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Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up. of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease. (C) 2013 Elsevier B.V. All rights reserved

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype–phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four ‘canonical’ genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood–adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.

Item does not contain fulltext Brody disease is an inherited myopathy associated with a defective function of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 1 (SERCA1) protein. Mutations in the ATP2A1 gene have been reported only in some patients. Therefore it has been proposed to distinguish patients with ATP2A1 mutations, Brody disease (BD), from patients without mutations, Brody syndrome (BS). We performed a detailed study of SERCA1 protein expression in muscle of patients with BD and BS, and evaluated the alternative splicing of SERCA1 in primary cultures of normal human muscle and in infant muscle. SERCA1 reactivity was observed in type 2 muscle fibers of patients with and without ATP2A1 mutations and staining intensity was similar in patients and controls. Immunoblot analysis showed a significant reduction of SERCA1 band in muscle of BD patients. In addition we demonstrated that the wild type and mutated protein exhibits similar solubility properties and that RIPA buffer improves the recovery of the wild type and mutated SERCA1 protein. We found that SERCA1b, the SERCA1 neonatal form, is the main protein isoform expressed in cultured human muscle fibers and infant muscle. Finally, we identified two novel heterozygous mutations within exon 3 of the ATP2A1 gene from a previously described patient with BD.

Hyperemesis gravidarum can impair correct absorption of an adequate amount of thiamine and can cause electrolyte imbalance. This study investigated the neurological complications in a pregnant woman with hyperemesis gravidarum. A 29-year-old pregnant woman was admitted for hyperemesis gravidarum. Besides undernutrition, a neurological examination disclosed weakness with hyporeflexia, ophthalmoparesis, multidirectional nystagmus and optic disks swelling; the patient became rapidly comatose. Brain MRI showed symmetric signal hyperintensity and swelling of periaqueductal area, hypothalamus and mammillary bodies, medial and posterior portions of the thalamus and columns of fornix, consistent with Wernicke encephalopathy (WE). Neurophysiological studies revealed an axonal sensory-motor polyneuropathy, likely due to thiamine deficiency or critical illness polyneuropathy. Sodium and potassium supplementation and parenteral thiamine were administered with improvement of consciousness state in a few days. WE evolved in Korsakoff syndrome. A repeat MRI showed a marked improvement of WE-related alterations and a new hyperintense lesion in the pons, suggestive of central pontine myelinolysis. No sign or symptom due to involvement of the pons was present.

Centronuclear myopathies (CNMs) are clinically and genetically heterogeneous diseases with common histological findings of centrally located nuclei in myofibers with predominance and hypotrophy of type 1 fibers. CNMs can be classified in 3 main forms: the X-linked myotubular myopathy (XLMTM), caused by mutations in the myotubularin gene (MTM1); the autosomal-dominant form caused by mutations in the dynamin 2 gene (DNM2); the autosomal-recessive form related to mutations in the amphiphysin 2 gene (BIN1). More recently mutations in ryanodine receptor 1 gene (RYR1) have also been associated to CNMs. We report the genetic findings of a cohort of 50 patients with clinical and histological diagnosis of CNM who have been referred in the last 2 decade to the main tertiary Italian centers for neuromuscular diseases. Most patients were screened for the 4 candidate genes although the flow-chart™ of genetic testing was addressed by gender, pattern of inheritance and age of onset and/or disease severity. The genetic defect was identified in 29 patients (58%): 14 were mutated in MTM1 (48%), 12 in DNM2 (42%), and 3 in RYR1(10%). No mutations in BIN1 were detected. A total of 21 different mutations were identified, 6 of which were not previously reported, including 5 in MTM1 and 1 in RYR1. All MTM1 patients had neonatal onset and all but 2 showed severe disease progression. Patients with mutations in DNM2 had variable age of onset and different degree of muscle weakness. The patient carrying recessive RYR1 mutations had severe congenital hypotonia and ophthalmoparesis, in contrast to heterozygous patients who had a milder phenotype. In conclusion our data confirm that (1) XLMTM represent the most severe phenotype (2) DNM2-related CNMs are associated to a wide spectrum of phenotypes (3) CNMs related to recessive RYR1 mutations can mimic XLMTM 4) 40% of our cohort is genetically uncharacterized further confirming the genetic heterogeneity of CNMs.