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Hereditary motor and sensory neuropathies (HMSN) are also called Charcot-Marie-Tooth disease (CMT) based on the nomenclature after their first description. Despite the wide range of phenotypic variation, gait disturbances and slowly progressive distal weakness in the feet and/ or hands accompained by sensory problems can frequently be observed. Nevertheless, there are several exogenic causes for peripheral neuropathies, i.e. alcohol abuse and diabetic neuropathy which carefully need to be distinguished from the inherited neuropathies.
Although the spectrum of hereditary peripheral neuropathies is heterogenous, a classification can be made based on electrophysiological criteria. In HMSN type I and III (demyelinating neuropathy), severely slowed motor and sensory nerve concuction velocities (NCV) are a characteristic feature. In HMSN type II (axonal neuropathy) sensory and motor NCV are normal or slightly reduced.
1) HMSN type I
The autosomal dominant, demyelinating forms are classified as HSMN type I.
HMSN type IA (OMIM #118220)
This is the most common form of HMSN. Clinically, there are characteristic deformations of the feet (pes cavus, claw toe and “storc legs”) and distal limb muscle atrophy and weakness. The clinical course of the disease is slowly progressive. At nerve biopsy, there is “onion bulb formation” caused by de- and remyelinating processes.
In most cases, HMSN type IA is caused by a duplication of the PMP22 gene. The gene encodes the peripheral myelin protein which is abundantly expressed in the myelin sheaths. Less frequently, point mutations in the PMP22 gene can be found.
Method: multiplex ligation dependent probe amplification (MLPA) duplication screening of the PMP22 gene, screening for point mutations in the PMP22 gene (on special request)
HMSN IB (OMIM #118200)
In HMSN IB, electrophysiological NCV can also point to an axonal neuropathy.
Method: screening for point mutations in the MPZ gene (on special request)
HMSN IC (OMIM #118200)
Method: screening for point mutations in the LITAF/SIMPLE gene (on special request)
HMSN ID (OMIM #607678)
Method: screening for point mutations in the EGR2 gene (on special request)
2) HMSN type III (Déjérine-Sottas syndrome) (OMIM #145900)
Déjérine-Sottas syndrome (DSS) is a severe form of HMSN type I. Onset is usually during early childhood and NCV are often extremely reduced. There are autosomal dominant as well as recessive forms. Mutations in the PMP22, MPZ, EGR2 and PRX genes, which can also be found in milder forms, have been found in DSS.
Method: screening for point mutations in the PMP22, MPZ and EGR2 gene (on special request)
3) HMSN type II
The axonal forms of HMSN with normal or slightly reduced nerve conduction velocities are designated as type II. These forms are inherited in an autosomal dominant mode. Mutations in the MFN2 gene are the most common cause for a HMSN type II.
Nevertheless, an electrophysiologically characterized rather axonal neuropathy can also be caused by mutations in the GJB1 (X-chromosomal inheritance mode) and MPZ genes. It can be useful to investigate these genes prior to the MFN2 gene, depending on family anamnesis and symtoms of the patient.
Suspicion on a rather axonal neuropathy suggests an investigation of the GJB1/Cx32 gene at first. A family history with known inheritance from father to son suggests an investigation of the MPZ gene. If mutations in these genes can be ruled out, the sustained suspicion on an axonal neuropathy suggests the analysis of the MFN2 gene.
HMSN IIA2 (OMIM #609260)Method: screening for point mutations in the MFN2 gene (on special request)
4) X chromosomal HMSN / CMTX1 (OMIM #302800)
Mutations in the GJB1/Cx32 gene are the second common cause for hereditary neuropathies. This form is inherited in dominant mode, inheritance from father to son is not present. NCV of HMSN type X patients reveal a high inter- and intra- individual variability within the range of HMSN I and HMSN II patients. A more severe phenotype can often be observed in males whereas mild progression is often observed in female patients.
Method: screening for point mutations in the GJB1/Cx32 gene (on special request)
5) HNPP (hereditary neuropathy with liability to pressure palsies) (OMIM #162500)
In this disease, there is intermittent paralysis, mostly after mechanical stress. Nerve biopsy shows characteristics of tomaculous neuropathy. HNPP is inherited in an autosomal dominant manner and is most frequently caused by a deletion of the PMP22 gene (see above, HMSN IA).
Method: multiplex ligation dependent probe amplification (MLPA) deletion-screening of the PMP22 gene. If a deletion can be ruled out by MLPA, the PMP22 gene is screened for point mutations.
Dr. W. M. Gerding
Humangenetik
Gebäude MA 5
Ruhr-Universität
Universitätsstr. 150
44801 Bochum
GermanyTel.: +49 234 32 23831
Fax: +49 234 32 14196
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