR	PHYH	See Table 1A	
PHARC syndrome (612674)	AR	ABHD12	See Table 1A	
AMACRD (614307)	AR	AMACR	See Table 1B	
SPG15 (270700)	AR	ZFYVE26	See Table 1B	
Cockayne syndrome (216400/133540)	AR	ERCC6/ERCC8	See Table 1C	
PBD9B (Refsum variant) (614879)	AR	PEX7	See Table 1C	
Congenital disorder of glycosylation type 1A (212065)	AR	PMM2	See Table 1C	
Cataracts and neuropathy syndromes	
Congenital cataracts, facial dysmorphism and neuropathy (CCFDN) (604168)	AR	CTDP1	Rudari Gypsies, congenital cataracts and microcornea, facial dysmorphism, mild cognitive impairment, neuropathy with SNCV	
CMTD1B or CMT2M (606482)	AR	DNM2	Intermediate CMT or CMT2, cataracts, ophthalmoplegia, ptosis	
Cerebrotendinous xanthomatosis (213700)	AR	CYP27A1	See Table 1A	
SPG9A (601162) / SPG9B (616586)	AD/AR	ALDH18A1	See Table 1B	
SPG46 (614409)	AR	GBA2	See Table 1B	
HLD5 / HCC (610532)	AR	FAM126A	See Table 1C	
	AR	PGDH	Cataracts, developmental delay, ataxia, axonal sensory and motor neuropathy	
C. Cranial and peripheral neuropathy syndromes	
FAP-4 (105120)	AD	GSN	Corneal lattice dystrophy, cranial neuropathies, cutix laxa	
Kearns-Sayre syndrome (530000)	mDNA deletions		Ophthalmoplegia, retinitis pigmentosa, heart block, ptosis	
MTDPS8B (612075)	AR	RRM2B	PEO, MNGIE, minimal neuropathy	
CFEOMA3 (600638)	AD	TUBB3	Congenital strabismus, rarely isolated axonal sensory-motor neuropathy, dysgenesis of the corpus callosum, finger and wrist contractures, developmental delay, Kallmann syndrome	
SBMA (313200)	XL	AR	Motor neuropathy, facial fasciculations, tremor, androgen insensitivity	
BVVLS2 (614707)	AR	SLC52A2	Facial and bulbar weakness, sensory ataxia, sensory-motor axonal neuropathy, optic atrophy, sensory neuronal hearing loss	
BVVLS1 (211530)	AR	SLC52A3	Sensory neuronal hearing loss, facial and bulbar weakness, upper limb predominant motor neuropathy	
PNMHH (614369)	AR	MYH14	Distal myopathy, motor axonal neuropathy, hoarseness, hearing loss	
Cowchock syndrome (310490)	X-linked	AIFM1	Mental retardation (60%), deafness, slowly progressive sensory and axonal neuropathy from childhood	
MELAS (540000)	Mitochondrial	MTTL1 m3243A>G	Myopathy, deafness, ophthalmoplegia, diabetes, stroke like episodes, predominantly sensory axonal neuropathy	
NF2 (101000)	AD	NF2	Bilateral acoustic schwannomas. Axonal sensory-motor neuropathy.	
Kanzaki disease (609242)	AR	NAGA	Adult onset – diffuse angiokeratoma, sensory-neural hearing loss, recurrent episodes of vertigo, sensory-motor axonal neuropathy. Periventricular white matter abnormalities on MRI.	
HSN1E (614116)	AD	DNMT1	Dementia, deafness and sensory neuropathy	
Arthrogryposis distal, with impaired proprioception and touch (617146)	AR	PIEZO2	Muscular atrophy with perinatal respiratory distress, ophthalmoplegia, arthrogryposis, and scoliosis	
ACPHD (616192)	AR	DNAJC3	Deafness. See Table 1A	
PHARC syndrome (612674)	AR	ABHD12	Deafness. See Table 1A	
Refsum Disease (266500)	AR	PHYH	Deafness. See Table 1A	
PBD9B (Refsum variant) (614879)	AR	PEX7	Deafness. See Table 1C	
MEDNIK (609313)	AR	AP1S1	Deafness. See Table 1C	
MTDPS5 (612073)	AR	SUCLA2	Deafness. See Table 1C	
MTDPS4B (613662)	AR	POLG	Deafness. See Table 2A	
CMTX5 (311070)	X-linked	PRPS1	Deafness. See Table 2B	
Perrault Syndrome (233400)	AR	HSD17B4, TWNK	Deafness, ovarian dysgenesis, learning difficulties, delayed motor development, cerebellar hypoplasia, peripheral axonal neuropathy	
ANOA (617717)	AR	FDXR	Deafness. See Table 2B.	
D. Endocrinopathy and neuropathy syndromes	
Gonadal dysgenesis with minifascicular neuropathy (607080)	AR	DHH	Gonadal dysgenesis, sensory-motor axonal neuropathy	
Adrenoleukodystrophy (300100)	XL	ABCD1	Adrenal failure, see Table 1B	
AAAS (231550)	AR	AAAS	Adrenal failure, see Table 1C	
