Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B

What is Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B?

Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B is a rare disease. It is also known as Charcot-Marie-Tooth disease type Ib Charcot-marie-tooth Disease, Autosomal Dominant, With Focally Folded Myelin Sheaths, Type 1b Charcot-marie-tooth Disease, Slow Nerve Conduction Type, Linked To Duffy Charcot-marie-tooth Neuropathy, Type 1b CharcotMarieToothdiseasetypeIb CMT1B(P0) CMT1BP0 Hereditary Motor And Sensory Neuropathy I; Hmsn I Hereditary Motor And Sensory Neuropathy Ib; Hmsn Ib HMSN type 1b Hmsn1 Hmsn1b HMSNtype1b Peroneal Muscular Atrophy.

In general, this entity is not clinically distinguishable from type Ia, and differs only in that it is not linked to chromosome 17. However there are some de novo mutations with a very early onset, severe disorder (see second paragraph). The mutation is in the myelin protein zero gene (P0) on chromosome 1 at q22, and to date point mutations, and deletions within the gene have been found (Hayasaka et al., 1993). The mutations are in the extracellular domain of the protein and are thought to play a role in the compaction of myelin. Intracellular mutations have also been reported (Fabrizi et al., 2006). Nelis et al., (1994) report a large family with a point mutation in exon 3 and 20% of French families had codon 98 mutations in exon 3 (Rouger et al., 1996). In a series of 10 patients with HMSN type I, who did not have the duplication on chromosome 17p11, two were found to have a mutation in the P0 gene (Latour et al., 1995).
It seems likely that the inherited Po mutations are just (clinically) like PMP 22 duplications, but fresh mutations are clinically just like HMSN type III. One of the patients reported by Meijerink et al., (1996), with a codon 69 mutation, had an onset at 2 years and died at 22 months. The same might apply to fresh mutation PMP22 point mutations (Ouvrier, 1996).
Uncompacted myelin is found in some with Po mutations, which is in keeping with the function of Po as a homophilic adhesion molecule (Gabreels-Festen et al., 1996). A patient with uncompacted myelin and severe disease had a de novo mutation of the Po gene (Komiyama et al., 1997). Patients with the Arg98His mutation might be especially prone to having uncompacted myelin (Ohnishi et al., 1999).
So, PO mutations can cause (Gabreels-Festin, 1999):
a) Chronic demyelinating neuropathy with uncompacted myelin
b) Chronic demyelinating neuropathy with focally folded myelin (But see separate recessive condition) - see Iida et al., (2012)
c) An axonal neuropathy. Note the family reported by Fabrizi et al., (2006). Heterozygotes for an intracellular PO mutation, were clinically normal, but homozygotes had an axonal neuropathy. The heterozygote (C59T mutation) reported by Finsterer et al., (2005) manifested an axonal neuropathy.
d) Mild recurrent CMT1B (Lagueny et al., 2001) - the patient presented with carpal tunnel syndrome. Also note that the mild patient reported by Watanabe et al., (2002) responded to steroids.
AND
e) There is now evidence that Thr124Met mutations in the myelin protein zero gene can give a phenotype of late onset, marked sensory signs, deafness and pupillary abnormalities (irregular and unresponsive (De Jonghe et al., 1999, Kurihara et al., 2004). Conduction velocities were only slightly reduced or normal. See also patient reported by Bienfait et al., (2002) with pupillary abnormalities and 2 PO mutations (His81Tyr and Val113Phe). In the family reported by Kurihara et al., (2003) with aThr124Met mutation, those who were heterozygous had an axonal neuropathy, Adi's pupil and deafness,, whereas the patient who was homozygous had a demyelinating neuropathy and rapid progression. Unresponsive pupils and deafness also occurred in the family reported by Young et al., (2013).
f) Somatic and germline mosaicm of a MPZ/Po mutation can cause the condition in sibs (Fabrizi et al., 2001).
g) Variabilty and expression can cause counselling problems Sowden et al., (2005) reported a family with a MPZ lys236del. Onset was late and the clinical picture varied between those who had no signs, to those with foot deformity, numbness and cramps.
h) Occasionally (Reyes-Marin et al., 2011), there are brain, white matter lesions
The original family, first reported by Bird et al., (1980), showing linkage to Duffy on chromosome 1, has now been shown to have a Po point mutation (Bird et al;., 1997). It is important that all CMT patients who do not have a 17p duplication, should be checked for point mutations in Cx32, PMP22 and P-zero (Po) - Silander et al., (1998).

