Peripheral nerve and skeletal muscle involvement in CADASIL

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder affecting small blood vessels.
• It is caused by Notch3 gene mutations and characterized by vascular smooth muscle cell (VSMC) degeneration.
• Neuromuscular symptoms are observed in some CADASIL patients, necessitating detailed investigation.

Purpose of the Study:

• To investigate the fine structural features of peripheral nerve and muscle biopsies in CADASIL patients.
• To correlate these findings with Notch3 gene mutations and VSMC pathology.
• To elucidate the underlying mechanisms of neuromuscular involvement in CADASIL.

Main Methods:

• Electron microscopy of peripheral nerve and muscle biopsy specimens from seven CADASIL patients.
• Genetic analysis (Notch3 gene sequencing) to identify mutations.
• Histopathological examination including assessment of nerve fiber degeneration, neurogenic atrophy, and myopathic changes.

Main Results:

• Degeneration and regeneration of nerve fibers were observed in sural nerves and intramuscular fascicles.
• Muscle biopsies showed neurogenic atrophy, myopathic changes, ragged red fibers, and abnormal mitochondria.
• Electron microscopy revealed enlarged mitochondria with calcium precipitates in VSMC.
• Notch3 mutations were identified in six of the seven patients.

Conclusions:

• CADASIL-related small blood vessel degeneration may originate from VSMC surface membrane defects.
• Chronic ischemia secondary to vascular dysfunction could explain the observed structural changes in skeletal muscle and peripheral nerves.
• While genetic defects are implicated, the precise interplay causing neuromuscular pathology requires further study.