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Recurrent de novo BICD2 mutation associated with severe arthrogryposis and polymicrogyria: Expanding the phenotype
S106
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
P.54 Case report: Non SMARD1 presentation of IGHMBP2 mutation with late onset diaphragmatic weakness R. Kulshrestha 1, T. Willis 1, K. Sethuraman 2, M. Samuels 3 1 Robert Jones and Agnes Hunt Orthopaedic \Hopsital, Oswestry, UK; 2 Shrewsbury and Telford Hospital NHS Trust, Telford, UK; 3 University Hospital of North Midlands NHS Trust, Stoke-on Trent, UK Immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. Individuals with the CMT2 (axonal neuropathy) phenotype have been described with slowly progressive weakness, wasting and sensory loss but no significant respiratory compromise. In the largest case series published (Houlden et al. 2014), none of the fifteen patients from 10 to 43 years with the CMT2 phenotype required respiratory support. We present a case of axonal neuropathy related to IGHMBP2 mutation with late onset diaphragmatic weakness at 11 years. A 6-month-old boy presented with late onset bilateral equinovarus deformities of feet. He had no significant movement at ankle and knee joints. Neurophysiology was consistent with an axonal neuropathy. He has two heterozygous variants in IGHMBP2 gene c.1156 > C in exon 8 and c.2747G > A in exon 14. These variants were inherited from father and mother respectively. The second variant has not been reported in the literature. He achieved walking at two years with support but had progressive distal and proximal weakness of both upper and lower limbs leading to wheelchair dependence at 8 years. He has developed scoliosis. Respiratory status was satisfactory at 10 years with annual respiratory review and sleep studies. Soon after his 10th birthday he developed recurrent respiratory tract infections and pleural effusion requiring drainage. His chest x ray had no evidence of diaphragmatic weakness. He was discharged home on air. He struggled to tolerate spinal brace for scoliosis. He had repeat sleep studies which identified bilateral diaphragmatic weakness. He is now established on non-invasive ventilation. His clinical condition has been stable and he is awaiting scoliosis repair. Our case emphasizes the importance of respiratory surveillance for patients with IGHMBP2 related axonal neuropathy patients. http://dx.doi.org/10.1016/j.nmd.2016.06.076
P.55 Two novel BICD2 mutations occurring de novo in sporadic Finnish SMALED2 patients S. Penttilä 1, D. Caminiti 1, J. Palmio 1, M. Jokela 1, R. Alen 2, B. Udd 1 1 Tampere University and University Hospital, Tampere, Finland; 2 Central Finland Healthcare District, Jyväskylä, Finland Lower extremity-predominant spinal muscular atrophy 2 (SMALED2) is an autosomal dominant disease causing early-childhood onset muscle weakness and atrophy. The disease affects predominantly proximal and distal muscles of the lower extremity, resulting in delayed walking, waddling gait, difficulty in walking, and loss of distal reflexes. The disorder shows very slow progression. SMALED2 is caused by heterozygous mutations in BICD2. We report two unrelated Finnish patients (P1 and P2) with SMALED2 caused by novel de novo mutations in BICD2. Both patients had lower limb muscle weakness, muscle atrophy and feet deformities in their first year of life with apparent normal upper body and limb muscles. ENMG showed neurogenic findings. In muscle biopsy there was clear predominance of type 1 fibers, and central core pathology was present in P2. Lower limb muscle MRI showed distinct findings with more dystrophic pattern of large muscle parts replaced by fatty connective tissue but characteristic dispersed small regions of remaining muscle tissue. The mother of P1 had mild affection with asymmetric non-progressive increase of tendon reflexes with hypotrophy of right lower limb, whereas both parents of P2 were asymptomatic. In targeted gene panel analysis (MYOcap) both patients were found to carry previously unknown heterozygous mutations in BICD2: c.1922T > C p.L641P and c.2114A > C p.E705A. Sanger sequencing analysis of the parents of the patients showed that none of the parents carried the mutation i.e. both mutations were de novo. Our study suggests that de novo
mutations in BICD2 may not be rare and that SMALED2 should be suspected even in the absence of positive family history. http://dx.doi.org/10.1016/j.nmd.2016.06.077
