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Charcot-Marie-Tooth disease type 2D(CMT2D)

MedGen UID:
316946
Concept ID:
C1832274
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth disease, axonal, Type 2D; Charcot-Marie-Tooth disease, neuronal, Type 2D; Charcot-Marie-Tooth Neuropathy Type 2D; CMT 2D; CMT2D
SNOMED CT: Autosomal dominant Charcot-Marie-Tooth disease type 2D (717011006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): GARS1 (7p14.3)
 
Monarch Initiative: MONDO:0011091
OMIM®: 601472
Orphanet: ORPHA99938

Definition

The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. [from GeneReviews]

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).
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.
Thenar muscle weakness
MedGen UID:
330427
Concept ID:
C1832276
Finding
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
A tendency to fall or the inability to keep oneself from falling; imbalance. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, Use of the retropulsion test includes a rapid balance perturbation in the backward direction, and the number of balance correcting steps (or total absence thereof) is used to rate the degree of postural instability. Healthy subjects correct such perturbations with either one or two large steps, or without taking any steps, hinging rapidly at the hips while swinging the arms forward as a counterweight. In patients with balance impairment, balance correcting steps are often too small, forcing patients to take more than two steps. Taking three or more steps is generally considered to be abnormal, and taking more than five steps is regarded as being clearly abnormal. Markedly affected patients continue to step backward without ever regaining their balance and must be caught by the examiner (this would be called true retropulsion). Even more severely affected patients fail to correct entirely, and fall backward like a pushed toy soldier, without taking any corrective steps.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
First dorsal interossei muscle weakness
MedGen UID:
371289
Concept ID:
C1832277
Finding
First dorsal interossei muscle atrophy
MedGen UID:
371290
Concept ID:
C1832278
Finding
Cold-induced hand cramps
MedGen UID:
330428
Concept ID:
C1832279
Finding
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Thenar muscle atrophy
MedGen UID:
355274
Concept ID:
C1864715
Finding
Wasting of thenar muscles, which are located on palm of the hand at the base of the thumb.
Upper limb amyotrophy
MedGen UID:
867165
Concept ID:
C4021523
Disease or Syndrome
Muscular atrophy involving the muscles of the upper limbs.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease type 2D in Orphanet.

Recent clinical studies

Etiology

Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC
PLoS One 2015;10(8):e0133423. Epub 2015 Aug 5 doi: 10.1371/journal.pone.0133423. PMID: 26244500Free PMC Article
Gardiner J, Marc J
J Exp Bot 2011 Jan;62(1):89-97. Epub 2010 Sep 2 doi: 10.1093/jxb/erq278. PMID: 20813785

Diagnosis

Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D, Grüneboom A, De Winter V, Gess B, Schara U, Pogoryelova O, Lochmüller H, Borchers CH, Roos A, Burgess RW, Timmerman V, Kleopa KA, Horvath R
Brain 2022 Nov 21;145(11):3999-4015. doi: 10.1093/brain/awac055. PMID: 35148379Free PMC Article
Huang Y, Bi B, Zhao P, Yu T, Luo S, Tan L, Liu Z, Liu J, He X
Mol Genet Genomic Med 2022 Jan;10(1):e1846. Epub 2021 Dec 12 doi: 10.1002/mgg3.1846. PMID: 34898052Free PMC Article
Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC
PLoS One 2015;10(8):e0133423. Epub 2015 Aug 5 doi: 10.1371/journal.pone.0133423. PMID: 26244500Free PMC Article

Prognosis

Lu PJ, Zhang P, Liu YC, Jing N, Guo YN, Wang PS, Su LL, Guo Q, Ma Q, Xu YM, Zhang ST
Curr Med Sci 2023 Apr;43(2):261-267. Epub 2023 Mar 18 doi: 10.1007/s11596-023-2707-8. PMID: 36932303
Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D, Grüneboom A, De Winter V, Gess B, Schara U, Pogoryelova O, Lochmüller H, Borchers CH, Roos A, Burgess RW, Timmerman V, Kleopa KA, Horvath R
Brain 2022 Nov 21;145(11):3999-4015. doi: 10.1093/brain/awac055. PMID: 35148379Free PMC Article
Smith AST, Kim JH, Chun C, Gharai A, Moon HW, Kim EY, Nam SH, Ha N, Song JY, Chung KW, Doo HM, Hesson J, Mathieu J, Bothwell M, Choi BO, Kim DH
Adv Biol (Weinh) 2022 Feb;6(2):e2101308. Epub 2021 Dec 26 doi: 10.1002/adbi.202101308. PMID: 34958183Free PMC Article

Clinical prediction guides

Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D, Grüneboom A, De Winter V, Gess B, Schara U, Pogoryelova O, Lochmüller H, Borchers CH, Roos A, Burgess RW, Timmerman V, Kleopa KA, Horvath R
Brain 2022 Nov 21;145(11):3999-4015. doi: 10.1093/brain/awac055. PMID: 35148379Free PMC Article
Smith AST, Kim JH, Chun C, Gharai A, Moon HW, Kim EY, Nam SH, Ha N, Song JY, Chung KW, Doo HM, Hesson J, Mathieu J, Bothwell M, Choi BO, Kim DH
Adv Biol (Weinh) 2022 Feb;6(2):e2101308. Epub 2021 Dec 26 doi: 10.1002/adbi.202101308. PMID: 34958183Free PMC Article
Mo Z, Zhao X, Liu H, Hu Q, Chen XQ, Pham J, Wei N, Liu Z, Zhou J, Burgess RW, Pfaff SL, Caskey CT, Wu C, Bai G, Yang XL
Nat Commun 2018 Mar 8;9(1):1007. doi: 10.1038/s41467-018-03461-z. PMID: 29520015Free PMC Article
Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW
PLoS Genet 2011 Dec;7(12):e1002399. Epub 2011 Dec 1 doi: 10.1371/journal.pgen.1002399. PMID: 22144914Free PMC Article
Sambuughin N, Sivakumar K, Selenge B, Lee HS, Friedlich D, Baasanjav D, Dalakas MC, Goldfarb LG
J Neurol Sci 1998 Nov 26;161(1):23-8. doi: 10.1016/s0022-510x(98)00264-0. PMID: 9879677