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* This information is courtesy of the L M D.

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What gene changes cause Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.


Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.


In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 118200 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
CHCHD10 - 22q11.23
REEP1 - 2p11.2
VCL - 10q22.2
KRAS - 12p12.1
DTNA - 18q12.1
DHTKD1 - 10p14
AIFM1 - Xq26.1
POLG - 15q26.1
SLC25A46 - 5q22.1
CLTCL1 - 22q11.21
PRPS1 - Xq22.3
L1CAM - Xq28
LDB3 - 10q23.2
ARHGEF10 - 8p23.3
SLC5A7 - 2q12.3
PRKAG2 - 7q36.1
SLC52A1 - 17p13.2
SYT2 - 1q32.1
FXN - 9q21.11
WNK1 - 12p13.33
PLEKHG5 - 1p36.31
DNAJB2 - 2q35
CCT5 - 5p15.2
SPG11 - 15q21.1
HADHA - 2p23.3
KIF1A - 2q37.3
DSG2 - 18q12.1
ACTC1 - 15q14
PTPN11 - 12q24.13
APTX - 9p21.1
NDRG1 - 8q24.22
CRYAB - 11q23.1
BSCL2 - 11q12.3
SACS - 13q12.12
TFG - 3q12.2
RAF1 - 3p25.2
MTTP - 4q23
ELP1 - 9q31.3
GATAD1 - 7q21.2
VCP - 9p13.3
MYOZ2 - 4q26
ABCC9 - 12p12.1
HINT1 - 5q23.3
HADHB - 2p23.3
TRIM2 - 4q31.3
SIGMAR1 - 9p13.3
WASHC5 - 8q24.13
SLC12A6 - 15q14
SIL1 - 5q31.2
SPTLC2 - 14q24.3
HSPB3 - 5q11.2
FGD4 - 12p11.21
LMNA - 1q22
ATP7A - Xq21.1
EMD - Xq28
SPART - 13q13.3
PKP2 - 12p11.21
RIT1 - 1q22
ACTN2 - 1q43
SLC52A2 - 8q24.3
TNNT2 - 1q32.1
TUBB3 - 16q24.3
SMN1 - 5q13.2
PEX7 - 6q23.3
TPM1 - 15q22.2
MYH7 - 14q11.2
NEBL - 10p12.31
JUP - 17q21.2
SCN9A - 2q24.3
MPV17 - 2p23.3
TNNI3 - 19q13.42
MFN2 - 1p36.22
KCNC3 - 19q13.33
CAV3 - 3p25.3
SCN11A - 3p22.2
GJB1 - Xq13.1
DES - 2q35
DSC2 - 18q12.1
HSPB8 - 12q24.23
ITPR1 - 3p26.1
TYMP - 22q13.33
SEPT9 - 17q25.3
GNB4 - 3q26.33
HOXD10 - 2q31.1
MAP2K2 - 19p13.3
KIF1B - 1p36.22
DHH - 12q13.12
PLN - 6q22.31
CACNB4 - 2q23.3
SPG7 - 16q24.3
MORC2 - 22q12.2
SCN5A - 3p22.2
SOS1 - 2p22.1
SBF1 - 22q13.33
DMD - Xp21.2-p21.1
MPZ - 1q23.3
GDAP1 - 8q21.11
TRPV4 - 12q24.11
MME - 3q25.2
LAMP2 - Xq24
PDK3 - Xp22.11
PMP22 - 17p12
SPAST - 2p22.3
PNPLA6 - 19p13.2
TTPA - 8q12.3
MYH14 - 19q13.33
TNNC1 - 3p21.1
KCNA1 - 12p13.32
NEXN - 1p31.1
COX6A1 - 12q24.31
TTN - 2q31.2
HRAS - 11p15.5
FKTN - 9q31.2
ATL3 - 11q13.1
