title: Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2.
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.
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.affiliation: 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.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Oates
authors.affiliation: 4 Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Salter
authors.affiliation: 4 Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: 9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Scoto
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: 9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: 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.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: 13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria 14 Department of Cognitive Science and Psychology, New Bulgarian University, Sofia.
authors.forename: Iyailo
authors.initials: I
authors.lastname: Tournev
authors.affiliation: 13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria.
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.affiliation: 15 Clinic of Child Neurology, Department of Paediatrics, Medical University-Sofia, Sofia 1000, Bulgaria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Litvinenko
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: 16 University of Rochester Medical Centre, Departments of Neurology and Pathology, Rochester, NY, 14642, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Herrmann
authors.affiliation: 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.affiliation: 19 University of Rochester Medical Centre, Department of Neurology, Rochester, NY, 14642, USA.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Sowden
authors.affiliation: 20 Connecticut Children's Medical Centre, Department of Neurology, Hartford Connecticut, 06106, USA.
authors.forename: Gyuda
authors.initials: G
authors.lastname: Acsadi
authors.affiliation: 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.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Rodriguez
authors.affiliation: 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.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: 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.
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.affiliation: 23 Division of Orthopaedics, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer Grumbach
authors.affiliation: 4 Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Bullock
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK m.reilly@ucl.ac.uk.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: 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.
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D013131:Spine / Q000473:pathology; D055815:Young Adult
chemical_list: C561542:BICD2 protein, human; D008869:Microtubule-Associated Proteins
keywords: BICD2; dominant congenital spinal muscular atrophy; hereditary motor neuropathy; lower extremity predominant; proximal spinal muscular atrophy; spinal muscular atrophy