G.P.102 SCN4A mutations in Finland

Abstracts / Neuromuscular Disorders 22 (2012) 804–908 G.P.102 SCN4A mutations in Finland T. Suominen 1, S. Sandell 2, S. Auvinen 3, B. Udd 2 1 University of Tampere, Neuromuscular Research Unit, Tampere, Finland; 2 Tampere University Hospital and University of Tampere, Department of Neurology, Neuromuscular Research Unit, Tampere, Finland; 3 Central Hospital of Jyva¨skyla¨, Department of Neurology, Jyva¨skyla¨, Finland Mutations in SCN4A gene are associated in several dominant myotonic disorders including potassium-aggravated myotonia, paramyotonia congenita, hyper- and hypokalemic periodic paralysis, myasthenic syndrome and acetazolamide-responsive myotonia congenita. Over 50 mutations have been identified all over the gene with some accumulation of mutations at the end of the protein. We have identified three different dominant mutations in Finnish patients: A1156T, V1293I and a novel R1460Q. These mutations are associated with different symptoms which can vary in patients even with the same mutation. Symptoms in patients with A1156T (n = 9) vary from clinical myotonia to only stiffness and myalgia with increased insertional activity in EMG. Patients carrying V1293I mutation (four patients in one family) have symptoms of paramyotonia congenita without paralysis. In one family five patients have been identified with R1460Q mutation which has not been reported previously. Two of them also carry a heterozygous CLCN1 R894X mutation. The patients with only the SCN4A mutation have paramyotonia or coldinduced myotonia in addition to periodic paralyses and one is almost asymptomatic. The two double-mutants have myasthenia and myotonia among other myalgic-stiffness symptoms. The novel R1460Q mutation is obviously pathogenic, because it resides in a highly conserved region of transmembrane segment S4 of domain IV. S4 is a voltage censor and has positively charged amino acids at every third position. The change of a positively charged arginine into an uncharged glutamine disrupts the pattern of positively charged amino acids and is thus very likely harmful for the protein function. The mutations in SCN4A cause variable phenotypes and combinations with other gene mutations, such as CLCN1, can modify the clinical outcome and complicate the diagnosis. The combination of SCN4A R1460Q and CLCN1 R894X seems to cause a distinct phenotype involving myasthenia. http://dx.doi:10.1016/j.nmd.2012.06.315

G.P.103 Brody syndrome: a clinically heterogeneous entity distinct from Brody disease: A review of literature and a cross-sectional clinical study in 17 patients N.C. Voermans 1, A.E. Laan 1, A. Oosterhof 2, A. van Kuppevelt 2, G. Drost 1, M. Lammens 3, E.J. Kamsteeg 4, C. Scotton 5, F. Gualandi 5, V. Guglielmi 6, L. Van den Heuvel 7, G. Vattemi 8, B.G.M. van Engelen 1 1 Radboud University Nijmegen Medical Centre, Neurology, Nijmegen, Netherlands; 2 Radboud University Nijmegen Medical Centre, Biochemistry, Nijmegen, Netherlands; 3 Radboud University Nijmegen Medical Centre, Neuropathology, Nijmegen, Netherlands; 4 Radboud University Nijmegen Medical Centre, Genetics, Nijmegen, Netherlands; 5 University of Ferrara, Medical Genetics, Ferrara, Italy; 6 University of Verona, Department of Neurological, Neuropsychological, Morphological, and Movement sciences, Ferrara, Italy; 7 Radboud University Nijmegen Medical Centre, Laboratory of pediatrics and neurology, Nijmegen, Netherlands; 8 University of Verona, Department of Neurological, Neuropsychological, Morphological, and Movement sciences, Verona, Italy Brody disease is a rare inherited myopathy due to reduced sarcoplasmic reticulum Ca2+ ATPase (SERCA)1 activity caused by mutations in ATP2A1, which causes delayed muscle relaxation and silent cramps. So far the disease has mostly been diagnosed by measurement of SERCA1 activity. Since mutation analysis became more widely available, it has

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appeared that not all patients with reduced SERCA1 activity indeed have ATP2A1 mutations, and a distinction between Brody disease (with ATP2A1 mutations) and Brody syndrome (without ATP2A1 mutations) was proposed. We aim to compare the clinical features of patients with Brody disease and those with Brody syndrome and detect clinical features which help to distinguish between the two. In addition, we describe the Brody syndrome phenotype in more detail. We therefore performed a literature review on clinical features of both Brody disease and Brody syndrome and a cross-sectional clinical study consisting of questionnaires, physical examination, and a review of medical files in 17 Brody syndrome patients in our centre. The results showed that Brody disease presents with an onset in the 1st decade, a generalized pattern of muscle stiffness, delayed muscle relaxation after repetitive contraction on physical examination, and autosomal recessive inheritance. Patients with Brody syndrome more often report myalgia and experience a considerable impact on daily life. Future research should focus on the possible mechanisms of reduction of SERCA activity in Brody syndrome and other genetic causes, and on evaluation of treatment options. http://dx.doi:10.1016/j.nmd.2012.06.316

G.P.104 Liver insulin resistance and insulin secretion abnormality in myotonic dystrophy type 1 H. Takada 1, T. Goto 2, S. Kon 1, Y. Oyama 1, M. Kobayashi 3 1 Aomori Hospital, National Hospital Organization, Neurology, Aomori, Japan; 2 Akita Red Cross Hospital, Internal Medicine, Akita, Japan; 3 Akita Hospital, National Hospital Organization, Neurology, Yurihonjo, Japan Insulin resistance (IR) is a characteristic feature of glucose intolerance in myotonic dystrophy type 1 (DM1). The mechanism of IR is still unknown. The aim of this study was to investigate IR in DM1 by means of some indexes derived from oral glucose tolerance test (OGTT Seventyseven non-diabetic patients with DM1 (the median value: age, 47 years; body mass index (BMI), 22.4) were classified into the normal glucose response group (NGTDM1) and the impaired glucose tolerance group (IGTDM1) by 75 g OGTT. For age and BMI matched controls, 100 normal glucose response subjects (NGTCT) and 130 impaired glucose tolerance cases (IGTCT) were picked up from our diabetic database. Liver and muscle insulin resistance indexes derived from OGTT supposed by Abdul-Ghani et al. were calculated: AUCgi30 for liver, glucose0– 30[AUC]  insulin0–30[AUC]; dG/dt/I for muscle, the rate of decay of plasma glucose concentration from its peak value to its nadir during OGTT divided by the mean plasma insulin concentration; AUC, area under curve. AUCgi30, dG/dt/I, fasting plasma glucose (FPG) and insulin (FIRI), plasma glucose (PG120) and insulin (IRI120) level at 120 min after oral glucose load, and Insulinogenic-Index (I-I) were analyzed. There was no significant difference between NGTDM1 and NGTCT for AUCgi30 or dG/dt/I. I-I in NGTDM1 was significantly lower than that in NGTCT. FPG and PG120 in NGTDM1 were significantly lower than those in NGTCT, whereas there was no significant difference in FIRI and IRI120. AUCgi30 in IGTDM1 was significantly higher than that in IGTCT, and dG/dt/I in IGTDM1 was significantly lower. I-I in IGTDM1 was also significantly lower than that in IGTCT. FPG in IGTDM1 was significantly lower than that in IGTCT. DM1 patients with dysglycaemia showed liver IR as well as muscle IR. Lower I-I in DM1 could represent abnormality of insulin secretion. Our data suggested IR in DM1 might result in multiple metabolic defects. http://dx.doi:10.1016/j.nmd.2012.06.317