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) (616263)	AR	PTRH2	See Table 1C	
SBMA (313200)	X-linked	AR	Androgen insensitivity, see Table 2 C	
PEPNS (616113)	AR	DMXL2	Growth retardation, hypoglycaemia, pyramidal and cerebellar signs. Peripheral neuropathy with slow conduction.	
Pituitary hormone deficiency, combined or isolated, 7 (618160)	AR	RNPC3	Hypopituitarism and neuropathy	
Lipodystrophy, Familial, Partial, Type 9	AR	PLAAT3	Lipodystrophy syndrome, demyelinating neuropathy and intellectual disability	
E. Musculoskeletal / myopathy and neuropathy syndromes	
Merosin deficient congenital muscular dystrophy (MDC1A) (607855)	AR	LAMA2	Congenital muscular dystrophy, mildly slowed PNS conduction, abnormal T2 MRI signal white matter	
MFM6 (612954)	AR	BAG3	Giant axons on nerve biopsy, myofibrillar myopathy, cardiomyopathy, scoliosis, sensory-motor axonal neuropathy.	
Limb girdle muscular dystrophy and neuropathy (181350)	AD	LMNA	Limb girdle muscular dystrophy, cardiomyopathy, sensory-motor axonal neuropathy	
MERRF (545000)	m8313G>A m8344A>G	MTTK	Myoclonic epilepsy, myopathy, lipoma, sensory axonal neuropathy	
Multiple acyl-CoA dehydrogenase deficiency (MADD) (231680)	AR	ETFDH	Neonatal and late onset forms. hypoglycaemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occur. Riboflavin responsive.	
HMN2A (158590)	AD	HSPB8	Distal hereditary motor neuropathy and proximal myopathy	
HMN2B (608634)	AD	HSPB1	Distal hereditary motor neuropathy. Myopathic changes on muscle biopsy	
Lethal congenital contracture syndrome 1 (253310)	AR	GLE1	Micrognathia, pulmonary hypoplasia, loss of anterior horn cells, intrauterine death.	
Lethal congenital contracture syndrome 2 (607598)	AR	ERBB3	Multiple joint contractures, anterior horn atrophy, death in neonatal period, distended urinary bladder	
Lethal congenital contracture syndrome 7 (602346)	AR	CNTNAP1	Congenital severe arthrogryposis multiplex congenital, demyelinating neuropathy	
Cataracts, Growth Hormone Deficiency, Sensory Neuropathy, Sensorineural hearing loss and skeletal dysplasia (CAGSSS) (616007)	AR	IARS2	Spondyloepiphyseal dysplasia, congenital cataracts, nystagmus, dysmorphic facies, sensory neuronal hearing loss, growth hormone deficiency, sensory axonal peripheral neuropathy.	
Arthrogryposis distal, with impaired proprioception and touch (617146)	AR	PIEZO2	Muscular atrophy with perinatal respiratory distress, ophthalmoplegia, arthrogryposis, and scoliosis	
Familial Neuropathic Chronic Itch	AD	COL6A5	Idiopathic chronic itch (small fibre neuropathy) and EDS (1 of 3 families)	
Arthrogryposis, Distal, Type 5D	AR	ECEL1	Contracture of lower limbs, ptosis, scoliosis, hip dislocation, short stature, Thigh MRI, fat replacement sparing rectus femoris and gracilis. EMG in one patient thought to be neurogenic.	
PNMHH (614369)	AR	MYH14	See Table 2C	
NEDHND (617519)	AR	SPTBN4	See Table 1C	
NEDCPMD (618356)	AR	NFASC	Congenital contractures, epilepsy, SNCV neuropathy	
SMABF1 (616866)	AR	TRIP4	Congenital onset, respiratory failure, slow NCV	
LCCS8 (616287)	AR	ADCY6	Distal arthrogryposis, hypotonia, respiratory distress, facial diplegia, no motor responses, no myelinated axons	
LCCS9 (616503)	AR	ADGRG6	Arthrogryposis, prenatal/neonatal death, lack of myelinated axons	
LCCS11 (617194)	AR	GLDN	Arthrogryposis, neonatal death, widened nodes of Ranvier	
AMCNMY (617468)	AR	LGI4	Arthrogryposis, foetal death, severe lack of myelinated axons	
MFM2 (608810)	AD	CRYAB	Myofibrillar myopathy, cataracts	
MFM3 (609200)	AD	MYOT	myofibrillary myopathy, cardiomyopathy	
MFM4 (609452)	AD	LDB3	myofibrillary myopathy, cardiomyopathy	
MFM5 (609524)	AD	FLNC	myofibrillary myopathy, cardiomyopathy	
				
