Spatial Assessment of the Association between Long-Term Exposure to Environmental Factors and the Occurrence of Amyotrophic Lateral Sclerosis in Catalonia, Spain: A Population-Based Nested Case-Control Study.

BACKGROUND: It is believed that an interaction between genetic and non-genetic factors may be involved in the development of amyotrophic lateral sclerosis (ALS). With the exception of exposure to agricultural chemicals like pesticides, evidence of an association between environmental risk factors and ALS is inconsistent. Our objective here was to investigate the association between long-term exposure to environmental factors and the occurrence of ALS in Catalonia, Spain, and to provide evidence that spatial clusters of ALS related to these environmental factors exist. METHODS: We carried out a nested case-control study constructed from a retrospective population-based cohort, covering the entire region. Environmental variables were the explanatory variables of interest. We controlled for both observed and unobserved confounders. RESULTS: We have found some spatial clusters of ALS. The results from the multivariate model suggest that these clusters could be related to some of the environmental variables, in particular agricultural chemicals. In addition, in high-risk clusters, besides corresponding to agricultural areas, key road infrastructures with a high density of traffic are also located. CONCLUSION: Our results indicate that some environmental factors, in particular those associated with exposure to pesticides and air pollutants as a result of urban traffic, could be associated with the occurrence of ALS.

Charcot-Marie-Tooth disease with intermediate conduction velocities caused by a novel mutation in the MPZ gene.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensory and motor neuropathies. Mutations in the gene that encodes for myelin protein zero (MPZ) can produce different phenotypes: CMT1 (with low conduction velocities), CMT2 (less frequent and with unaffected conduction velocities), and CMTID (with intermediate conduction velocities). We report a study of seven patients from a four-generation family. All the affected members of the family had a typical CMT phenotype, but three of them had calf hypertrophy. The nerve conduction velocities (NCV) in all of them were between 35 and 43 m/s. Molecular study revealed the novel mutation Lys214Met in the MPZ gene. Molecular study of the MPZ gene would be useful in cases of CMT in families with intermediate NCV, especially if no mutations in the GJB-1 gene are found or there is male-to-male transmission.

Diagnosis of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data.

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene.

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations.

A novel mutation in the caveolin-3 gene causing familial isolated hyperCKaemia.

Three members of a family were known to have persistent elevated serum CK levels without muscle weakness. A muscle biopsy showed a partial reduction of caveolin-3 at the sarcolemma of muscle fibres, which was confirmed by Western blot analysis. Mutational analysis identified a novel heterozygous mutation: G-->A transition at nucleotide position 169 in exon 2 in the CAV-3 gene, generating a Val-->Met change at codon 57 of the aminoacid chain. This is the second mutation in the CAV-3 gene associated with familial isolated hyperCKaemia.

Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.

Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.