SOX10 - 22q13.1
MED25 - 19q13.33
PDHA1 - Xp22.12
HSPB1 - 7q11.23
GAA - 17q25.3
SETX - 9q34.13
PRNP - 20p13
RBM20 - 10q25.2
SBF2 - 11p15.4
CASQ2 - 1p13.1
SH3TC2 - 5q32
DNMT1 - 19p13.2
SPTBN2 - 11q13.2
GAN - 16q23.2
PDLIM3 - 4q35.1
NTRK1 - 1q23.1
LAMA4 - 6q21
FGF14 - 13q33.1
SLC1A3 - 5p13.2
TTR - 18q12.1
TAZ - Xq28
PHYH - 10p13
TTBK2 - 15q15.2
BAG3 - 10q26.11
NAGLU - 17q21.2
DSP - 6p24.3
PRDM12 - 9q34.12
MAP2K1 - 15q22.31
MYL2 - 12q24.11
DCAF8 - 1q23.2
SGCD - 5q33.2-q33.3
TMEM43 - 3p25.1
FBLN5 - 14q32.12
MTTP -
TDP1 - 14q32.11
MTMR2 - 11q21
NRAS - 1p13.2
BRAF - 7q34
HK1 - 10q22.1
CTDP1 - 18q23
IGHMBP2 - 11q13.3
PRKCG - 19q13.42
LAS1L - Xq12
ANKRD1 - 10q23.31
DCTN1 - 2p13.1
ATL1 - 14q22.1
ALDH3A2 - 17p11.2
ZFYVE27 - 10q24.2
MYPN - 10q21.3
SLC52A3 - 20p13
RYR2 - 1q43
INF2 - 14q32.33
ZFYVE26 - 14q24.1
LRSAM1 - 9q33.3-q34.1
TWNK - 10q24.31
EGR2 - 10q21.3
CSRP3 - 11p15.1
KIF5A - 12q13.3
MRE11 - 11q21
PRX - 19q13.2
DYNC1H1 - 14q32.31
NEFL - 8p21.2
FIG4 - 6q21
FBXO38 - 5q32
MYH6 - 14q11.2
MYBPC3 - 11p11.2
PLP1 - Xq22.2
TCAP - 17q12
BICD2 - 9q22.31
DNM2 - 19p13.2
COQ8A - 1q42.13
LITAF - 16p13.13
SPTLC1 - 9q22.31
JPH2 - 20q13.12
GLA - Xq22.1
DRP2 - Xq22.1
NGF - 1p13.2
MYL3 - 3p21.31

What are the main symptoms of Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B?

The typical symptoms of the syndrome are:
Areflexia, Ulnar claw, Heterogeneous, Tonic pupil, Variable expressivity, Insidious onset, Juvenile onset, Slow progression, Steppage gait, Foot dorsiflexor weakness, Hypertrophic nerve changes, Hammertoe, Hyporeflexia, Distal amyotrophy, Distal sensory impairment, Distal muscle weakness, Cold-induced muscle cramps, Peripheral demyelination, Decreased number of peripheral myelinated nerve fibers, Decreased motor nerve conduction velocity, Autosomal dominant inheritance, Pes cavus, Onion bulb formation, Kyphoscoliosis, Myelin outfoldings

How does someone get tested for Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B?

The initial testing for Charcot-Marie-Tooth Disease, Demyelinating, type 1B; CMT1B can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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