F. Cardiomyopathy and neuropathy syndromes	
FAP-1 (105210)	AD	TTR	Dysautonomia, cardiac disease carpel tunnel syndrome, painful sensory-motor axonal neuropathy, SNCV may mimic CIDP.	
Fabry disease (301500)	X-linked	GLA	Angiokeratoma, painful sensory axonal and small fibre neuropathy, cardiomyopathy, renal failure	
Mitochondrial complex V deficiency (516070)	m8529G>A	MTATP8	Hypertrophic cardiomyopathy, ataxia, PEO, dysarthria, sensory-motor axonal neuropathy	
Noonan Syndrome 1 (163950)	AD	PTPN11	Congenital heart defect, multiple lentigines, hypertrophic neuropathy of lumbar plexus	
NARP (551500)	mitochondrial	MTATP6	See Table 1A	
Friedreich ataxia (229300)	AR	FXN	See Table 1A	
HAYOS (617183)	AD	ATAD3A	See Table 1C	
McLeod syndrome (300842)	XL	XK	See Table 2A	
Kearns-Sayre syndrome (530000)	mitochondrial		See Table 2B	
MFM6 (612954)	AR	BAG3	See Table 2E	
COXPD3 (610505)	AR	TSFM	Infantile-onset mitochondrial cardiomyopathy, progressing to Leigh syndrome, neuropathy, and optic atrophy. Mild sensory and motor axonal neuropathy	
G. Hepatic, gastrointestinal and neuropathy syndromes	
Hepatic	
MTDPS3 (251880)	AR	DGUOK	Neonatal liver failure, myopathy, sensory-motor axonal neuropathy	
MTDPS6 (256810)	AR	MPV17	Corneal opacification, neonatal liver failure, acromutilation, sensory axonal neuropathy, scoliosis, severe motor and sensory axonal neuropathy, cyclical vomiting	
SCAR21 (607982)	AR	SCYL1	See Table 1A	
Tyrosinemia type 1 (276700)	AR	FAH	See Table 2H	
Gastrointestinal	
MTDPS1 (603041)	AR	TYMP	MNGIE: Chronic pseudo-obstruction, Sensory-motor neuropathy with slow conduction (may mimic CIDP), myopathic weakness, cachexia. Leukodystrophy on MRI.	
MTDPS4B (613662)	AR	POLG	MNGIE: Chronic pseudo-obstruction, axonal sensory ataxic neuropathy, myopathic weakness, cachexia. Normal brain MRI	
MTDPS8B (612075)	AR	RRM2B	PEO, MNGIE, minimal neuropathy	
familial visceral amyloidosis (105200)	AD	B2M	Adult onset chronic diarrhoea. Autonomic and sensory-motor axonal neuropathy.	
Somatic and autonomic neuropathy	AD	PRNP	Autonomic and sensory axonal neuropathy preceding cognitive decline, Chronic diarrhoea.	
Goldberg-Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy. (609460)	AR	KIAA1279	Intellectual disability, microcephaly, dysmorphic facies, Hirschsprung disease, pachygyria, cerebellar hypoplasia (defect in neural crest migration)	
Waardenburg syndrome type 2E (611584) / PWCH (609136)	AD	SOX10	Hypopigmentation of the hair and skin, sensory hearing loss, demyelinating neuropathy, dysmyelinating leukodystrophy, developmental delay, spasticity, ataxia, Hirschsprung disease.	
AAAS (231550)	AR	AAAS	Achalasia. See Table 1C	
MEDNIK (609313)	AR	AP1S1	Congenital diarrhoea. See Table 1C	
Cerebrotendinous xanthomatosis (213700)	AR	CRP27A1	Congenital diarrhoea. See Table 1C	
FAP-1 (105210)	AD	TTR	See Table 2F	
