Epilepsia mioclónica progresiva secundaria a enfermedad por cuerpos de Lafora / Progressive myoclonic epilepsy secondary to Lafora's body disease

La enfermedad de Lafora es infrecuente; sin embargo, es una de las causas más comunes de epilepsia mioclónica progresiva. Presentamos el caso de una mujer de 19 años sin comorbilidades y pautas madurativas normales, que inició a los 8 años con convulsiones y que a partir de los 15 años agregó deterioro cognitivo progresivo. Fue internada en nuestra institución con diagnóstico de estatus epiléptico super refractario. Se diagnosticó enfermedad de Lafora, confirmada por la anatomía patológica, y posteriormente se realizó un test genético que informó una variante patogénica del gen EPM2A, que confirmó el diagnóstico. Presentamos una causa de epilepsia mioclónica progresiva, con un pronóstico ominoso y un tratamiento orientado a medidas paliativas, por lo que es importante analizar los diagnósticos diferenciales con otras entidades, a fin de establecer un pronóstico, ofrecer mejor calidad de vida, asistencia médica adecuada y brindar asesoría genética a los familiares.

Lafora's disease is infrequent. However, it is one of the most common causes of progressive myoclonus epilepsy. We present the case of a 19-year-old woman, without comorbidities and normal development that started at 8 years with seizures and that from 15 years, had progressive cognitive deterioration. She was admitted to our institution with a diagnosis of super refractory status epilepticus. The diagnosis of Lafora's disease was made through pathological anatomy, later a genetic test was performed that reported a pathogenic variant of the EPM2A gene, confirming the diagnosis. We present a cause of progressive myoclonic epilepsy, with an ominous prognosis and a treatment oriented to palliative measures, so it is important to analyze the differential diagnoses with other entities, in order to establish a prognosis, offer better quality of life, adequate medical care and provide genetic counseling to family members.

Two Cases of X-Linked Myotubular Myopathy with Novel MTM1 Mutations

BACKGROUND: Myotubular myopathy (MTM) is a congenital myopathy characterized by centrally placed nuclei in muscle fibers. Mutations in the myotubularin 1 gene (MTM1) have been identified in the most of the patients with the X-linked recessive form. CASE REPORT: This report describes two male infants with X-linked MTM (XLMTM). Both patients presented with generalized hypotonia and respiratory difficulties since birth. We did not perform a muscle biopsy in either patient, but their conditions were diagnosed by genetic testing of MTM1. One splicing mutation, c.63+1G>C, and a frame-shift mutation, c.473delA (p. Lys158SerfxX28), were identified. Neither mutation has been reported previously. CONCLUSIONS: Genetic testing for MTM1 is helpful for the differential diagnosis of floppy male infants. We suggest that advanced molecular genetic testing may permit a correct diagnosis while avoiding invasive procedures.

X-linked Myotubular Myopathy in a Family with Two Infant Siblings: A Case with MTM1 Mutation

X-linked myotubular myopathy (XLMTM) is a rare congenital muscle disorder, caused by mutations in the MTM1 gene. Affected male infants present severe hypotonia, and generalized muscle weakness, and the disorder is most often complicated by respiratory failure. Herein, we describe a family with 2 infants with XLMTM which was diagnosed by gene analysis and muscle biopsy. In both cases, histological findings of muscle showed severely hypoplastic muscle fibers with centrally placed nuclei. From the family gene analysis, the Arg486STOP mutation in the MTM1 gene was confirmed.

Mutation studies in x-linked myotubular myopathy in three indian families.

Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neontal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked Myotubular myopathy from India.

Research progress of several protein tyrosine phosphatases in diabetes / 生理学报

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet beta cells and/or insulin resistance in liver, muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B (PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway, insulin secretion and autoreactive attack to pancreatic beta cells. Genetic mutation or overexpression of these phosphotases has been found to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B, a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model and PTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares more than 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substrates overlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP may have role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic beta cell apoptosis. The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutant have impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanism of R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. A receptor tyrosine phosphatase, PTPIA-2/beta is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/beta autoantibodies is valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2 are involved in type 2 diabetes via regulation of insulin production, beta cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulin response and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic and therapeutic strategies for diabetes.

Floppy infant caused by MTM1 mutation: a first genetically-confirmed X-linked myotubular myopathy patient in Thailand.

Floppy infant syndrome (FIS) refers to a condition wherein an infant manifests generalized hypotonia since birth or in early life. It is heterogeneous and can be caused by various central nervous system disorders, neuromuscular diseases and genetic disorders. X-linked myotubular myopathy (XMTM) is a progressive congenital myopathy morphologically characterized by the presence of centrally placed nuclei in numerous muscle fibers without any other particular pathological abnormalities. Patients are frequently born with floppiness and respiratory distress. The vast majority of patients carry a truncating or missense mutation in MTM1. The authors report here a full term male baby with clinicopathological features of XMTM. The diagnosis is validated by the finding of a c. 141-144delAGAA mutation ofMTM1. To the best of the authors' knowledge, the present case is the first genetically confirmed XMTM in Thailand. A brief review of various neuromuscular disorders causing floppy infant syndrome is also included.