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Charcot-Marie-Tooth disease type 4B1(CMT4B; CMT4B1)

MedGen UID:
321947
Concept ID:
C1832399
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, WITH FOCALLY FOLDED MYELIN SHEATHS, AUTOSOMAL RECESSIVE, TYPE 4B1; CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4B1; Charcot-Marie-Tooth disease, Type 4B; Charcot-Marie-Tooth Neuropathy Type 4B1; Charcot-Marie-Tooth Neuropathy Type 4B1 (CMT4B1); CMT 4B; CMT 4B1
SNOMED CT: Charcot-Marie-Tooth disease type 4B1 (715803003)
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): MTMR2 (11q21)
 
Monarch Initiative: MONDO:0011066
OMIM®: 601382
Orphanet: ORPHA99955

Definition

Charcot-Marie-Tooth disease, type 4B1 (CMT4B1) is a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy. It was initially described in an Italian family and around 10 additional families have been described so far. Onset occurs during early childhood with distal and proximal muscular weakness starting in the lower extremities, sensory loss and cranial nerve involvement. Foot deformities are frequent and diaphragmatic and facial involvement has been reported. CMT4B1 is caused by mutations in the gene encoding myotubularin-related protein 2 (MTMR2; 11q22), involved in polyphosphoinositide signaling. Transmitted in an autosomal recessive manner. [from SNOMEDCT_US]

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).
Abnormal auditory evoked potentials
MedGen UID:
141758
Concept ID:
C0522216
Finding
An abnormality of the auditory evoked potentials, which are used to trace the signal generated by a sound, from the cochlear nerve, through the lateral lemniscus, to the medial geniculate nucleus, and to the cortex.
Myelin outfoldings
MedGen UID:
334341
Concept ID:
C1843168
Finding
The presence of excessive redundant myelin in the peripheral nerve sheath.
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.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Irregular myelin loops
MedGen UID:
870476
Concept ID:
C4024922
Anatomical Abnormality
Presence of irregular redundant loops of focally folded myelin in a peripheral nerve.
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.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease type 4B1 in Orphanet.

Recent clinical studies

Etiology

Sawade L, Grandi F, Mignanelli M, Patiño-López G, Klinkert K, Langa-Vives F, Di Guardo R, Echard A, Bolino A, Haucke V
Nat Commun 2020 Jun 5;11(1):2835. doi: 10.1038/s41467-020-16696-6. PMID: 32503983Free PMC Article
Pareyson D, Stojkovic T, Reilly MM, Leonard-Louis S, Laurà M, Blake J, Parman Y, Battaloglu E, Tazir M, Bellatache M, Bonello-Palot N, Lévy N, Sacconi S, Guimarães-Costa R, Attarian S, Latour P, Solé G, Megarbane A, Horvath R, Ricci G, Choi BO, Schenone A, Gemelli C, Geroldi A, Sabatelli M, Luigetti M, Santoro L, Manganelli F, Quattrone A, Valentino P, Murakami T, Scherer SS, Dankwa L, Shy ME, Bacon CJ, Herrmann DN, Zambon A, Tramacere I, Pisciotta C, Magri S, Previtali SC, Bolino A
Ann Neurol 2019 Jul;86(1):55-67. Epub 2019 May 27 doi: 10.1002/ana.25500. PMID: 31070812Free PMC Article
Abdalla-Moady T, Peleg A, Sadeh O, Badarneh K, Fares F
Mol Neurobiol 2018 Apr;55(4):3546-3550. Epub 2017 May 16 doi: 10.1007/s12035-017-0588-1. PMID: 28509084
Azzedine H, Bolino A, Taïeb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E
Am J Hum Genet 2003 May;72(5):1141-53. Epub 2003 Apr 8 doi: 10.1086/375034. PMID: 12687498Free PMC Article