P.56 The ASCC1 gene is involved in spinal muscular atrophy with congenital fractures: Evidence provided by the identification of a second case J. Oliveira 1, M. Martins 2, M. Sousa 3, R. Santos 1 1 Centro Hospitalar do Porto, Porto, Portugal; 2 Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal; 3 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal We report the second known case of a severe spinal muscular atrophy (SMA) with bone fractures due to a defect in the activating signal cointegrator 1 complex (ASC-1) subunit 1 (ASCC1) gene. A healthy non-consanguineous couple had an intrauterine fetal death (32 weeks gestation) followed by two live births (female and male) presenting severe hypotonia, congenital bone fractures and lack of spontaneous respiratory movements, both of whom died shortly after birth. Results of the genetic diagnostic workup of the female patient were negative for karyotyping and for sequencing of several genes related with SMA (SMN1), myotonic dystrophy (DMPK) and congenital myopathies (ACTA1, MTM1, TNNT1, TPM2 and TPM3). Whole-exome sequencing (WES) was performed. Variant filtering resorted to a recessive disease model and variants with frequency <0.1% in candidate genes related with congenital myopathies (n = 20 genes), primary muscle diseases (n = 146) and finally neuromuscular diseases (n = 407), which included those defective in motor neuron diseases. Given the initial clinical suspicion, genes implicated in osteogenesis imperfecta (n = 14) were also evaluated. No plausible disease-causing variants were identified in any of these sets of genes. Knierim and collaborators (2016) recently reported a severe prenatal SMA with respiratory distress and congenital bone fractures, in patients with recessive loss-of-function mutations in two genes: TRIP4 (3 families) and ASCC1 (1 Turkish family), both encoding subunits of the nuclear ASC-1. Based on this report we reassessed our WES data and identified a homozygous frameshift variant (c.157dupG, p. Glu53Glyfs*19), identical to that found in the Turkish patient. Sanger sequencing confirmed the genotype in our patient and showed that the parents are heterozygotes. The identification of an additional patient with a mutation in ASCC1, showing similar clinical features, corroborates the involvement of this gene in a severe form of SMA with bone fractures. http://dx.doi.org/10.1016/j.nmd.2016.06.078
P.57 Recurrent de novo BICD2 mutation associated with severe arthrogryposis and polymicrogyria: Expanding the phenotype G. Ravenscroft 1, N. Di Donato 2, M. Davis 3, P. Craven 4, G. Poke 5, K. Neas 5, T. Neuhann 2, W. Dobyns 6, N. Laing 7 1 Centre for Medical Research, The University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, Australia; 2 Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Institut für Klinische Genetik, Dresden, Germany; 3 Department of Diagnostic Genomics, Pathwest, Nedlands, Australia; 4 John Hunter Children’s Hospital, Newcastle, NSW, Australia; 5 Genetic Health Services, Christchurch, New Zealand; 6 Seattle Children’s Research Institute, Seattle, Washington State, USA; 7 Centre for Medical Research, The University of Western Australia and Harry Perkins Institute for Medical Research, Nedlands, Australia Autosomal dominantly inherited mutations of bicaudal D homolog 2 (Drosophila) gene (BICD2) are associated with congenital-onset spinal muscular atrophy characterized by lower limb predominance and upper motor neuron pathology. The age-of-onset for the published families is usually at birth but also included cases with childhood- (2–6 years) and adult-onset disease (20–70 years of age). In this report we described two isolated probands (one
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212 German and one Australian) that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, macrocephaly and unilateral or bilateral perisylvian polymicrogyria. The Australian patient passed away at 7 weeks of age. The German patient is 4 years of age and stable, but shows significant motor developmental delay and mildly delayed speech. With whole exome sequencing we identified the same missense substitution in BICD2 (NM_015250.3:c.2080C > T,p.Arg694Cys). The arginine at residue 694 is highly conserved through evolution (including C. elegans) and resides within a bicaudal-D protein, microtubule-associated domain. This substitution is predicted to be disease