U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Charcot-Marie-Tooth disease type 4C(CMT4C)

MedGen UID:
356581
Concept ID:
C1866636
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4C; Charcot-Marie-Tooth Neuropathy Type 4C; Charcot-Marie-Tooth Neuropathy Type 4C (CMT4C); CMT 4C; CMT4C
SNOMED CT: Charcot-Marie-Tooth disease type 4C (715797002)
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).
 
Gene (location): SH3TC2 (5q32)
 
Monarch Initiative: MONDO:0011113
OMIM®: 601596
Orphanet: ORPHA99949

Definition

SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems. [from GeneReviews]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
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).
Hammertoe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Upper limb muscle weakness
MedGen UID:
305607
Concept ID:
C1698196
Finding
Weakness of the muscles of the arms.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Abnormal cranial nerve morphology
MedGen UID:
344302
Concept ID:
C1854510
Anatomical Abnormality
Structural abnormality affecting one or more of the cranial nerves, which emerge directly from the brain stem.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Decreased number of large peripheral myelinated nerve fibers
MedGen UID:
395303
Concept ID:
C1859606
Finding
A reduced number of large myelinated nerve fibers.
Basal lamina onion bulb formation
MedGen UID:
401045
Concept ID:
C1866637
Finding
A type of onion bulb formation prominently affecting the area of the basal lamina.
Segmental peripheral demyelination
MedGen UID:
870491
Concept ID:
C4024938
Finding
A loss of myelin from the internode regions along myelinated nerve fibers from segments of the peripheral nervous system.
Delayed brainstem auditory evoked response conduction time
MedGen UID:
870862
Concept ID:
C4025322
Finding
An abnormal increase (delay) in the conduction time of the brainstem auditory-evoked response.
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
Greater auricular nerve thickening
MedGen UID:
1815090
Concept ID:
C5706184
Anatomical Abnormality
Increase in thickness of the great auricular nerve, a cutaneous nerve of the head. It originates from the cervical plexus, with branches of spinal nerves C2 and C3. Thickening may lead to the nerve being palpable or even visible in this region.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.
Tongue atrophy
MedGen UID:
66828
Concept ID:
C0241423
Finding
Wasting of the tongue.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Abnormal pupillary light reflex
MedGen UID:
370954
Concept ID:
C1970591
Finding
An abnormality of the reflex that controls the diameter of the pupil, in response to the intensity of light that falls on the retina of the eye.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease type 4C in Orphanet.

Professional guidelines

PubMed

Georgiou E, Kagiava A, Sargiannidou I, Schiza N, Stavrou M, Richter J, Tryfonos C, Heslegrave A, Zetterberg H, Christodoulou C, Kleopa KA
Mol Ther 2023 Nov 1;31(11):3290-3307. Epub 2023 Aug 28 doi: 10.1016/j.ymthe.2023.08.020. PMID: 37641403Free PMC Article

Recent clinical studies

Etiology

Kanwal S, Choi YJ, Lim SO, Choi HJ, Park JH, Nuzhat R, Khan A, Perveen S, Choi BO, Chung KW
BMC Med Genomics 2021 Jun 30;14(1):174. doi: 10.1186/s12920-021-01019-5. PMID: 34193129Free PMC Article
Jerath NU, Mankodi A, Crawford TO, Grunseich C, Baloui H, Nnamdi-Emeratom C, Schindler AB, Heiman-Patterson T, Chrast R, Shy ME
Muscle Nerve 2018 May;57(5):749-755. Epub 2017 Oct 24 doi: 10.1002/mus.25981. PMID: 28981955Free PMC Article
Sivera R, Cavalle L, Vílchez JJ, Espinós C, Pérez Garrigues H, Sevilla T
J Int Adv Otol 2017 Apr;13(1):93-99. doi: 10.5152/iao.2017.3379. PMID: 28555600
Piscosquito G, Saveri P, Magri S, Ciano C, Gandioli C, Morbin M, Bella DD, Moroni I, Taroni F, Pareyson D
J Peripher Nerv Syst 2016 Sep;21(3):142-9. doi: 10.1111/jns.12175. PMID: 27231023Free PMC Article
Houlden H, Laura M, Ginsberg L, Jungbluth H, Robb SA, Blake J, Robinson S, King RH, Reilly MM
Neuromuscul Disord 2009 Apr;19(4):264-9. Epub 2009 Mar 9 doi: 10.1016/j.nmd.2009.01.006. PMID: 19272779

