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

Alexander M. Rossor, Emily C. Oates, Hannah K. Salter, Yang Liu, Sinead M. Murphy, Rebecca Schule, Michael A. Gonzalez, Mariacristina Scoto, Rahul Phadke, Caroline A. Sewry, Henry Houlden, Albena Jordanova, Iyailo Tournev, Teodora Chamova, Ivan Litvinenko, Stephan L Zuchner, David N. Herrmann, Julian Blake, Janet E. Sowden, Gyuda AcsadiMichael L. Rodriguez, Manoj P. Menezes, Nigel F. Clarke, Michaela Auer Grumbach, Simon L. Bullock, Francesco Muntoni, Mary M. Reilly, Kathryn N. North

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)293-310
Number of pages18
JournalBrain
Volume138
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Spinal Muscular Atrophy
Motor Neurons
Mutation
Lower Extremity
Muscles
Hereditary Spastic Paraplegia
Arthrogryposis
Microtubule Proteins
Phenotype
Congenital Hip Dislocation
Dyneins
Muscle Weakness
Genetic Testing
Contracture
Pathologic Processes
Thigh
Natural History
Ankle
Drosophila
Neuron

Keywords

  • BICD2
  • Dominant congenital spinal muscular atrophy
  • Hereditary motor neuropathy
  • Lower extremity predominant
  • Proximal spinal muscular atrophy
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Rossor, A. M., Oates, E. C., Salter, H. K., Liu, Y., Murphy, S. M., Schule, R., ... North, K. N. (2015). Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain, 138(2), 293-310. https://doi.org/10.1093/brain/awu356

Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. / Rossor, Alexander M.; Oates, Emily C.; Salter, Hannah K.; Liu, Yang; Murphy, Sinead M.; Schule, Rebecca; Gonzalez, Michael A.; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A.; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan L; Herrmann, David N.; Blake, Julian; Sowden, Janet E.; Acsadi, Gyuda; Rodriguez, Michael L.; Menezes, Manoj P.; Clarke, Nigel F.; Grumbach, Michaela Auer; Bullock, Simon L.; Muntoni, Francesco; Reilly, Mary M.; North, Kathryn N.

In: Brain, Vol. 138, No. 2, 01.02.2015, p. 293-310.

Research output: Contribution to journalArticle

Rossor, AM, Oates, EC, Salter, HK, Liu, Y, Murphy, SM, Schule, R, Gonzalez, MA, Scoto, M, Phadke, R, Sewry, CA, Houlden, H, Jordanova, A, Tournev, I, Chamova, T, Litvinenko, I, Zuchner, SL, Herrmann, DN, Blake, J, Sowden, JE, Acsadi, G, Rodriguez, ML, Menezes, MP, Clarke, NF, Grumbach, MA, Bullock, SL, Muntoni, F, Reilly, MM & North, KN 2015, 'Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2', Brain, vol. 138, no. 2, pp. 293-310. https://doi.org/10.1093/brain/awu356
Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R et al. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb 1;138(2):293-310. https://doi.org/10.1093/brain/awu356
Rossor, Alexander M. ; Oates, Emily C. ; Salter, Hannah K. ; Liu, Yang ; Murphy, Sinead M. ; Schule, Rebecca ; Gonzalez, Michael A. ; Scoto, Mariacristina ; Phadke, Rahul ; Sewry, Caroline A. ; Houlden, Henry ; Jordanova, Albena ; Tournev, Iyailo ; Chamova, Teodora ; Litvinenko, Ivan ; Zuchner, Stephan L ; Herrmann, David N. ; Blake, Julian ; Sowden, Janet E. ; Acsadi, Gyuda ; Rodriguez, Michael L. ; Menezes, Manoj P. ; Clarke, Nigel F. ; Grumbach, Michaela Auer ; Bullock, Simon L. ; Muntoni, Francesco ; Reilly, Mary M. ; North, Kathryn N. / Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. In: Brain. 2015 ; Vol. 138, No. 2. pp. 293-310.
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AU - Rossor, Alexander M.

AU - Oates, Emily C.

AU - Salter, Hannah K.

AU - Liu, Yang

AU - Murphy, Sinead M.

AU - Schule, Rebecca

AU - Gonzalez, Michael A.

AU - Scoto, Mariacristina

AU - Phadke, Rahul

AU - Sewry, Caroline A.

AU - Houlden, Henry

AU - Jordanova, Albena

AU - Tournev, Iyailo

AU - Chamova, Teodora

AU - Litvinenko, Ivan

AU - Zuchner, Stephan L

AU - Herrmann, David N.

AU - Blake, Julian

AU - Sowden, Janet E.

AU - Acsadi, Gyuda

AU - Rodriguez, Michael L.

AU - Menezes, Manoj P.

AU - Clarke, Nigel F.

AU - Grumbach, Michaela Auer

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AU - Muntoni, Francesco

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N2 - 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.

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KW - Dominant congenital spinal muscular atrophy

KW - Hereditary motor neuropathy

KW - Lower extremity predominant

KW - Proximal spinal muscular atrophy

KW - Spinal muscular atrophy

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