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Dominant spinal muscular atrophy due to BICD2: a novel mutation refines the phenotype
  1. Matthis Synofzik1,2,
  2. Lilian A Martinez-Carrera3,
  3. Tobias Lindig4,
  4. Ludger Schöls1,2,
  5. Brunhilde Wirth3
  1. 1Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  2. 2German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  3. 3Institute of Human Genetics, Institute for Genetics and Center for Molecular Medicine, Cologne, University of Cologne, Cologne, Germany
  4. 4Department of Radiology, Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany
  1. Correspondence to Dr Matthis Synofzik, Department of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, Tübingen 72076, Germany; matthis.synofzik{at}uni-tuebingen.de

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Spinal muscular atrophies (SMA) are a genetically and clinically heterogeneous group of disorders predominantly of the anterior horn. While the large majority of recessive SMA cases can be explained by mutations in SMN1, the genetic basis of dominant SMA has remained largely elusive. Although mutations have been identified in >12 genes, mutations are found only in less than 30% of dominant SMA cases.1 Recently, BICD2 has been identified to cause dominant SMA.1–3 Here, we provide additional evidence that BICD2 is a cause of dominant SMA and report detailed clinical, electrophysiological and MRI data from a three-generation family with cosegregation of a novel BICD2 mutation. These findings extend current notions of BICD2, demonstrating that it can present with adult-onset combined proximal and distal lower extremity SMA. Our clinical observations not only extend the phenotype of BICD2-related disease, but might also provide novel insights in the pathophysiology of the disease.

The 44-year-old German female index patient (III-2, figure 1A) presented with a 3-year history of a mild symmetric proximal (Medical Research Council (MRC) grade 4) and distal (MRC grade 3) paresis of lower extremities. While able to ambulate independently, she was unable to walk on heels and had difficulties walking on toes and climbing >10 stairs. There was areflexia of lower limbs, high-arched feet (figure 1C) and complete atrophy of the quadriceps muscle (figure 1D) without genu recurvatum. She recalled minor problems in jumping during sports at school, however had not sought medical advice so far. …

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