causing by all in silico prediction programs and was not present in the Exome Aggregate Consortium (ExAC) Browser or 1000 Genomes Project. Sanger sequencing confirmed the mutation and showed that in both cases the mutation arose de novo. Thus our report widens the phenotypic spectrum associated with BICD2 mutations to include arthrogryposis multiplex congenita and cortical malformations. Both cases displayed in utero onset of symptoms suggesting that the p. Arg694Cys substitution may have a more deleterious effect on BICD2 function than the previously described mutations. These findings are not dissimilar to the evolving phenotypes arising from DYNC1H1 mutations. http://dx.doi.org/10.1016/j.nmd.2016.06.079
P.58 Arthrogryposis multiplex congenita (AMC): Spectrum and classification at a tertiary referral center I. Oncel, G. Haliloglu, E. Utine, C. Aksoy, K. Boduroglu, H. Topaloglu Hacettepe Children’s Hospital, Ankara, Turkey Arthrogryposis is a descriptive term representing a general category of disorders characterized by multiple joint contractures. We reviewed clinical features and etiological classification of patients with AMC who presented to our pediatric neurology clinic between March 2014 and November 2015. A total of 48 children (Male: 26, Female: 22) were included in the study. Median age at the first evaluation was 22 months (range: 9 days–180 months). There was a history of decreased intrauterine movements in 27 (56%) patients. Suggestive prenatal diagnosis by fetal ultrasonography was achieved in 19 (40%) patients. Distribution of the patients was as follows; primarily limb involvement (n = 19), limbs and other system involvement (n = 22), limbs and central nervous system involvement ± intellectual disability (n = 7). Clinical diagnosis was distal arthrogryposis in 13 (27%), and amyoplasia in 9 (%18) patients. Etiological distribution of the rest was; neuropathies (n = 12), myopathies (n = 4), neuromuscular end plate disorders (n = 3), connective tissue disorders (n = 3), and space limitations (n = 1). Three patients could not be specified to date. Neuromuscular diseases are overrepresented, probably due to the nature of our department being a referral center for neuromuscular diseases. Time lag between birth and evaluation is challenging due to evolution of contractures, serial orthopedic interventions, physiotherapy and casting. Clinical and etiological documentation of this group will be a preliminary step for further molecular genetic work-up. http://dx.doi.org/10.1016/j.nmd.2016.06.080
POMPE DISEASE P.59 Screening for late onset Pompe disease – Single center experience A. Kostera-Pruszczyk, A. Potulska-Chromik, A. Lusakowska, A. Macias, B. Ryniewicz, A. Nowakowska-Jastrze˛bska, M. Jastrzebski, A. Kaminska Medical University of Warsaw, Warsaw, Poland
S107
Late onset Pompe disease (LOPD, OMIM# 32300) is an autosomal recessive disorder caused by mutations of GAA gene encoding acid maltase. LOPD can present with a variety of neuromuscular phenotypes, from limb-girdle weakness to asymptomatic CK-emia. Several diagnostic approaches were proposed. Search for decreased GAA activity can be done either when other known causes of neuromuscular symptoms were excluded, or it can be the first screening step in a predefined population. Material and methods: a cohort of patients older than 5 y. with limb-girdle weakness or persistently elevated CK (more than 1.5× ULN). Enzyme activity from a dry blood spot (DBS) was estimated, followed by confirmatory testing if GAA levels were significantly reduced. 178 patients were tested (mean age 29.5 years, SD 19, range 5–78), 40% were women. Decreased GAA activity was detected in eight patients at first screening. It led to diagnosis of LOPD in 4 patients (2.2%), including two siblings of a boy originally tested for persistent CK-emia. DBS is useful for LOPD screening in patients with isolated CK-emia or limb-girdle weakness. LOPD ratio in our screened cohort is similar as in previously reported populations. http://dx.doi.org/10.1016/j.nmd.2016.06.081