Visceral neuropathy, Familial 1, Autosomal Recessive (243180)	AR	ERBB3	Hirschsprung, progressive axonal peripheral neuropathy, dysautonomia, Chronic Intestinal Pseudo-obstruction, hypoplasia of olfactory bulbs, external auditory canal agenesis and hearing loss	
	AR	ERBB2	As above	
H. Renal failure and neuropathy syndromes	
FAP-3 (105200)	AD	APOA1	Axonal sensory-motor neuropathy similar to TTR FAP, amyloid nephropathy	
Action myoclonus-renal failure syndrome (AMRF) (254900)	AR	SCARB2	Progressive myoclonic epilepsy with preserved cognition, onset 2nd decade, renal impairment, rarely demyelinating sensory-motor neuropathy (without renal failure)	
CMTDIE (614455)	AD	INF2	Focal segmental glomerulonephritis and sensory-motor neuropathy with intermediate conduction velocities.	
Fabry disease (301500)	X-Linked	GLA	See Table 2F	
MMACHC (277400)	AR	MMACHC	Thrombotic microangiopathy of kidneys (See Table 2I below)	
Primary hyperoxaluria type 1 (259900)	AR	AGXT	Renal failure and deposition of calcium oxalate crystals in tissues including nerve and muscle. Sensory and motor axonal neuropathy (some slowing)	
Lethal congenital contracture syndrome 2 (607598)	AR	ERBB3	See 2E. Distended urinary bladder	
I. Haematological and immunological neuropathy syndromes	
Methylmalonic aciduria and homocystinuria type Cb1c (MMACHC) (277400)	AR	MMACHC	Onset infancy to adulthood; thrombotic thrombocytopenia with encephalopathy, myelopathy, renal and pulmonary complications (can be life threatening), retinitis pigmentosa, axonal motor neuropathy. Treated with high dose vitamin B12.	
Chediak-Higashi syndrome (214500)	AR	LYST	Partial albinism, immunodeficiency, cerebellar atrophy, sensory-motor axonal neuropathy.	
Early-onset chronic axonal neuropathy, strokes, and haemolysis: inherited CD59 deficiency (612300)	AR	CD59	Onset 1st and 2nd decade. Haemolytic anaemia, strokes and relapsing immune-mediated demyelinating neuropathy	
Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) (240300)	AR (rarely AD)	AIRE	Multiple autoimmune diseases, classical triad of chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. CIDP ‘like illness’ in some patients.	
McLeod Syndrome (300842)	X-Linked	XK	See Table 2A	
J. Skin and connective tissue and neuropathy syndromes	
Xeroderma pigmentosum (278700)	AR	XPA	Photosensitivity and increased risk of cutaneous malignancy, global developmental delay, deafness, sensory-motor axonal peripheral neuropathy.	
HNARMD (608895)	AD	FBLN5	Age related macular degeneration, hyperelastic skin, demyelinating neuropathy also described.	
EDS6 (225400)	AR	PLOD1	Congenital hypotonia, joint laxity, scleral fragility, susceptibility to large vessel injury, mild sensory-motor axonal neuropathy.	
Connective tissue disorder and peripheral neuropathy (130660)	AD	EMILIN1	Aortic aneurysm, skin laxity and sensory-motor axonal neuropathy (single family reported)	
