Summary
NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
Clinical characteristics.
Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.
Diagnosis/testing.
The diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and molecular genetic testing. Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J).
Management.
Treatment of manifestations: Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless leg syndrome.
Prevention of secondary complications: Daily heel cord stretching to prevent Achilles' tendon shortening.
Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.
Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage.
Other: Career and employment counseling.
Genetic counseling.
The CMT4 subtypes are inherited in an autosomal recessive manner. Parents of an affected individual are obligate carriers of the CMT4-related pathogenic variant present in their family. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in an affected family member are known.
Clinical Characteristics
Clinical Description
The clinical findings of a peripheral neuropathy, slow NCV, mode of inheritance, and biallelic pathogenic variants in a specific gene have been the basis for classification for the majority of CMT subtypes.
Individuals with CMT4 usually have the clinical characteristics of the CMT phenotype, including distal muscle weakness and atrophy, sensory loss, and, often, pes cavus foot deformity. (See CMT Overview for more details.) Both axonal and demyelinating neuropathies are included in CMT4.
The autosomal recessive neuropathies tend to have an earlier onset (early childhood) and more severe progression than the autosomal dominant varieties. Except in the case of consanguinity, they also appear only in sibs or as simplex cases.
CMT4A was first identified in families in Tunisia. Typically, delayed motor development is noted in the second year of life. Distal muscle weakness and atrophy of feet progress to involve the proximal muscles by the end of the first decade. Hand atrophy may occur later. It is common for affected individuals to become wheelchair dependent, often by age 30 years [Claramunt et al 2005].
Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [Nelis et al 2002b, Claramunt et al 2005, Kabzińska et al 2006b]. NCVs range from very slow to normal (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a].
Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. Vocal cord paresis may occur [Sevilla et al 2003, Stojkovic et al 2004, Sevilla et al 2008].
Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [Nelis et al 2002b, Kabzińska et al 2005, Kabzińska et al 2006b].
Cerebrospinal fluid protein concentration is normal.
Manifesting heterozygotes. Some individuals with a heterozygous GDAP1 pathogenic variant can have mild signs and symptoms of neuropathy compatible with autosomal dominant inheritance [Zimoń et al 2011, Kabzińska et al 2014].
CMT4B1 was first described in an Italian family by Quattrone et al [1996]. Five families of Italian and Saudi Arabian ancestry have been reported [Bolino et al 2000, Houlden 2001]. Nelis et al [2002a] and Parman et al [2004] reported two additional families showing variability in age of onset and severity. Progressive distal and proximal weakness of the lower limbs is noted in early childhood (mean onset age 34 months). Pes cavus foot deformity is common and a few individuals develop facial weakness. Nouioua et al [2011] reported associated vocal cord paresis, chest deformities, and claw hands.
Adults who are affected are seriously handicapped and frequently require wheelchairs by age 20 years. Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade. Intellect is normal.
Two families were reported by Parman et al [2004].
In a family with an MTMR2 pathogenic variant and a 17p11.2 duplication, the phenotype was severe early childhood-onset demyelinating neuropathy [Verny et al 2004].
Auditory evoked potentials are abnormal.
NCVs are very slow (15-17 m/s) and often undetectable.
Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.
CMT4B2 was identified in a Turkish family with a severe sensorimotor neuropathy with slow nerve conduction and focally folded myelin [Othmane et al 1999]. Azzedine et al [2003] identified two families from Tunisia and Morocco who also had early-onset glaucoma. Additional families have been reported [Conforti et al 2004, Chen et al 2014] including one with juvenile glaucoma [Hirano et al 2004].
A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [Kiwaki et al 2000]. A pathogenic variant in SBF2 was subsequently identified in this family [Hirano et al 2004].
CMT4B3 was identified in a single Korean family with demyelinating phenotype and focally folded myelin sheaths on nerve biopsy [Nakhro et al 2013]. Bohlega et al [2011] reported a consanguineous Saudi family with sensory motor neuropathy with marked hand weakness, microcephaly, and cognitive impairment.
CMT4C was initially reported in consanguineous Algerian families, and subsequently in families from other countries of North Africa and western Europe [Gabreëls-Festen et al 1999, Senderek et al 2003b, Parman et al 2004]. Onset is in childhood or adolescence, often associated with pes cavus foot deformity and a mild walking disability with a progressive, often severe scoliosis after a 15-year disease duration. Houlden et al [2009b] noted considerable clinical variability, ranging from severe childhood onset to mild scoliosis and foot deformity.
Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by Ferrarini et al [2011].
Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).
Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [Gabreëls-Festen et al 1999].
Manifesting heterozygotes.
Lupski et al [2010] have suggested that persons heterozygous for either the SH3TC2 pathogenic variant p.Arg954Ter or p.Tyr169His may be at risk for a mild late-onset neuropathy.
CMT4D has been reported in Bulgarian Gypsies by Kalaydjieva et al [1998] originating from the community of Lom on the Danube caused by a founder NDRG1 pathogenic variant (p.Arg148Ter). Progressive sensory motor neuropathy with slow NCVs is present and foot deformity is common [Guergueltcheva et al 2006, Claramunt et al 2007, Ricard et al 2013, Okamoto et al 2014].
CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade. Tongue atrophy has also been described.
A non-Gypsy family with CNS white matter lesions has been reported [Echaniz-Laguna et al 2007].
Nerve biopsy shows a hypertrophic onion bulb change.
CMT4E is a congenital hypomyelinating neuropathy (CHN) with early-onset slow NCVs and a Déjérine-Sottas syndrome-like presentation (see Nomenclature) [Boerkoel et al 2001a, Chung et al 2005]. Respiratory dysfunction and cranial nerve abnormalities may occur [Szigeti et al 2007].
Funalot et al [2012] have reported a child with severe CHN.
CMT4F is the designation for a severe demyelinating neuropathy with slow NCVs reported in three families [Delague et al 2000, Boerkoel et al 2001b, Guilbot et al 2001, Kijima et al 2004, Parman et al 2004].
Takashima et al [2002] described sibs in whom the phenotype was initially a marked sensory neuropathy with prominent demyelinating features.
A child had delayed motor milestones and marked weakness. Additional families are described by Kabzińska et al [2006a] and Otagiri et al [2006].
A more benign phenotype with later age of onset (7-12 years) but with marked spine deformities was reported by Nouioua et al [2011]. Tokunaga et al [2012] have also reported later onset and more benign course (including vocal cord paresis in one individual).
Prominent sensory loss occurred in one family [Auer-Grumbach et al 2008]. Sensory loss was also emphasized by Marchesi et al [2010].
Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.
CMT4G is a severe disabling form of peripheral neuropathy with prominent sensory loss and moderately reduced motor NCVs in Balkan (Russe) Gypsies linked to 10q22 [Guergueltcheva et al 2006, Hantke et al 2009]. CMT4G is less severe than CMT4D.
CMT4H was reported by De Sandre-Giovannoli et al [2005] as a severe demyelinating neuropathy linked to 12p11.2- p13.1. Associated findings are severe scoliosis, loss of myelinated nerve fibers, and outfoldings of the myelin sheath [Stendel et al 2007]. The early onset and prominent kyphoscoliosis have been confirmed in a Tunisian family reported by Boubaker et al [2013].
Two sibs in Ireland remained ambulatory into middle age [Houlden et al 2009a].
An Algerian and a Lebanese affected individual had marked slowing of nerve conductions [Baudot et al 2012].
CMT4J is a syndrome of severe childhood-onset demyelinating neuropathy [Chow et al 2007]. An individual with rapidly progressive paralysis without sensory symptoms was reported [Zhang et al 2008]. Nicholson et al [2011] have emphasized the highly variable onset age and severity, proximal and distal weakness that may be asymmetric, and frequent progression to severe amyotrophy.
Menezes et al [2014] reported a two generation family with a variety of compound heterozygous FIG4 pathogenic variants that masqueraded as “autosomal dominant” inheritance.
Nomenclature
Severe neuropathy with slow NCVs and onset in early childhood is often called the Déjérine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by pathogenic variants in multiple genes [Plante-Bordeneuve & Said 2002] (see CMT Overview).
Differential Diagnosis
See CMT Overview for a discussion of approach to diagnosis of other autosomal recessive disorders with peripheral neuropathy. Guidelines for genetic testing of individuals suspected of having a neuromuscular condition, such as CMT, have been published by Burgunder et al [2011] and Murphy et al [2012].
Baets et al [2011] reviewed the genetic spectrum of hereditary neuropathies presenting in the first year of life. The most common disorders are the CMT4 subtypes CMT4B2 (SBF2), CMT4C (SH3TC2), CMT4F (PRX), and CMT4H (FGD4).
