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Brain. 2015 Feb;138(Pt 2):293-310. doi: 10.1093/brain/awu356. Epub 2014 Dec 14.

Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2.

Author information

1
1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
2
2 Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, New South Wales, 2145, Australia 3 Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, 2006, Australia.
3
4 Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
4
5 Department of Neurology, Adelaide and Meath Hospitals Incorporating the National Children's Hospital, Tallaght, Dublin, Ireland 6 Academic Unit of Neurology, Trinity College Dublin, Ireland.
5
7 Hertie Institute for Clinical Brain Research and Centre for Neurology, Department of Neurodegenerative Disease, University of Tübingen and the German Research Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany 8 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, 33136, USA.
6
8 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, 33136, USA.
7
9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
8
10 Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, Antwerp 2610, Belgium 11 Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium 12 Department of Medical Chemistry and Biochemistry, Molecular Medicine Centre, Medical University-Sofia, Sofia 1431, Bulgaria.
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13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria 14 Department of Cognitive Science and Psychology, New Bulgarian University, Sofia.
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13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria.
11
15 Clinic of Child Neurology, Department of Paediatrics, Medical University-Sofia, Sofia 1000, Bulgaria.
12
16 University of Rochester Medical Centre, Departments of Neurology and Pathology, Rochester, NY, 14642, USA.
13
17 Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 18 Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, UK.
14
19 University of Rochester Medical Centre, Department of Neurology, Rochester, NY, 14642, USA.
15
20 Connecticut Children's Medical Centre, Department of Neurology, Hartford Connecticut, 06106, USA.
16
21 Department of Forensic Medicine, Sydney Local Health District, New South Wales, 2037, Australia 22 Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, 2006, Australia.
17
23 Division of Orthopaedics, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
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1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK 9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
19
1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK m.reilly@ucl.ac.uk.
20
2 Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, New South Wales, 2145, Australia 3 Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, 2006, Australia 24 Murdoch Children's Research Institute. The Royal Children's Hospital, Parkville Victoria 3052 Australia 25 Department of Paediatrics, University of Melbourne Parkville Victoria 3010 Australia.

Abstract

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.

KEYWORDS:

BICD2; dominant congenital spinal muscular atrophy; hereditary motor neuropathy; lower extremity predominant; proximal spinal muscular atrophy; spinal muscular atrophy

PMID:
25497877
PMCID:
PMC4306822
DOI:
10.1093/brain/awu356
[Indexed for MEDLINE]
Free PMC Article

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