Refsum disease (266500)	AR	PHYH	Ichthyosis. See Table 1A	
PBD9B (Refsum variant) (614879)	AR	PEX7	Ichthyosis. See Table 1A	
Cerebrotendinous xanthomaosis (213700)	AR	CRP27A1	Xanthoma. See Table 1A	
SPG23 (270750)	AR	DSTYK	Skin and hair pigment abnormalities. See Table 1B	
CEDNIK syndrome (609528)	AR	SNAP29	Icthyosis and palmoplantar keratoderma. See Table 1C.	
MEDNIK (609313)	AR	AP1S1	Icthyosis and palmoplantar keratoderma. See Table 1C.	
Cowden syndrome (158350)	AD	PTEN	Skin hamartoma. See Table 1C.	
Cockayne syndrome (216400/133540)	AR	ERCC6/ERCC8	Cutaneous photosensitivity. See Table 1C	
FAP-4 (105120)	AD	GSN	Cutis laxa. See Table 2C	
Kanzaki disease (609242)	AR	NAGA	Angiokeratoma. See Table 2C	
Fabry disease (301500)	X-linked	GLA	Angiokeratoma. See Table 2C	
Phosphoserine Aminotransferase Deficiency (610992)	AR	PSAT1	Ichthyosis, arthrogryposis, axonal sensory and motor neuropathy	
K. Relapsing complex inherited neuropathy syndromes	
Porphyria, acute intermittent (AIP) (176000)	AD	HMBS	Abdominal pain, psychosis, depression, seizures, axonal predominantly motor neuropathy	
Coproporphyria (121300)	AD	CPOX	Skin photosensitivity and haemolytic anaemia. Can present acutely similar to AIP	
Porphyria, variegata (176200)	AD	PPOX	Skin photosensitivity. Acute episodes similar to AIP.	
Tyrosinemia type 1 (276700)	AR	FAH	Infantile or adolescent onset liver disease, renal tubular dysfunction and hypophosphatemic rickets. Acute episodes of neuropathy similar to AIP.	
Trifunctional protein deficiency with myopathy and neuropathy (609015)	AR	HADHA HADHB	Disorder of mitochondrial beta oxidation of fatty acids. Severe neonatal, infantile and late adolescent onset described, the latter characterised by a progressive myopathy with recurrent rhabdomyloysis and a sensory-motor axonal neuropathy. Abnormal urine organic acids.	
Maple syrup urine disease Ib (248600)	AR	CKDHB	Metabolic encephalopathy, elevated branched chain amino acids in urine, acute axonal neuropathy	
Thiamine metabolism dysfunction syndrome 4 THMD4 (613710)	AR	SLC25A19	Acute encephalopathic episodes and paralysis following febrile illness with almost complete recovery. Absent sensory-motor action potential during illness. Bilateral striatal necrosis on MRI. Additional chronic progressive axonal neuropathy	
Tangier disease (205400)	AR	ABC1	Multifocal relapsing mononeuropathies. Orange tonsils, organomegaly; pain, paresthesia, anaesthesia.	
Inherited CD59 deficiency (612300)	AR	CD59	See Table 2I	
VAIHS (615688)	AR	ADA2	Small to medium artery vasculitis	
Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK)	AR	SLC13A3	Acute encephalopathy, MRI mimicking HIE, raised urinary 2-ketoglutarate. Sensory and motor neuropathy with slow conduction velocity	
VEXAS syndrome (301054)	Somatic mutation in haematopoietic progenitor cells	UBA1	Polychondritis, myelodysplasia, demyelinating neuropathy.	