CMT1E. Autosomal recessive inheritance of severe neuropathy has also been reported with homozygosity for single nucleotide variants in PMP22, in which heterozygous pathogenic variants typically cause the CMT1 phenotype. Parman et al [1999] and Numakura et al [2000] reported pathogenic variants in codon 157 (p.Arg157Gly) of PMP22 (NM_000304.2). The family reported by Parman et al [1999] included three sibs homozygous for the pathogenic variant and heterozygous, consanguineous, unaffected parents.
CMT2B1 is inherited in an autosomal recessive manner. In Algerian families, an autosomal recessive childhood- or adult-onset axonal neuropathy with progressively severe muscle weakness and wasting has been attributed to a unique homozygous pathogenic variant (p.Arg298Cys) in LMNA (NM_005572.3) which encodes the lamin A/C nuclear envelope proteins [De Sandre-Giovannoli et al 2002, Tazir et al 2004, Bouhouche et al 2007]. LMNA is mutated in several other genetic diseases, including Hutchinson-Gilford progeria syndrome.
CMT2B2.
Leal et al [2001] reported an axonal neuropathy of late onset (mean age 34 years) in a Costa Rican family linked to 19q13.3. Berghoff et al [2004] further characterized this family and Rautenstrauss et al [2005] preliminarily reported a pathogenic variant in MED25. Some authors refer to this as CMT2B2 because it is an axonal neuropathy (although inherited in an autosomal recessive manner rather than an autosomal dominant manner).
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum, an autosomal recessive severe sensorimotor neuropathy with intellectual disability and agenesis of the corpus callosum has been reported in individuals from Quebec. It is caused by pathogenic variants in SLC12A6 (former names: ACCPN, KCC3), the gene encoding the K-Cl cotransporter [Howard et al 2002].
Other unclassified autosomal recessive neuropathies
HINT1. Loss-of-function pathogenic variants cause a motor (greater than sensory) axonal neuropathy with neuromyotonia (spontaneous high-frequency motor unit potentials on EMG) and myokymia [
Zimoń et al 2012].
Hahn et al [1991] described the clinical details of this disorder including muscle cramping, twitching, distal weakness, and increased perspiration.
MME.
Higuchi et al [2016] reported ten families from Japan with late onset (4
th-6
th decade) of axonal neuropathy associated with weakness, muscle atrophy, and sensory loss in the lower limbs. Homozygous and
compound heterozygous missense and
nonsense variants were identified in
MME. Although
MME encodes neprilysin (NEP) which is known to degrade beta amyloid, no evidence of dementia or Aβ accumulation was found [
Higuchi et al 2016].
SIGMAR1.
Li et al [2015] reported a
consanguineous Chinese family with a childhood-onset distal motor neuropathy associated with distal muscle weakness and atrophy,
pes cavus, and claw hands segregating an alternative
splicing event in SIGMAR1 resulting in a truncated protein.
SURF1. Three individuals from
consanguineous families with childhood-onset demyelinating motor/sensory neuropathy associated with nystagmus, lactic acidosis, hyperintense lesions in the putamen on T
1-weighted MRI, and later development of cerebellar ataxia had complex IV deficiency in muscle fibers associated with
biallelic (i.e.,
homozygous or
compound heterozygous)
SURF1 pathogenic variants [
Echaniz-Laguna et al 2013]. Mutation of
SURF1 has also been associated with
Leigh syndrome.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Charcot-Marie-Tooth Neuropathy Type 4: Genes and Databases
View in own window
Locus Name | Gene | Chromosome Locus | Protein | Locus-Specific Databases | HGMD | ClinVar |
---|
CMT4B1 |
MTMR2
|
11q21
|
Myotubularin-related protein 2
|
MTMR2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MTMR2
|
MTMR2
|
MTMR2
|
CMT4B2 |
SBF2
|
11p15.4
|
Myotubularin-related protein 13
|
SBF2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, SBF4
|
SBF2
|
SBF2
|
CMT4B3 |
SBF1
|
22q13.33
|
Myotubularin-related protein 5
| |
SBF1
|
SBF1
|
CMT4C |
SH3TC2
|
5q32
|
SH3 domain and tetratricopeptide repeat-containing protein 2
|
SH3TC2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, SH3TC2
|
SH3TC2
|
SH3TC2
|
CMT4D |
NDRG1
|
8q24.22
|
Protein NDRG1
|