P.60 Pompe disease in patients with undetermined myopathies or asymptomatic hyperCKemia: Searching for late-onset Pompe disease in Aegean region of Turkey H. Karasoy, O. Ekmekci, A. Yuceyar, E. Sozmen Ege University, Faculty of Medicine, Bornova-Izmir, Turkey Late-onset Pompe disease (LOPD) is a rare, potentially treatable metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glycosidase (GAA). LOPD patients are often difficult to diagnose, easily missed and associated with a diagnostic delay. We aimed to identify patients with LOPD among patients admitted to the neuromuscular outpatient clinic at Ege University Medical Faculty Hospital. Between the years 2010 and 2012, 94 patients with suggestive symptoms of LOPD, undetermined myopathy or asymptomatic persistent hyperCKemia were elected to perform the dried-blood spot (DBS) test. 51 patients were male (54.3 %). 10 patients had no weakness but persistent hyperCKemia. The initial DBS studies revealed normal results in 76 patients. The results were in low or borderline range in 18 patients. Re-analysis of these patients with a second DBS test, only 3 patients showed very low GAA levels. Later, the diagnosis of LOPD confirmed by lymphocyte analysis and molecular genetic testing. All 3 patients were male, presented with limb-girdle weakness and restrictive type respiratory involvement in two of them. Their CK levels were between 400–4866 UI/L. Muscle biopsy findings were also suggestive for glycogen storage disease. However, definite diagnosis was delayed 3 to 7 years. In our study, LOPD was detected in 3.2% of patients along with possible high risk groups. With regard to enzyme replacement therapy being available, we suggest that LOPD should be considered as a first tier test among patients with myopathy of unknown origin. http://dx.doi.org/10.1016/j.nmd.2016.06.082
P.61 Targeted screening for detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) using dried blood spot (DBS) T. Chamova 1, I. Sinigerska 2, M. Gospodinova 3, V. Bojinova 4, V. Guergueltcheva 5, K. Genov 6, I. Staykov 7, H. Dimitrova 6, D. Bogdanova 8, A. Kaprelyan 9, T. Todorov 10, A. Todorova 11, I. Tournev 12,13 1 University Hospital Alexandrovska, Medical University-Sofia, Sofia, Bulgaria; 2 Medical University-Sofia, Sofia, Bulgaria; 3 Medical Institute of Ministry of Interior Affairs, Sofia, Bulgaria; 4 University Hospital of Neurology and Psychiatry Sv. Naum Sofia, Medical University-Sofia, Bulgaria; 5 University hospital Sofiamed, Sofia, Bulgaria; 6 Military medical academy, Sofia, Bulgaria; 7 Tokuda hospital, Sofia, Bulgaria; 8 University Hospital of Neurology and Psychiatry Sv. Naum, Medical University-Sofia, Sofia, Bulgaria;
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
P.54 Case report: Non SMARD1 presentation of IGHMBP2 mutation with late onset diaphragmatic weakness R. Kulshrestha 1, T. Willis 1, K. Sethuraman 2, M. Samuels 3 1 Robert Jones and Agnes Hunt Orthopaedic \Hopsital, Oswestry, UK; 2 Shrewsbury and Telford Hospital NHS Trust, Telford, UK; 3 University Hospital of North Midlands NHS Trust, Stoke-on Trent, UK Immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. Individuals with the CMT2 (axonal neuropathy) phenotype have been described with slowly progressive weakness, wasting and sensory loss but no significant respiratory compromise. In the largest case series published (Houlden et al. 2014), none of the fifteen patients from 10 to 43 years with the CMT2 phenotype required respiratory support. We present a case of axonal neuropathy related to IGHMBP2 mutation with late onset diaphragmatic weakness at 11 years. A 6-month-old boy presented with late onset bilateral equinovarus deformities of feet. He had no significant movement at ankle and knee joints. Neurophysiology was consistent with an axonal neuropathy. He has two heterozygous variants in IGHMBP2 gene c.1156 > C in exon 8 and c.2747G > A in exon 14. These variants were inherited from father and mother respectively. The second variant has not been reported in the literature. He achieved walking at two years with support but had progressive distal and proximal weakness of both upper and lower limbs leading to wheelchair dependence at 8 years. He has developed scoliosis. Respiratory status was satisfactory at 10 years with annual respiratory review and sleep studies. Soon after his 10th birthday he developed recurrent respiratory tract infections and pleural effusion requiring drainage. His chest x ray had no evidence of diaphragmatic weakness. He was discharged home on air. He struggled to tolerate spinal brace for scoliosis. He had repeat sleep studies which identified bilateral diaphragmatic weakness. He is now established on non-invasive ventilation. His clinical condition has been stable and he is awaiting scoliosis repair. Our case emphasizes the importance of respiratory surveillance for patients with IGHMBP2 related axonal neuropathy patients. http://dx.doi.org/10.1016/j.nmd.2016.06.076
