Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.
In two siblings with limb-girdle muscle weakness and episodic headaches and vomiting from early childhood, progressive neurologic degeneration later developed, and both children died. In one child, corticosteroids induced improvement in both cerebral and muscular symptoms that lasted 1 year. This patient had elevated blood, urine, and spinal fluid lactate levels, together with increased cardiac output and oxygen consumption at rest. Several muscle fibers were characterized by a "ragged red" appearance with the trichrome stain. Subsarcolemmal and intermyofibrillar excess of mitochondrial oxidative enzyme reaction product was correlated with abnormal mitochondrial aggregates by electron microscopy. The brain revealed focal areas of cortical degeneration and necrosis with adjacent gliosis or edema. Ferrocalcific deposits were prominent in the globus pallidus. The other sibling had similar changes in the brain at autopsy. This familial multisystem disorder especially involving the brain, skeletal muscle, and heart appears to represent a defect in some mitochondrial oxidative mechanism.
The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.
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