Diagnosis

Guimarães-Costa R, Villar-Quiles RN, Latour P, Sole G, Husson I, Lacour A, Leonard-Louis S, Stojkovic T
Neuromuscul Disord 2020 Jul;30(7):576-582. Epub 2020 May 16 doi: 10.1016/j.nmd.2020.05.003. PMID: 32586600
Halperin D, Sapir A, Wormser O, Drabkin M, Yogev Y, Dolgin V, Flusser H, Birk OS
Neurogenetics 2020 Oct;21(4):301-304. Epub 2020 Jun 3 doi: 10.1007/s10048-020-00617-2. PMID: 32488727
Pareyson D, Stojkovic T, Reilly MM, Leonard-Louis S, Laurà M, Blake J, Parman Y, Battaloglu E, Tazir M, Bellatache M, Bonello-Palot N, Lévy N, Sacconi S, Guimarães-Costa R, Attarian S, Latour P, Solé G, Megarbane A, Horvath R, Ricci G, Choi BO, Schenone A, Gemelli C, Geroldi A, Sabatelli M, Luigetti M, Santoro L, Manganelli F, Quattrone A, Valentino P, Murakami T, Scherer SS, Dankwa L, Shy ME, Bacon CJ, Herrmann DN, Zambon A, Tramacere I, Pisciotta C, Magri S, Previtali SC, Bolino A
Ann Neurol 2019 Jul;86(1):55-67. Epub 2019 May 27 doi: 10.1002/ana.25500. PMID: 31070812Free PMC Article
Zambon AA, Natali Sora MG, Cantarella G, Cerri F, Quattrini A, Comi G, Previtali SC, Bolino A
Neuromuscul Disord 2017 May;27(5):487-491. Epub 2017 Jan 16 doi: 10.1016/j.nmd.2017.01.006. PMID: 28190646Free PMC Article

Prognosis

Pareyson D, Stojkovic T, Reilly MM, Leonard-Louis S, Laurà M, Blake J, Parman Y, Battaloglu E, Tazir M, Bellatache M, Bonello-Palot N, Lévy N, Sacconi S, Guimarães-Costa R, Attarian S, Latour P, Solé G, Megarbane A, Horvath R, Ricci G, Choi BO, Schenone A, Gemelli C, Geroldi A, Sabatelli M, Luigetti M, Santoro L, Manganelli F, Quattrone A, Valentino P, Murakami T, Scherer SS, Dankwa L, Shy ME, Bacon CJ, Herrmann DN, Zambon A, Tramacere I, Pisciotta C, Magri S, Previtali SC, Bolino A
Ann Neurol 2019 Jul;86(1):55-67. Epub 2019 May 27 doi: 10.1002/ana.25500. PMID: 31070812Free PMC Article
Fogarty EA, Brewer MH, Rodriguez-Molina JF, Law WD, Ma KH, Steinberg NM, Svaren J, Antonellis A
Hum Mol Genet 2016 Sep 15;25(18):3925-3936. Epub 2016 Jul 27 doi: 10.1093/hmg/ddw233. PMID: 27466180Free PMC Article

Clinical prediction guides

Halperin D, Sapir A, Wormser O, Drabkin M, Yogev Y, Dolgin V, Flusser H, Birk OS
Neurogenetics 2020 Oct;21(4):301-304. Epub 2020 Jun 3 doi: 10.1007/s10048-020-00617-2. PMID: 32488727
Pareyson D, Stojkovic T, Reilly MM, Leonard-Louis S, Laurà M, Blake J, Parman Y, Battaloglu E, Tazir M, Bellatache M, Bonello-Palot N, Lévy N, Sacconi S, Guimarães-Costa R, Attarian S, Latour P, Solé G, Megarbane A, Horvath R, Ricci G, Choi BO, Schenone A, Gemelli C, Geroldi A, Sabatelli M, Luigetti M, Santoro L, Manganelli F, Quattrone A, Valentino P, Murakami T, Scherer SS, Dankwa L, Shy ME, Bacon CJ, Herrmann DN, Zambon A, Tramacere I, Pisciotta C, Magri S, Previtali SC, Bolino A
Ann Neurol 2019 Jul;86(1):55-67. Epub 2019 May 27 doi: 10.1002/ana.25500. PMID: 31070812Free PMC Article
Fogarty EA, Brewer MH, Rodriguez-Molina JF, Law WD, Ma KH, Steinberg NM, Svaren J, Antonellis A
Hum Mol Genet 2016 Sep 15;25(18):3925-3936. Epub 2016 Jul 27 doi: 10.1093/hmg/ddw233. PMID: 27466180Free PMC Article
Bonneick S, Boentert M, Berger P, Atanasoski S, Mantei N, Wessig C, Toyka KV, Young P, Suter U
Hum Mol Genet 2005 Dec 1;14(23):3685-95. Epub 2005 Oct 25 doi: 10.1093/hmg/ddi400. PMID: 16249189

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