Paula and Bobby
Parents of Lillie
Charcot-Marie-Tooth Disease, Type 4C; CMT4C
What is Charcot-Marie-Tooth Disease, Type 4C; CMT4C?
Charcot-Marie-Tooth Disease, Type 4C; CMT4C is a rare disease. It is also known as Charcot-marie-tooth Disease, Demyelinating, Autosomal Recessive, Type 4c Charcot-marie-tooth Neuropathy, Type 4c CMT4C (5q32) HMSN II AR.
This category is much rarer than the autosomal dominant type II and must be diagnosed with caution. The main clinical problem is that parents need to be thoroughly examined to exclude minimal manifestations so that dominant transmission is not missed. Conduction velocities are normal (not always - see below) so that electrophysiological examination of the parents is less helpful in clinically normal subjects than in type I. Clinically, type I recessive cannot be distinguished from type II dominant. Harding and Thomas (1980) suggest a sib-risk of one in 16 for type II in the absence of a family history. Offspring risks might be as high as one in five.
In a study from north Sweden, of 29 families there were three in which the inheritance seemed recessive and in whom no duplications at 17p11.2 were found (Holmberg et al., 1994).
Two Algerian families map to 5q23-33 (LeGuern et al., 1996), where the gene neuegulin-2 gene is situated (Ring et al., 1999). This locus has been refined to 5q32 (Guilbot et al., 1999). Mutations have now been found in a gene encoding a novel SH3/TPR domain protein (Senderek et al., 2003, Parman et al., 2004). This condition is the commonest AR CMT in Spanish Gypsies (Gooding et al., 2005). In a large Gypsy family, Gooding et al., (2005). conduction velocities were slow and sural nerve biopsy showed demyelination and onion bulb formation.
In a study of European Gypsy families, Colomer et al., (2006) comment on the variable presentation. One family had a severe phenotype with hypotonia, scoliosis and major motor disability in late childhood. In another family, there was a milder phenotype, but with deafness, lingual fasciculations and slow pupillary light reflexes. All had a SH3TC mutation. Scoliosis seems to be an important hallmark of the disease (Azzedine et al., 2006) and this was again found in the report by Houlden et al., (2008). deafness, facial weakness, tongue atrophy and asymmetrical pupils were commented upon.
Jerath et al., (2017) described five patients with biallelic mutations in the SH3TC2 gene and demyelinating neuropathy. Motor impairment was evident within the first years of life. Occasional features were optic atrophy, retinitis pigmentosa, and arrhythmia.
* This information is courtesy of the L M D.
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What gene changes cause Charcot-Marie-Tooth Disease, Type 4C; CMT4C?
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.
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 - 601596 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
SH3TC2 - 5q32
What are the main symptoms of Charcot-Marie-Tooth Disease, Type 4C; CMT4C?
The typical symptoms of the syndrome are:
Difficulty walking, Distal sensory impairment, Distal muscle weakness, Distal amyotrophy, Decreased number of large peripheral myelinated nerve fibers, Decreased motor nerve conduction velocity, Motor delay, Facial palsy, Peripheral axonal degeneration, Basal lamina onion bulb formation, Nystagmus, Pes cavus, Autosomal recessive inheritance, Abnormal pupillary light reflex, Scoliosis, Tongue fasciculations, Tongue atrophy, Prolonged brainstem auditory evoked potentials, Segmental peripheral demyelination, Phenotypic variability, Upper limb muscle weakness, Hearing impairment
How does someone get tested for Charcot-Marie-Tooth Disease, Type 4C; CMT4C?
The initial testing for Charcot-Marie-Tooth Disease, Type 4C; CMT4C 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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