NDRG1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, NDRG1
|
NDRG1
|
NDRG1
|
CMT4E |
EGR2
|
10q21.3
|
E3 SUMO-protein ligase EGR2
|
EGR2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, EGR2
|
EGR2
|
EGR2
|
CMT4F |
PRX
|
19q13.2
|
Periaxin
|
PRX homepage - Leiden Muscular Dystrophy pages
IPN Mutations, PRX
|
PRX
|
PRX
|
CMT4G |
HK1
|
10q22.1
|
Hexokinase-1
|
HK1 database
|
HK1
|
HK1
|
CMT4H |
FGD4
|
12p11.21
|
FYVE, RhoGEF and PH domain-containing protein 4
|
IPN Mutations, FGD4
FGD4 homepage - Leiden Muscular Dystrophy pages
|
FGD4
|
FGD4
|
CMT4J |
FIG4
|
6q21
|
Polyphosphoinositide phosphatase
|
IPN Mutations, FIG4
alsod/FIG4 genetic mutations
FIG4 homepage - Leiden Muscular Dystrophy pages
|
FIG4
|
FIG4
|
|
GDAP1
|
8q21.11
|
Ganglioside-induced differentiation-associated protein 1
|
GDAP1 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, GAPD1
|
GDAP1
|
GDAP1
|
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
View in own window
129010 | EARLY GROWTH RESPONSE 2; EGR2 |
142600 | HEXOKINASE 1; HK1 |
145900 | HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS |
214400 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4A; CMT4A |
601382 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B1; CMT4B1 |
601455 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4D; CMT4D |
601596 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4C; CMT4C |
603557 | MYOTUBULARIN-RELATED PROTEIN 2; MTMR2 |
603560 | SET-BINDING FACTOR 1; SBF1 |
604563 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B2; CMT4B2 |
605253 | NEUROPATHY, CONGENITAL HYPOMYELINATING OR AMYELINATING, AUTOSOMAL RECESSIVE; CHN |
605262 | NMYC DOWNSTREAM-REGULATED GENE 1; NDRG1 |
605285 | NEUROPATHY, HEREDITARY MOTOR AND SENSORY, RUSSE TYPE; HMSNR |
605725 | PERIAXIN; PRX |
606598 | GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1 |
607697 | SET-BINDING FACTOR 2; SBF2 |
608206 | SH3 DOMAIN AND TETRATRICOPEPTIDE REPEAT DOMAIN 2; SH3TC2 |
609311 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4H; CMT4H |
609390 | FIG4, S. CEREVISIAE, HOMOLOG OF; FIG4 |
611104 | FYVE, RhoGEF, AND PH DOMAIN-CONTAINING PROTEIN 4; FGD4 |
611228 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J; CMT4J |
615284 | CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B3; CMT4B3 |
For a detailed summary of gene and protein information for the following genes, see Table A, Gene.
GDAP1
Gene structure. The gene comprises six exons, 13.9 kb, and an open reading frame of 1,077 nucleotides.
Pathogenic variants. Nonsense, missense, and frameshift variants
Table 3.
Selected GDAP1 Pathogenic Variants
View in own window
DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.347T>G | p.Met116Arg |
NM_018972.2
NP_061845.2
|
c.487C>T | p.Gln163Ter |
c.358C>T 1 | p.Arg120Trp |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. Ganglioside-induced differentiation-associated protein 1 [Baxter et al 2002]. The protein is highly expressed in neuronal mitochondria [Pedrola et al 2005].
Abnormal gene product. It is speculated that pathogenic variants may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells. Pathogenic variants in GDAP1 cause abnormalities of mitochondrial dynamics [Cassereau et al 2011, Noack et al 2012].
MTMR2
Gene structure. The gene comprises 18 exons with an ORF of 1,932 nucleotides.
Pathogenic variants. Missense, nonsense, and splicing variants and small deletions
Table 4.
Selected MTMR2 Pathogenic Variants
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Myotubularin-related protein 2 (MTMR2), a 643-amino acid protein, dephosphorylates phosphatidylinositol 3-phosphate. MTMR2 may interact with SBF2/MTMR13, the protein involved in CMT4B2 [Bolis et al 2007].
Abnormal gene product. Reduced phosphatase activity could cause malfunction of neural membrane recycling or trafficking [Berger et al 2002]. A mouse model with the equivalent of the human p.Glu276Ter pathogenic variant has been produced [Bonneick et al 2005] with myelin infoldings and outfoldings but no electrophysiologic changes. Cotter et al [2010] and Vaccari et al [2011]. show evidence that MTMR2 and FIG4 interact in both Schwann cells and neurons and that imbalance of PtdIns(3,5)P(2) is the basis of altered myelin growth.
SBF2 (MTMR13)
Gene structure.
