Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg 2+ ) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg 2+ levels, with a prominent function for the Mg 2+ -transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg 2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane. Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K + ) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K + channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg 2+ reabsorption.

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Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

ObjectiveTo identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.MethodsWe performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.ResultsClinical electrophysiology studies of the patient revealed several‐fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C‐terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization‐evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type.InterpretationThe mutation is pathogenic because elongation of the intravesicular C‐terminus of the A and D isoforms increases the energy required to move their C‐terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.

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Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c.70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c.70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000.

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Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies include stiff-person syndrome (SPS) and its variants -stiff trunk syndrome, stiff limbs syndrome, progressive encephalomyelitis with rigidity, SPS-plus and paraneoplastic SPS -as well as epilepsy and ataxia [1][2][3][4][5][6][7][8] . These syndromes are often found in association with other autoimmune disorders, such as diabetes mellitus, in more than one thirds of all cases, and, less commonly, those caused by antithyroid, antinuclear and antiparietal cell antibodies (5-10%) [1][2][3][9][10][11][12][13] . GAD is a cytoplasmic enzyme that accelerates the conversion of glutamic acid to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter present in the brain and spinal cord. GAD is synthesized mainly in presynaptic GABAergic neurons in the central nervous system and in the b cells in the islets of Langerhans in the pancreas. GAD autoantibodies are found in around 60 to 80% of SPS cases. Although there are two GAD isoforms ¾ GAD65 and GAD67 ¾ the main target for GAD autoantibodies in SPS is GAD65 [9][10][11][12][13][14] . The pathogenetic role of autoantibodies in SPS is unclear. However, all SPS autoantigens identified to date are synaptic proteins involved in inhibitory synaptic transmission, such as GAD and amphiphysin (presynaptic antigens) and GABA(A) receptor-associated protein (GABARAP) and gephyrin (postsynaptic antigens). The autoantibodies anti-amphiphysin and anti-gephyrin have been linked to paraneoplastic SPS [9][10][11][12][13][14][15] . The objective of this study was to present the clinical and laboratory findings of 12 patients with neurological disorders associated with anti-GAD antibodies. ABSTRACT Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.