CAPN3 mutations in patients with idiopathic eosinophilic myositis.

OBJECTIVE: Eosinophilic myositis (EM) constitutes a rare pathological entity characterized by eosinophilic infiltration of skeletal muscles, usually associated with parasite infections, systemic disorders, or the intake of drugs or L-tryptophan. The exclusion of such causes defines the spectrum of idiopathic EM. Based on a protein analysis performed in one affected patient, we identified the gene encoding calpain-3, CAPN3, as a candidate for a subset of idiopathic EM. METHODS: We screened CAPN3 for mutations using DHPLC and direct sequencing in six unrelated patients, recruited for EM diagnosed after histological examination of muscle biopsy samples, without any identified causative factor. RESULTS: We identified CAPN3 mutations in the six unrelated patients originally diagnosed with idiopathic EM. INTERPRETATION: Mutations in CAPN3 can cause EM. Thus, a subset of idiopathic EM is genetically determined, with an autosomal recessive mode of inheritance. Patients presented with a triad that appears to be indicative of CAPN3 mutations: (1) EM in the first decade, (2) elevated serum creatine phosphokinase levels (isolated or with little corresponding weakness), and (3) inconstant peripheral hypereosinophilia. However, that EM represents a distinct phenotype associated to CAPN3 mutations or, rather, an early histopathological picture of LGMD2A must be further evaluated. Our findings should be of interest toward further investigating the role of calpain-3 in skeletal muscle. Furthermore, patients with idiopathic EM should undergo calpain-3 protein analysis and be considered for subsequent molecular analysis of the CAPN3 gene.

Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy.

Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.