SBF2 (also called MTMR13; myotubularin-related 13 gene) has at least 40 exons spanning approximately 600 kb.
Pathogenic variants. One family with CMT4B2 has a homozygous in-frame deletion of SBF2 exons 11 and 12 [Senderek et al 2003c]. Two nonsense variants in exons 23 and 27 have been reported [Azzedine et al 2003]. An Italian family had a pathogenic variant in the splice donor site of intron 32 [Conforti et al 2004].
Normal gene product.
SBF2 is an 1849-amino acid member of the pseudophosphatase branch of myotubularins with striking homology to MTMR2, the gene that is mutated in CMT4B1.
Abnormal gene product. The pathogenic variant associated with SBF2 is predicted to disrupt an N-terminal domain of SBF2 that is highly conserved and may be important in sequestering proteins in the cytoplasmic compartment. A mouse model has reduced nerve conductions and myelin outfoldings/infoldings [Robinson et al 2008].
SBF1 (MTMR5)
Gene structure.
SBF1 comprises 41 exons (NM_002972.2).
Pathogenic variants.
Nakhro et al [2013] found the heterozygous missense variants (c.1249A>G;p.Met417Val and c.4768A>G;p.Thr1590Ala) in a family with autosomal recessive demyelinating CMT.
Normal gene product. SET binding factor 1 is a member of the myotublarin family without known enzymatic function. SBF1 protein (1893 amino acids) and its mRNA have 59% overall sequence identity to SBF2.
Abnormal gene product. Mutation results in abnormal peripheral nerve/Schwann cell dysfunction by unknown mechanisms, possibly through interaction with myotubularin related protein 2 (MTMR2).
SH3TC2
Gene structure. 62 kb of genomic sequence with 18 exons. Alternative splicing events may occur at exon 6 and between exons 8 and 9 with retention of intron 10.
Pathogenic variants. Eight protein-truncating pathogenic variants and three missense variants (homozygous or compound heterozygous) [Senderek et al 2003b]; p.Arg954Ter is a common pathogenic variant [Houlden et al 2009b].
Table 5.
Selected SH3TC2 Pathogenic Variants
View in own window
DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.505T>C | p.Tyr169His |
NM_024577.3
NP_078853.2
|
c.2860C>T | p.Arg954Ter |
c.3325C>T | p.Arg1109Ter 1 |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. The ORF predicts a protein of 1,288 amino acids with no known function.
Abnormal gene product. Pathogenic variants may disrupt the formation of protein complexes. SH3TC2 pathogenic variants disrupt an interaction with Rab11 in myelin formation [Stendel et al 2010].
NDRG1
Gene structure. 60 kb of genomic DNA containing 16 exons, including an untranslated first exon
Pathogenic variants. A premature termination codon at position 148 (p.Arg148Ter) [Kalaydjieva et al 2000]
Table 6.
Selected NDRG1 Pathogenic Variants
View in own window
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. It is proposed that the protein NDRG1 is involved in growth arrest and cell differentiation during development. It is highly expressed in peripheral nerves and Schwann cells.
Abnormal gene product. Abnormal protein NDRG1 may have abnormal interaction with PMP22 preventing development and maintenance of peripheral nerve/Schwann cell function and integrity.
EGR2
Gene structure.
EGR2 spans 4.3 kb and has two coding exons.
Pathogenic variants. Homozygosity for p.Ile268Asn has been observed.
Table 7.
Selected EGR2 Pathogenic Variants
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Early growth response protein 2. Zinc finger transcription factor. Ortholog of murine Krox-2. Induces expression of several proteins involved in myelin sheath formation and maintenance.
Abnormal gene product. Krox-2 null mice show a block of Schwann cell differentiation. Conduction block occurs in a mouse model with the p.Ile268Asn pathogenic variant in EGR2 [Baloh et al 2009].
PRX
Gene structure.
Boerkoel et al [2001b] found two PRX transcripts of 4853 and 5502 bp, excluding the polyA tails. The shorter mRNA is transcribed from seven exons and the deduced coding sequence extends from exon 4 through exon 7. The longer transcript arises by retention of intron 6, which introduces a stop codon and results in a truncated protein with an intron-encoded carboxyl terminus of 21 amino acids.
Pathogenic variants. Nonsense and frameshift pathogenic variants. The pathogenic variant p.Arg1070Ter is a mutation hot spot [Otagiri et al 2006].
Table 8.