P.55 Two novel BICD2 mutations occurring de novo in sporadic Finnish SMALED2 patients S. Penttilä 1, D. Caminiti 1, J. Palmio 1, M. Jokela 1, R. Alen 2, B. Udd 1 1 Tampere University and University Hospital, Tampere, Finland; 2 Central Finland Healthcare District, Jyväskylä, Finland Lower extremity-predominant spinal muscular atrophy 2 (SMALED2) is an autosomal dominant disease causing early-childhood onset muscle weakness and atrophy. The disease affects predominantly proximal and distal muscles of the lower extremity, resulting in delayed walking, waddling gait, difficulty in walking, and loss of distal reflexes. The disorder shows very slow progression. SMALED2 is caused by heterozygous mutations in BICD2. We report two unrelated Finnish patients (P1 and P2) with SMALED2 caused by novel de novo mutations in BICD2. Both patients had lower limb muscle weakness, muscle atrophy and feet deformities in their first year of life with apparent normal upper body and limb muscles. ENMG showed neurogenic findings. In muscle biopsy there was clear predominance of type 1 fibers, and central core pathology was present in P2. Lower limb muscle MRI showed distinct findings with more dystrophic pattern of large muscle parts replaced by fatty connective tissue but characteristic dispersed small regions of remaining muscle tissue. The mother of P1 had mild affection with asymmetric non-progressive increase of tendon reflexes with hypotrophy of right lower limb, whereas both parents of P2 were asymptomatic. In targeted gene panel analysis (MYOcap) both patients were found to carry previously unknown heterozygous mutations in BICD2: c.1922T > C p.L641P and c.2114A > C p.E705A. Sanger sequencing analysis of the parents of the patients showed that none of the parents carried the mutation i.e. both mutations were de novo. Our study suggests that de novo
mutations in BICD2 may not be rare and that SMALED2 should be suspected even in the absence of positive family history. http://dx.doi.org/10.1016/j.nmd.2016.06.077
P.56 The ASCC1 gene is involved in spinal muscular atrophy with congenital fractures: Evidence provided by the identification of a second case J. Oliveira 1, M. Martins 2, M. Sousa 3, R. Santos 1 1 Centro Hospitalar do Porto, Porto, Portugal; 2 Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal; 3 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal We report the second known case of a severe spinal muscular atrophy (SMA) with bone fractures due to a defect in the activating signal cointegrator 1 complex (ASC-1) subunit 1 (ASCC1) gene. A healthy non-consanguineous couple had an intrauterine fetal death (32 weeks gestation) followed by two live births (female and male) presenting severe hypotonia, congenital bone fractures and lack of spontaneous respiratory movements, both of whom died shortly after birth. Results of the genetic diagnostic workup of the female patient were negative for karyotyping and for sequencing of several genes related with SMA (SMN1), myotonic dystrophy (DMPK) and congenital myopathies (ACTA1, MTM1, TNNT1, TPM2 and TPM3). Whole-exome sequencing (WES) was performed. Variant filtering resorted to a recessive disease model and variants with frequency <0.1% in candidate genes related with congenital myopathies (n = 20 genes), primary muscle diseases (n = 146) and finally neuromuscular diseases (n = 407), which included those defective in motor neuron diseases. Given the initial clinical suspicion, genes implicated in osteogenesis imperfecta (n = 14) were also evaluated. No plausible disease-causing variants were identified in any of these sets of genes. Knierim and collaborators (2016) recently reported a severe prenatal SMA with respiratory distress and congenital bone fractures, in patients with recessive loss-of-function mutations in two genes: TRIP4 (3 families) and ASCC1 (1 Turkish family), both encoding subunits of the nuclear ASC-1. Based on this report we reassessed our WES data and identified a homozygous frameshift variant (c.157dupG, p. Glu53Glyfs*19), identical to that found in the Turkish patient. Sanger sequencing confirmed the genotype in our patient and showed that the parents are heterozygotes. The identification of an additional patient with a mutation in ASCC1, showing similar clinical features, corroborates the involvement of this gene in a severe form of SMA with bone fractures. http://dx.doi.org/10.1016/j.nmd.2016.06.078
