Objectives: Recent studies indicate that Notch3 gene mutations not only manifest as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but also in the peripheral nerves and skeletal muscles.
Methods: A MEDLINE search with appropriate terms was carried out. Six articles, dealing with neuromuscular involvement in CADASIL, were selected and reviewed.
Results: Several case studies presented CADASIL patients with clinical features of myopathy. Neurological diagnostic workup in these patients revealed weakness, wasting, reduced/exaggerated tendon reflexes, abnormal nerve conduction and electromyography, muscle biopsy with ragged red muscle fibers, reduced COX staining, decreased complex I respiratory chain activity, abnormally structured mitochondria, or mitochondrial DNA (mtDNA) mutations, such as G5650A in the tRNAAla gene, or various other mtDNA substitutions. Additionally, fibroblasts in skin biopsy may show reduced complex V respiratory chain activity.
Conclusions: These findings suggest Notch3 mutations to be associated with mitochondrial disease, particularly affecting the skeletal muscle. Whether mtDNA mutations were induced by Notch3 mutations, by oxidative stress due to chronic hypoxia, resulting from arteriopathy, or occurred spontaneously remains elusive. Patients carrying Notch3 mutations should be systematically investigated for neuromuscular involvement, which may have therapeutic and prognostic implications for these patients.
(c) 2007 S. Karger AG, Basel