FIGURE 1 A diagnostic approach for patients with complex inherited neuropathy syndromes.

RECENT ADVANCES

Since our last review in 2017, there has been a substantial increase in the number of genes associated with complex neuropathy syndromes. This includes an increased number of repeat expansion diseases, the discovery of dominant negative variants for known recessive complex neuropathy syndromes, a new treatable complex syndrome and the discovery of genes such as SMDA9l, which causes an ataxic neuropathy syndrome associated with pancytopenia in which the pathogenic variant is selected against in haematopoietic progenitor cells potentially leading to false negative testing [2].

Complex neuropathy syndromes due to repeat expansions

NOTCH2NLC

Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disease that may present with dementia, peripheral neuropathy, autonomic dysfunction, cerebellar ataxia, parkinsonism, seizures or stroke like episodes and fluctuating encephalopathy [3,4]. The disease was described in 1968 and was defined by the presence of eosinophilic intranuclear inclusions on brain biopsy at post mortem that can also be seen in other organs including skin biopsy [5]. In addition to a histopathological signature, brain MRI in NIID commonly reveals leukoencephalopathy on fluid-attenuated inversion recovery (FLAIR) sequences and symmetrical high signal on diffusion weighted imaging (DWI) in corticomedullary junctions [6,7]. Whilst sporadic cases of NIID tend to present with dementia, familial cases cluster into two main phenotypes, a dementia dominant form and a limb weakness dominant form [8].

In 2019, three independent groups identified heterozygous CGG repeat expansions in cohorts of sporadic and familial cases of NIID from Japan and China in the 5’UTR of NOTCH2NLC[4,7,8]. These original reports included familial cases presenting with motor and sensory neuropathy and autonomic disturbance. Since the discovery of the genetic cause of NIID, there have been several reports of similar expansions in NOTCH2NLC in Chinese and Japanese peripheral neuropathy cohorts [9,10,11▪▪]. These include one Taiwanese study in which NOTCH2NLC repeat expansions accounted for 10.6% of unassigned CMT2 cases. All patients developed a sensory predominant neuropathy with an average age of onset of 37.1 (range 21–55) [9]. A separate study by Wang et al. in an unsolved peripheral neuropathy cohort, found that repeat expansions in NOTCH2NLC accounted for 3.52% of Chinese inherited neuropathy patients [12].

The largest study reporting on the prevalence and phenotype of NOTCH2NLC related peripheral neuropathy comes from a large case series of inherited peripheral neuropathy in Japan [11▪▪]. The cohort comprised 2692 Japanese patients with a diagnosis of CMT, 1783 of whom were without a genetic diagnosis. This cohort was screened for alternative causes with whole exome sequencing and RFC1 repeat analysis prior to undergoing NOTCH2NLC analysis by repeat prime PCR. Using this approach, NOTCH2NLC repeat expansions were identified in 26 cases from 22 unrelated families representing 1.2% of genetically undiagnosed Japanese patients with CMT and the seventh most common causative gene in their series excluding CMT1A. The phenotype was characterised by distal wasting and weakness (>90%) with sensory disturbance in 50% of patients. Autonomic dysfunction was common (44%) and characterised by neurogenic bladder, constipation, orthostatic hypotension and erectile dysfunction. Tremor was present in 29% of patients and myoclonus in 4%. Cognitive impairment and ataxia were present in 13 and 9% respectively. Creatine kinase was elevated (mean 559 range 51–1681). Neurophysiology revealed motor nerve conduction velocity slowing in the intermediate range (range 32–49 m/s). Brain MRI was performed in 16 out of 26 patients and was abnormal in 13/16, the most common finding being atrophy and leucoariosis. Only one MRI revealed the characteristic U-fibre high signal on DWI. Both sural nerve and peroneus brevis muscle biopsies revealed positive p62 intranuclear inclusions.

Whilst it is clear that repeat expansions in NOTCHNLC are an important cause of inherited peripheral neuropathy in far East populations, similar studies have not been reported in Northern European, North American and African populations. In Caucasian movement disorder patients in the UK, repeat expansions in NOTCH2NLC are rare suggesting a possible founder effect in East Asian populations [13].

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and RFC1

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is one of the commonest causes of late onset inherited peripheral neuropathy. It is an autosomal recessive neurodegenerative disease characterised by adult onset sensory neuropathy. Until recently, CANVAS syndrome was thought to be solely caused by biallelic repeat expansions (AAGGG) in the second intron of RFC1, which encodes for the large subunit of replication factor C, a 5 subunit DNA polymerase accessory protein [14]. As widespread screening for the repeat expansion has been introduced into clinical practice, a small proportion of individuals with typical CANVAS have been identified that do not carry two (biallelic) repeat expansions.

In two unrelated studies, compound heterozygous variants in RFC1 comprising one repeat expansion in the second intron of RFC1 on one allele and a truncating variant in RFC1 on the other allele were reported in individuals with CANVAS syndrome [15,16▪▪]. Although the total number of cases in these two studies was small (n < 10), individuals with truncating variants seemed to display a more severe phenotype with two individuals requiring a wheelchair by 50 years of age and one requiring gastrostomy feeding due to severe dysphagia. In one patient the onset of the disease was in the 3rd decade and characterised by spasticity [16▪▪].

