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Charcot-Marie-Tooth disease recessive intermediate C(CMTRIC; RI-CMTC)

MedGen UID:: 815639
•Concept ID:: C3809309
•: Disease or Syndrome

Synonym:	CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE C
Modes of inheritance:	Autosomal recessive inheritance MedGen UID: 141025 •Concept ID: C0441748 • Intellectual Product Source: Orphanet A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	PLEKHG5 (1p36.31)

Monarch Initiative:	MONDO:0014154
OMIM®:	615376
Orphanet:	ORPHA369867

Definition

CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by Azzedine et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (608340). [from OMIM]

Clinical features

From HPO

Pes cavus

MedGen UID:: 675590
•Concept ID:: C0728829
•: Congenital Abnormality

An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).

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Hammertoe

MedGen UID:: 209712
•Concept ID:: C1136179
•: Anatomical Abnormality

Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.

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Areflexia

MedGen UID:: 115943
•Concept ID:: C0234146
•: Finding

Absence of neurologic reflexes such as the knee-jerk reaction.

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Steppage gait

MedGen UID:: 98105
•Concept ID:: C0427149
•: Finding

An abnormal gait pattern that arises from weakness of the pretibial and peroneal muscles due to a lower motor neuron lesion. Affected patients have footdrop and are unable to dorsiflex and evert the foot. The leg is lifted high on walking so that the toes clear the ground, and there may be a slapping noise when the foot strikes the ground again.

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Distal sensory impairment

MedGen UID:: 335722
•Concept ID:: C1847584
•: Finding

An abnormal reduction in sensation in the distal portions of the extremities.

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Decreased motor nerve conduction velocity

MedGen UID:: 388130
•Concept ID:: C1858729
•: Finding

A type of decreased nerve conduction velocity that affects the motor neuron.

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Decreased number of large peripheral myelinated nerve fibers

MedGen UID:: 395303
•Concept ID:: C1859606
•: Finding

A reduced number of large myelinated nerve fibers.

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Somatic sensory dysfunction

MedGen UID:: 1790456
•Concept ID:: C5551413
•: Finding

An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hypesthesia) refers to a reduction in cutaneous sensation to a specific type of testing.

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Scoliosis

MedGen UID:: 11348
•Concept ID:: C0036439
•: Disease or Syndrome

The presence of an abnormal lateral curvature of the spine.

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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Distal amyotrophy

MedGen UID:: 338530
•Concept ID:: C1848736
•: Disease or Syndrome

Muscular atrophy affecting muscles in the distal portions of the extremities.

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Mildly elevated creatine kinase

MedGen UID:: 342469
•Concept ID:: C1850309
•: Finding

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Abnormality of limbs
- Hammertoe
- Pes cavus
Abnormality of metabolism/homeostasis
- Mildly elevated creatine kinase
Abnormality of the musculoskeletal system
Abnormality of the nervous system

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVCharcot-Marie-Tooth disease recessive intermediate C

Autosomal recessive intermediate Charcot-Marie-Tooth disease
- Charcot-Marie-Tooth disease recessive intermediate C

Follow this link to review classifications for Charcot-Marie-Tooth disease recessive intermediate C in Orphanet.

Recent clinical studies

Etiology

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

Nicolaou P, Cianchetti C, Minaidou A, Marrosu G, Zamba-Papanicolaou E, Middleton L, Christodoulou K
Eur J Hum Genet 2013 Feb;21(2):190-4. Epub 2012 Jul 11 doi: 10.1038/ejhg.2012.146. PMID: 22781092 Free PMC Article

See all (1)

Diagnosis

Pons N, Fernández-Eulate G, Pegat A, Théaudin M, Guieu R, Ripellino P, Devedjian M, Mace P, Masingue M, Léonard-Louis S, Petiot P, Roche P, Bernard E, Bouhour F, Good JM, Verschueren A, Grapperon AM, Salort E, Grosset A, Chanson JB, Nadaj-Pakleza A, Bédat-Millet AL, Choumert A, Barnier A, Hamdi G, Lesca G, Prieur F, Bruneel A, Latour P, Stojkovic T, Attarian S, Bonello-Palot N
Eur J Neurol 2023 Jul;30(7):2001-2011. Epub 2023 Apr 4 doi: 10.1111/ene.15793. PMID: 36943151

See all (1)

Prognosis

Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.

Shi J, Zhao F, Pang X, Huang S, Wang J, Chang X, Zhang J, Liu Y, Guo J, Zhang W
Neuromuscul Disord 2021 Feb;31(2):149-157. Epub 2020 Nov 18 doi: 10.1016/j.nmd.2020.11.002. PMID: 33323309

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy.

Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S, Tazir M, Demir E, Topaloglu H, Korinthenberg R, Tüysüz B, Landrieu P, Hentati F, Koenig M
Nat Genet 2000 Nov;26(3):370-4. doi: 10.1038/81701. PMID: 11062483

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Clinical prediction guides

Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy.

Shi J, Zhao F, Pang X, Huang S, Wang J, Chang X, Zhang J, Liu Y, Guo J, Zhang W
Neuromuscul Disord 2021 Feb;31(2):149-157. Epub 2020 Nov 18 doi: 10.1016/j.nmd.2020.11.002. PMID: 33323309

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.

Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A, Züchner S, De Jonghe P, Rudnik-Schöneborn S, Zerres K, Schröder JM
Brain 2003 Mar;126(Pt 3):642-9. doi: 10.1093/brain/awg068. PMID: 12566285

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy.

See all (4)

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Charcot-Marie-Tooth disease recessive intermediate C(CMTRIC; RI-CMTC)

Definition

Clinical features

Term Hierarchy

Recent clinical studies

Etiology

Diagnosis

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

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