Selected PRX Pathogenic Variants
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DNA Nucleotide Change | Predicted Protein Change (Alias 1) | Reference Sequences |
---|
c.247delC | p.Leu83CysfsTer14 (Arg82fsTer96) |
NM_181882.2
NP_870998.2
|
c.1951G>A | p.Asp651Asn |
c.2098delG | p.Ala700ProfsTer18 (Ala700ProfsTer17) |
c.2145T>A | p.Cys715Ter |
c.3208C>T | p.Arg1070Ter |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product. L and S periaxin, cytoskeletal proteins that may regulate Schwann cell shape and bind dystroglycan dystrophin-related protein-2. Found in the paranodal region of mature myelin sheaths. As myelin matures, periaxin moves from the adaxonal to the abaxonal membrane [Saifi et al 2003].
Abnormal gene product. Mice disrupted for Prx develop PNS compact myelin that degenerates as animals age [Gillespie et al 2000].
HK1
Gene structure. HK1 transcript variant NM_033498.2 has 21 exons including two noncoding exons. The gene spans 75-100kb. Alternative splicing results in five different transcript variants, some of which are tissue-specific. For details, see Table A, Gene. Note that HK1 is one of four different genes (with HK2, HK3, and HK4) encoding different forms of hexokinase.
Pathogenic variants. c.-249-3838G>C in an alternative untranslated exon of HK1 [Gabrikova et al 2013, Sevilla et al 2013] is a founder variant in the Balkan (Russe) Gypsies [Rogers et al 2000, Thomas et al 2001, Sevilla et al 2013].
Table 9.
HK1 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change (Alias 1) | Predicted Protein Change | Reference Sequence |
---|
c.-249-3838G>C 2, 3 (g.9712G>C) 4 | None 2 |
NM_033498.2
|
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
- 2.
- 3.
See rs397514654 for additional HGVS names and reference sequences for this variant.
- 4.
Normal gene product. Hexokinase catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Mitochondrially associated HK1 plays a role in growth factor- and Akt-mediated cell survival.
Abnormal gene product. Pathogenic variants in the HK1 coding sequence lead to enzyme deficiency and nonspherocytic hemolytic anemia. The consequence of the c.-249-3838G>C change in the untranslated exon associated with neuropathy is unknown.
FGD4
Gene structure.
FGD4 has 17 exons and a transcript of 2931 nucleotides [Delague et al 2007].
Pathogenic variants. Homozygous missense variants (p.Met298Arg and p.Met298Thr) [Delague et al 2007] as well as nonsense and frameshift variants are reported [Stendel et al 2007]. Missense, frameshift, and nonsense pathogenic variants and deletion of exon 2 have been reported [Delague et al 2007, Nicholson et al 2011].
Table 10.
Selected FGD4 Pathogenic Variants
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.823C>T | p.Arg275Ter |
NM_139241.2
NP_640334.2
|
c.893T>G | p.Met298Arg |
c.1325G>A | p.Arg442His |
c.893T>C | p.Met298Thr |
c.1698G>H 1 | p.Met566Ile |
c.1762-2A>G | -- |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
H indicates sequence ambiguity; could be A, C, or T nucleotide.
Normal gene product.
FGD4 encodes FYVE, RhoGEF and PH domain-containing protein 4 (frabin), a 766 amino-acid protein nucleotide exchange factor mediating actin cytoskeletal changes.
Abnormal gene product. Rat spiral motoneurons with Fgd4 pathogenic variants have reduced microspike formation [Delague et al 2007].
FIG4
Gene structure.
FIG4 has 23 coding exons.
Pathogenic variants. In four families, the p.Ile41Thr missense pathogenic variant in exon 2 occurs in the compound heterozygous state with several other protein truncating variants in affected persons [Chow et al 2007].
Table 11.
Selected FIG4 Pathogenic Variants
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Phosphatidylinositol 3, 5 biphosphate (PtdIns (3,5) P2)
Abnormal gene product. Mice with a pathogenic variant in Fig4 (pale tremor mouse) have a complex phenotype that includes peripheral neuropathy and neurodegeneration in autonomic ganglia, cerebral cortex, and deep cerebellar nuclei, skin, and spleen [Chow et al 2007, Winters et al 2011]. Cotter et al [2010] and Vaccari et al [2011] show evidence that MTMR2 and FIG4 interact in both Schwann cells and neurons and that imbalance of PtdIns(3,5)P(2) is the basis of altered myelin growth. The common p.Ile41Thr pathogenic variant produces an unstable protein and a level of 10% of normal may be sufficient for nerve survival [Lenk et al 2011].