FGF14

Autosomal dominant missense variants in FGF14 were first described as a cause of SCA27, a rare, early onset ataxic syndrome accompanied by tremor [17]. More recently, a GAA repeat expansion in intron 1 of the same gene, FGF14 was described as a common cause of autosomal dominant late onset cerebellar ataxia in a cohort of 128 patients [18]. The mean age of onset was in the 6th decade and the phenotype was characterised by gait ataxia, down beat and gaze evoked nystagmus, diplopia, cerebellar dysarthria and cerebellar atrophy on MRI. Peripheral neuropathy was rarely seen in this cohort.

In a study of 45 patients with a combination of cerebellar ataxia and either peripheral neuropathy or bilateral vestibular failure or both (and negative for the RFC1 repeat expansion), screening for the FGF14 GAA repeat expansion was positive in 43% of patients with ataxia and vestibular failure, 38% with ataxia and neuropathy and 27% with ataxia, neuropathy and vestibular areflexia [19▪]. This has led some to claim that heterozygous FGF14 repeat expansions are a phenocopy of CANVAS syndrome. Whilst this may be technically true, it is important to recognise that in this study the neuropathy was extremely mild and was a mixed motor and sensory neuropathy whereas in CANVAS syndrome due to RFC1 biallelic repeat expansions, the neuropathy is an early and prominent feature and usually purely sensory. From the available data, it does not appear that repeat expansions in FGF14 present with peripheral neuropathy unlike CANVAS syndrome.

Dominant negative variants in recessive complex diseases

Interpreting the pathogenicity of novel variants is dependent on the pattern of inheritance. For example, single heterozygous variants are usually not relevant to a recessive disease. The exception to this is the increasing discovery of heterozygous, often de novo dominant variants in genes such as SLC12A6, UCHL1 and NARS1 traditionally associated with autosomal recessive inheritance, which are thought to act through a dominant negative mechanism.

SLC12A6

Potassium chloride co-transporters (KCC) are encoded by the SLC12A family of solute carriers, of which SLC12A6 encodes for the co-transporter protein KCC3 [20]. Recessive variants in SLC12A6 cause Aldermann's syndrome, a severe early onset motor predominant peripheral neuropathy associated with variable degrees of agenesis of the corpus callosum and developmental delay [21]. In 2016, a child with a severe and progressive peripheral neuropathy was reported in association with a de novo heterozygous variant in SLC12A6[22]. In the last 4 years, there have been several case series and case reports describing patients with heterozygous variants in SLC12A6 and a broad phenotype ranging from severe cases with a childhood onset motor predominant axonal neuropathy and developmental delay similar to Alderman's syndrome through to a late onset (5th decade) sensory predominant peripheral neuropathy with no central nervous system involvement [23–26].

Ubiquitin C-terminal hydrolase L1

Autosomal recessive missense variants in Ubiquitin C-terminal hydrolase L1 (UCHL1) are a recognised cause of autosomal recessive spastic paraplegia type 79 (SPG79) which is characterised by early onset cerebellar ataxia, spastic paraplegia and optic atrophy [27–29]. In two independent case–control gene burden analyses performed in German and UK cohorts (the latter within the 100 000 genomes project), loss of function heterozygous variants in UCHL1 were found to be enriched in patients with hereditary ataxia and spastic paraplegia [30]. In the German cohort this was in addition to rare variants in SPAST, KIF5A but also POLR3A, the latter also having only previously been associated with autosomal recessive disease. The core clinical phenotype included cerebellar ataxia (present in 83%), spasticity in 77% and sensory or sensory motor axonal neuropathy in 52% although only 61% underwent neurophysiology testing. Global developmental delay was a less common feature in dominant UCHL1 disease and the age of onset ranged from childhood to 70 years of age.