Diagnosis

Pisciotta C, Bertini A, Tramacere I, Manganelli F, Fabrizi GM, Schenone A, Tozza S, Cavallaro T, Taioli F, Ferrarini M, Grandis M, Bellone E, Mandich P, Previtali SC, Falzone Y, Allegri I, Padua L, Pazzaglia C, Quattrone A, Valentino P, Gentile L, Russo M, Calabrese D, Moroni I, Pagliano E, Saveri P, Magri S, Baratta S, Taroni F, Mazzeo A, Santoro L, Vita G, Pareyson D; Italian CMT Network
Eur J Neurol 2023 Aug;30(8):2461-2470. Epub 2023 May 26 doi: 10.1111/ene.15860. PMID: 37170966
Sun B, He ZQ, Li YR, Bai JM, Wang HR, Wang HF, Cui F, Yang F, Huang XS
Acta Neurol Belg 2022 Oct;122(5):1169-1175. Epub 2021 Feb 15 doi: 10.1007/s13760-021-01605-5. PMID: 33587240
Kanwal S, Choi YJ, Lim SO, Choi HJ, Park JH, Nuzhat R, Khan A, Perveen S, Choi BO, Chung KW
BMC Med Genomics 2021 Jun 30;14(1):174. doi: 10.1186/s12920-021-01019-5. PMID: 34193129Free PMC Article
Jerath NU, Mankodi A, Crawford TO, Grunseich C, Baloui H, Nnamdi-Emeratom C, Schindler AB, Heiman-Patterson T, Chrast R, Shy ME
Muscle Nerve 2018 May;57(5):749-755. Epub 2017 Oct 24 doi: 10.1002/mus.25981. PMID: 28981955Free PMC Article
Sivera R, Cavalle L, Vílchez JJ, Espinós C, Pérez Garrigues H, Sevilla T
J Int Adv Otol 2017 Apr;13(1):93-99. doi: 10.5152/iao.2017.3379. PMID: 28555600

Therapy

Lee AJ, Nam SH, Park JM, Kanwal S, Choi YJ, Lee HJ, Lee KS, Lee JE, Park JS, Choi BO, Chung KW
J Hum Genet 2019 Sep;64(9):961-965. Epub 2019 Jun 21 doi: 10.1038/s10038-019-0636-y. PMID: 31227790
Schiza N, Georgiou E, Kagiava A, Médard JJ, Richter J, Tryfonos C, Sargiannidou I, Heslegrave AJ, Rossor AM, Zetterberg H, Reilly MM, Christodoulou C, Chrast R, Kleopa KA
Brain 2019 May 1;142(5):1227-1241. doi: 10.1093/brain/awz064. PMID: 30907403Free PMC Article

Prognosis

Sivera R, Cavalle L, Vílchez JJ, Espinós C, Pérez Garrigues H, Sevilla T
J Int Adv Otol 2017 Apr;13(1):93-99. doi: 10.5152/iao.2017.3379. PMID: 28555600
Piscosquito G, Saveri P, Magri S, Ciano C, Gandioli C, Morbin M, Bella DD, Moroni I, Taroni F, Pareyson D
J Peripher Nerv Syst 2016 Sep;21(3):142-9. doi: 10.1111/jns.12175. PMID: 27231023Free PMC Article
Brewer MH, Ma KH, Beecham GW, Gopinath C, Baas F, Choi BO, Reilly MM, Shy ME, Züchner S, Svaren J, Antonellis A
Hum Mol Genet 2014 Oct 1;23(19):5171-87. Epub 2014 May 15 doi: 10.1093/hmg/ddu240. PMID: 24833716Free PMC Article

Clinical prediction guides

Pisciotta C, Bertini A, Tramacere I, Manganelli F, Fabrizi GM, Schenone A, Tozza S, Cavallaro T, Taioli F, Ferrarini M, Grandis M, Bellone E, Mandich P, Previtali SC, Falzone Y, Allegri I, Padua L, Pazzaglia C, Quattrone A, Valentino P, Gentile L, Russo M, Calabrese D, Moroni I, Pagliano E, Saveri P, Magri S, Baratta S, Taroni F, Mazzeo A, Santoro L, Vita G, Pareyson D; Italian CMT Network
Eur J Neurol 2023 Aug;30(8):2461-2470. Epub 2023 May 26 doi: 10.1111/ene.15860. PMID: 37170966
Sivera R, Cavalle L, Vílchez JJ, Espinós C, Pérez Garrigues H, Sevilla T
J Int Adv Otol 2017 Apr;13(1):93-99. doi: 10.5152/iao.2017.3379. PMID: 28555600
Piscosquito G, Saveri P, Magri S, Ciano C, Gandioli C, Morbin M, Bella DD, Moroni I, Taroni F, Pareyson D
J Peripher Nerv Syst 2016 Sep;21(3):142-9. doi: 10.1111/jns.12175. PMID: 27231023Free PMC Article
Brewer MH, Ma KH, Beecham GW, Gopinath C, Baas F, Choi BO, Reilly MM, Shy ME, Züchner S, Svaren J, Antonellis A
Hum Mol Genet 2014 Oct 1;23(19):5171-87. Epub 2014 May 15 doi: 10.1093/hmg/ddu240. PMID: 24833716Free PMC Article
Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R, Verheijen MH, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Müller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schöneborn S, Züchner S, Michael Schröder J, Buchheim E, Straub V, Klepper J, Huehne K, Rautenstrauss B, Büttner R, Nelis E, Zerres K
Am J Hum Genet 2003 Nov;73(5):1106-19. Epub 2003 Oct 21 doi: 10.1086/379525. PMID: 14574644Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...