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Published on: June 15, 2018
[Clinical, pathologic and molecular genetic studies of patients with hereditary motor and sensory neuropathy (HMSN)]
1Department of Neurology, University of Occupational & Environmental Health.
Abstract:
Clinical, pathologic and molecular genetic studies of Japanese HMSN patients were reported. Among 26 HMSN I probands tested, the PMP22 gene region was duplicated in 18 (69%). A proband of HNPP, whose PMP22 gene region was deleted, was described. A proband with HMSN I was found to have a mutant allele that caused a substitution of arginine for glycine at amino acid 93 of PMP22. The mutation was located in the transmembrane portion of PMP22. The patient's sural nerve showed decrease of large myelinated fibers and frequent segmental demyelination and remyelination. A family with HMSN IB was found to have a mutant allele that caused a substitution of histidine for arginine at amino acid 98 of Po. The mutation was located in the extracellular domain of Po. The sural nerve from a proband showed uncompaction of major dense lines, wide-spaced major dense lines, and thin myelin sheath relative to axon size. One family of HMSN X with a mutant allele that caused a substitution of leucine for serine at amino acid 26 of Cx32 was found. The mutation was located in the fist transmembrane portion of Cx32. A variety of genetic abnormalities, probably underlying pathologic changes of the peripheral nerve, found among Caucasians were also noticed among Japanese.
Insights
Genetic studies in Japanese patients reveal common causes of hereditary neuropathies. PMP22 gene duplications are frequent in Charcot-Marie-Tooth disease type 1, while mutations in PMP22, Po, and Cx32 genes are linked to various subtypes.
Area of Science:
- Neurogenetics
- Molecular Biology
- Pathology
Background:
- Hereditary neuropathies, including Charcot-Marie-Tooth disease (HMSN) and hereditary neuropathy with liability to pressure palsies (HNPP), are a group of disorders affecting peripheral nerves.
- Understanding the genetic basis of these conditions is crucial for diagnosis and potential therapeutic strategies.
Observation:
- This study investigated clinical, pathological, and molecular genetic aspects of Japanese patients with hereditary neuropathies.
- Analysis of 26 HMSN I probands revealed PMP22 gene region duplication in 69% of cases.
- A case of HNPP with PMP22 gene deletion was documented.
Findings:
- Specific mutations were identified in genes associated with different HMSN subtypes: a PMP22 mutation (R93G) in HMSN I, a Po mutation (R98H) in HMSN IB, and a Cx32 mutation (S26L) in HMSN X.
- Pathological examination of sural nerves showed characteristic changes such as demyelination, remyelination, uncompaction of major dense lines, and thin myelin sheaths.
- The identified genetic abnormalities in Japanese patients mirrored those previously observed in Caucasian populations.
Implications:
- The findings highlight the significant role of PMP22 gene alterations in the etiology of HMSN I in the Japanese population.
- The study confirms that genetic defects in PMP22, Po, and Cx32 are common causes of peripheral neuropathies across different ethnicities.
- This research contributes to a better understanding of the molecular pathogenesis of hereditary neuropathies and may inform genetic counseling and diagnostic approaches.
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