P.57 Recurrent de novo BICD2 mutation associated with severe arthrogryposis and polymicrogyria: Expanding the phenotype G. Ravenscroft 1, N. Di Donato 2, M. Davis 3, P. Craven 4, G. Poke 5, K. Neas 5, T. Neuhann 2, W. Dobyns 6, N. Laing 7 1 Centre for Medical Research, The University of Western Australia and Harry Perkins Institute of Medical Research, Nedlands, Australia; 2 Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Institut für Klinische Genetik, Dresden, Germany; 3 Department of Diagnostic Genomics, Pathwest, Nedlands, Australia; 4 John Hunter Children’s Hospital, Newcastle, NSW, Australia; 5 Genetic Health Services, Christchurch, New Zealand; 6 Seattle Children’s Research Institute, Seattle, Washington State, USA; 7 Centre for Medical Research, The University of Western Australia and Harry Perkins Institute for Medical Research, Nedlands, Australia Autosomal dominantly inherited mutations of bicaudal D homolog 2 (Drosophila) gene (BICD2) are associated with congenital-onset spinal muscular atrophy characterized by lower limb predominance and upper motor neuron pathology. The age-of-onset for the published families is usually at birth but also included cases with childhood- (2–6 years) and adult-onset disease (20–70 years of age). In this report we described two isolated probands (one
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212 German and one Australian) that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, macrocephaly and unilateral or bilateral perisylvian polymicrogyria. The Australian patient passed away at 7 weeks of age. The German patient is 4 years of age and stable, but shows significant motor developmental delay and mildly delayed speech. With whole exome sequencing we identified the same missense substitution in BICD2 (NM_015250.3:c.2080C > T,p.Arg694Cys). The arginine at residue 694 is highly conserved through evolution (including C. elegans) and resides within a bicaudal-D protein, microtubule-associated domain. This substitution is predicted to be disease causing by all in silico prediction programs and was not present in the Exome Aggregate Consortium (ExAC) Browser or 1000 Genomes Project. Sanger sequencing confirmed the mutation and showed that in both cases the mutation arose de novo. Thus our report widens the phenotypic spectrum associated with BICD2 mutations to include arthrogryposis multiplex congenita and cortical malformations. Both cases displayed in utero onset of symptoms suggesting that the p. Arg694Cys substitution may have a more deleterious effect on BICD2 function than the previously described mutations. These findings are not dissimilar to the evolving phenotypes arising from DYNC1H1 mutations. http://dx.doi.org/10.1016/j.nmd.2016.06.079
P.58 Arthrogryposis multiplex congenita (AMC): Spectrum and classification at a tertiary referral center I. Oncel, G. Haliloglu, E. Utine, C. Aksoy, K. Boduroglu, H. Topaloglu Hacettepe Children’s Hospital, Ankara, Turkey Arthrogryposis is a descriptive term representing a general category of disorders characterized by multiple joint contractures. We reviewed clinical features and etiological classification of patients with AMC who presented to our pediatric neurology clinic between March 2014 and November 2015. A total of 48 children (Male: 26, Female: 22) were included in the study. Median age at the first evaluation was 22 months (range: 9 days–180 months). There was a history of decreased intrauterine movements in 27 (56%) patients. Suggestive prenatal diagnosis by fetal ultrasonography was achieved in 19 (40%) patients. Distribution of the patients was as follows; primarily limb involvement (n = 19), limbs and other system involvement (n = 22), limbs and central nervous system involvement ± intellectual disability (n = 7). Clinical diagnosis was distal arthrogryposis in 13 (27%), and amyoplasia in 9 (%18) patients. Etiological distribution of the rest was; neuropathies (n = 12), myopathies (n = 4), neuromuscular end plate disorders (n = 3), connective tissue disorders (n = 3), and space limitations (n = 1). Three patients could not be specified to date. Neuromuscular diseases are overrepresented, probably due to the nature of our department being a referral center for neuromuscular diseases. Time lag between birth and evaluation is challenging due to evolution of contractures, serial orthopedic interventions, physiotherapy and casting. Clinical and etiological documentation of this group will be a preliminary step for further molecular genetic work-up. http://dx.doi.org/10.1016/j.nmd.2016.06.080