Asparaginyl-tRNA synthetase

Asparaginyl-tRNA synthetase (NARS1) is a member of the amino acyl tRNA synthetases, a group of enzymes that attach amino acids to their respective tRNA. Recessive loss of function variants have been reported in several AARS genes as a cause of complex hereditary spastic paraplegia including AARS, GARS1 and DARS2[31]. This is in contrast to toxic gain of function heterozygous variants that cause a peripheral neuropathy and fall within the CMT spectrum [32]. Recently, both recessive and de novo dominant variants in NARS1 have been described to cause a complex phenotype characterised by severe global (and motor) developmental delay, microcephaly, epilepsy, ataxia and a peripheral neuropathy with slow conduction in 25% [33]. Both recessive and de-novo variants showed a similarly severe phenotype and were associated with loss of amino acetylation activity.

More recently, two variants in two families were reported in association with a pure axonal neuropathy, however a mouse model showed no phenotype in the heterozygous state and it remains uncertain as to whether dominant NARS1 variants can cause a pure neuropathy [34].

Treatable complex diseases

SLC5A6 encodes a nonselective sodium dependent transporter for biotin (B7), pantothenic acid (B5) and lipoic acid. Recessive variants in the gene were originally described in 2017 [35] in individuals presenting in the first few years of life with failure to thrive, developmental delay or regression, seizures, diarrhoea and vomiting, immunodeficiency and osteopenia. As clinical testing has become more widespread, recessive variants have been reported in families with mixed sensory and motor axonal neuropathy with variable conduction velocity slowing associated with optic atrophy and recurrent episodes of pseudo obstruction [36]. In one study, recessive variants in SLC5A6 were described in three families with onset in the second decade characterised by a motor predominant neuropathy and with subjective improvement or stabilisation with biotin, pantothenic and lipoic acid supplementation [37].

Ataxia pancytopenia syndrome and loss of pathogenic germ line variants in SAMD9L from leukocyte derived DNA

Ataxia- pancytopenia syndrome (ATXPC) due to heterozygous variants in SAMD9L was first reported in 2016 [38]. The initial clinical descriptions were of a syndrome of cerebellar ataxia and atrophy with mild pyramidal signs and white matter disease in addition to haematological abnormalities characterised by cytopenia, immunodeficiency and myelodysplasia. More recently a length dependent peripheral neuropathy with slow conduction velocity and pes-cavus has been described and in some families this can be the initial presenting feature [2,39].

Clinical and research genetic testing in the vast majority of cases of peripheral neuropathy is conducted on DNA extracted from white blood cells. This can be problematic for detecting pathogenic SAMD9L variants in affected individuals for the reasons I will outline below.

SAMD9L is a tumour suppressor gene that inhibits unregulated proliferation of haematological progenitor cells in the bone marrow. Heterozygous pathogenic variants in SAMD9L causing ATXPC exhibit a toxic gain of this function resulting in reduced cell proliferation and cytopenia. This leads to a genetic pressure whereby spontaneous somatic variants including deletions in SAMD9L that disrupt or render the inherited pathogenic SAMD9L variant null are preferentially selected for that may result in a low level of the mutant allele in blood below the limit of variant calling for many algorithms. This can be overcome by extracting DNA from nonhaematological cells or tissues such as skin. A patient with cytopenia and a peripheral neuropathy, especially with slow NCV in whom gene panel testing on blood has been negative may therefore require further testing on nonhaematological derived DNA.

CONCLUSION

As more patients are screened for an increasing number of genes, the phenotypes and presentations associated with each gene continue to expand. In the case of inherited peripheral neuropathies, it has become apparent that repeat expansions are emerging as a major cause of complex neuropathy syndromes often in association with cerebellar ataxia. As many of the 250 genes associated with a complex neuropathy syndrome can present with peripheral neuropathy, routine clinical genetic testing in CMT may need to expand to include many of these genes

Acknowledgements

We would like to thank Steven Scherer for his assistance in identifying genes associated with complex neuropathy syndromes

Financial support and sponsorship

This research was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. MMR and SH are grateful to the Wellcome Trust (G104817) for funding and MMR also acknowledges funding from the Medical Research Council (MRC MR/S005021/1), National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712 and 1UOINS109403-01), Muscular Dystrophy Association (MDA510281), Charcot Marie Tooth Association (CMTA), Alnylam Pharmaceuticals and Applied Therapeutics.

Conflicts of interest

A.M.R. has received honoraria from Anylam and AstraZeneca pharmaceuticals.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

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