Long-term follow-up of a patient with autosomal dominant lower extremity-predominant spinal muscular atrophy-2 due to a BICD2 variant



      Bicaudal D homolog 2 (BICD2) is a causative gene of autosomal-dominant lower extremity-predominant spinal muscular atrophy-2 (SMA-LED2). The severity of SMA-LED2 varies widely, ranging from cases in which patients are able to walk to cases in which severe joint contractures lead to respiratory failure. In this study, we report the long-term course of a case of SMA-LED2 in comparison with previous reports.

      Case report

      The patient was a 19-year-old woman. She had knee and hip dislocations with contractures, femoral fracture, and talipes calcaneovalgus since birth, and was diagnosed with arthrogryposis multiplex congenita. Intense respiratory support was not needed during the neonatal period. She had aspiration pneumonia repeatedly, necessitating NICU admission until 8 months of age. She achieved head control at 9 months of age and was able to sit at 2 years of age; however, she could not walk. Tube feeding was required until 3 years of age. At present, she can eat orally, move around with a wheelchair, and write words by herself. She needs non-invasive positive pressure ventilation during sleep because of a restrictive respiratory disorder during adolescence. Exome analysis identified a de novo heterozygous missense variant (c.2320G>A; p.Glu774Lys) in BICD2.


      Patients with SMA-LED2 may have a relatively better prognosis in terms of social activities in comparison with the dysfunction in the neonatal period. Moreover, it is important to periodically evaluate respiratory function in patients with SMA-LED2 because respiratory dysfunction may occur during adolescence.


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        • Trimouille A.
        • Obre É.
        • Banneau G.
        • Durr A.
        • Stevanin G.
        • Clot F.
        • et al.
        An in-frame deletion in BICD2 associated with a non-progressive form of SMALED.
        Clin Neurol Neurosurg. 2018; 166: 1-3
        • Harms M.B.
        • Ori-McKenney K.M.
        • Scoto M.
        • Tuck E.P.
        • Bell S.
        • Ma D.
        • et al.
        Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.
        Neurology. 2012; 78: 1714-1720
        • Neveling K.
        • Martinez-Carrera L.
        • Hölker I.
        • Heister A.
        • Verrips A.
        • Hosseini-Barkooie S.
        • et al.
        Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy.
        Am J Hum Genet. 2013; 92: 946-954
        • Koboldt D.C.
        • Waldrop M.A.
        • Wilson R.K.
        • Flanigan K.M.
        The genotypic and phenotypic spectrum of BICD2 variants in spinal muscular atrophy.
        Ann Neurol. 2020; 87: 487-496
        • Storbeck M.
        • Horsberg Eriksen B.
        • Unger A.
        • Hölker I.
        • Aukrust I.
        • Martínez-Carrera L.A.
        • et al.
        Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features.
        Eur J Hum Genet. 2017; 25: 1040-1048
        • Peeters K.
        • Litvinenko I.
        • Asselbergh B.
        • Almeida-Souza L.
        • Chamova T.
        • Geuens T.
        • et al.
        Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance.
        Am J Hum Genet. 2013; 92: 955-964
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Oates E.
        • Rossor A.
        • Hafezparast M.
        • Gonzalez M.
        • Speziani F.
        • MacArthur D.
        • et al.
        Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia.
        Am J Hum Genet. 2013; 92: 965-973
      1. Bansagi B, Griffin H, Ramesh V, Duff J, Pyle A, Chinnery PF, et al. The p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscular atrophy. Brain 2015;138:e391.

        • Ueda Y.
        • Suganuma T.
        • Narumi-Kishimoto Y.
        • Kaname T.
        • Sato T.
        A case of severe autosomal dominant spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 mutation.
        Brain Dev. 2021; 43: 135-139
        • Ravenscroft G.
        • Di Donato N.
        • Hahn G.
        • Davis M.R.
        • Craven P.D.
        • Poke G.
        • et al.
        Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria.
        Neuromuscul Disord. 2016; 26: 744-748
        • Koboldt D.C.
        • Kastury R.D.
        • Waldrop M.A.
        • Kelly B.J.
        • Mosher T.M.
        • McLaughlin H.
        • et al.
        In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.
        Cold Spring Harb Mol Case Stud. 2018; 4: a003160
        • Rudnik-Schöneborn S.
        • Deden F.
        • Eggermann K.
        • Eggermann T.
        • Wieczorek D.
        • Sellhaus B.
        • et al.
        Autosomal dominant spinal muscular atrophy with lower extremity predominance: a recognizable phenotype of BICD2 mutations.
        Muscle Nerve. 2016; 54: 496-500