POMPE DISEASE P.59 Screening for late onset Pompe disease – Single center experience A. Kostera-Pruszczyk, A. Potulska-Chromik, A. Lusakowska, A. Macias, B. Ryniewicz, A. Nowakowska-Jastrze˛bska, M. Jastrzebski, A. Kaminska Medical University of Warsaw, Warsaw, Poland
S107
Late onset Pompe disease (LOPD, OMIM# 32300) is an autosomal recessive disorder caused by mutations of GAA gene encoding acid maltase. LOPD can present with a variety of neuromuscular phenotypes, from limb-girdle weakness to asymptomatic CK-emia. Several diagnostic approaches were proposed. Search for decreased GAA activity can be done either when other known causes of neuromuscular symptoms were excluded, or it can be the first screening step in a predefined population. Material and methods: a cohort of patients older than 5 y. with limb-girdle weakness or persistently elevated CK (more than 1.5× ULN). Enzyme activity from a dry blood spot (DBS) was estimated, followed by confirmatory testing if GAA levels were significantly reduced. 178 patients were tested (mean age 29.5 years, SD 19, range 5–78), 40% were women. Decreased GAA activity was detected in eight patients at first screening. It led to diagnosis of LOPD in 4 patients (2.2%), including two siblings of a boy originally tested for persistent CK-emia. DBS is useful for LOPD screening in patients with isolated CK-emia or limb-girdle weakness. LOPD ratio in our screened cohort is similar as in previously reported populations. http://dx.doi.org/10.1016/j.nmd.2016.06.081
P.60 Pompe disease in patients with undetermined myopathies or asymptomatic hyperCKemia: Searching for late-onset Pompe disease in Aegean region of Turkey H. Karasoy, O. Ekmekci, A. Yuceyar, E. Sozmen Ege University, Faculty of Medicine, Bornova-Izmir, Turkey Late-onset Pompe disease (LOPD) is a rare, potentially treatable metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glycosidase (GAA). LOPD patients are often difficult to diagnose, easily missed and associated with a diagnostic delay. We aimed to identify patients with LOPD among patients admitted to the neuromuscular outpatient clinic at Ege University Medical Faculty Hospital. Between the years 2010 and 2012, 94 patients with suggestive symptoms of LOPD, undetermined myopathy or asymptomatic persistent hyperCKemia were elected to perform the dried-blood spot (DBS) test. 51 patients were male (54.3 %). 10 patients had no weakness but persistent hyperCKemia. The initial DBS studies revealed normal results in 76 patients. The results were in low or borderline range in 18 patients. Re-analysis of these patients with a second DBS test, only 3 patients showed very low GAA levels. Later, the diagnosis of LOPD confirmed by lymphocyte analysis and molecular genetic testing. All 3 patients were male, presented with limb-girdle weakness and restrictive type respiratory involvement in two of them. Their CK levels were between 400–4866 UI/L. Muscle biopsy findings were also suggestive for glycogen storage disease. However, definite diagnosis was delayed 3 to 7 years. In our study, LOPD was detected in 3.2% of patients along with possible high risk groups. With regard to enzyme replacement therapy being available, we suggest that LOPD should be considered as a first tier test among patients with myopathy of unknown origin. http://dx.doi.org/10.1016/j.nmd.2016.06.082
P.61 Targeted screening for detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) using dried blood spot (DBS) T. Chamova 1, I. Sinigerska 2, M. Gospodinova 3, V. Bojinova 4, V. Guergueltcheva 5, K. Genov 6, I. Staykov 7, H. Dimitrova 6, D. Bogdanova 8, A. Kaprelyan 9, T. Todorov 10, A. Todorova 11, I. Tournev 12,13 1 University Hospital Alexandrovska, Medical University-Sofia, Sofia, Bulgaria; 2 Medical University-Sofia, Sofia, Bulgaria; 3 Medical Institute of Ministry of Interior Affairs, Sofia, Bulgaria; 4 University Hospital of Neurology and Psychiatry Sv. Naum Sofia, Medical University-Sofia, Bulgaria; 5 University hospital Sofiamed, Sofia, Bulgaria; 6 Military medical academy, Sofia, Bulgaria; 7 Tokuda hospital, Sofia, Bulgaria; 8 University Hospital of Neurology and Psychiatry Sv. Naum, Medical University-Sofia, Sofia, Bulgaria;