Interfamilial phenotypic heterogeneity in SMARD1.

Department of Neurology, Evelina Children's Hospital, Lambeth Palace Road, London SE1 7EH, UK.
Neuromuscular Disorders (Impact Factor: 3.13). 02/2009; 19(3):193-5. DOI: 10.1016/j.nmd.2008.11.013
Source: PubMed

ABSTRACT Spinal muscular atrophy with respiratory distress (SMARD1: mu-binding protein 2 gene mutation) is characterised by low birth weight, progressive distal limb weakness, diaphragmatic paralysis and subsequent respiratory failure manifesting before 13 months of age. Our case report illustrates marked phenotype variability in two siblings with an identical genetic mutation of SMARD1, one of whom died of fulminant respiratory failure aged 6 months, whereas the other shows limb weakness but, only mild sleep hypoventilation aged 12 years. This suggests other compensatory mechanisms may play a role in modifying SMARD1; broadening our perception of phenotype. Therefore, SMARD1 phenotype should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Children with spinal muscular atrophy with respiratory distress (SMARD1) usually present within their first year of life, with respiratory failure due to diaphragmatic paralysis and progressive distal limb weakness. We present a child with a confirmed compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3years. Autonomic system involvement with neurogenic bladder and urine retention were found at 3years. In summary, our patient highlights the broad spectrum of phenotypes observed in SMARD1. Currently, no prediction of phenotype according to genotype is possible, suggesting that yet unknown factors cause the observed phenotypic variation. Even in the absence of obvious diaphragmatic weakness, SMARD1 should be considered in severe infantile onset neuropathies. High throughput techniques, such as next generation sequencing, will possibly offer a useful approach in the heterogeneous group of inherited neuropathies.
    Neuromuscular Disorders 12/2013; 24(3). DOI:10.1016/j.nmd.2013.11.013 · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.
    European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 01/2013; 18(2). DOI:10.1016/j.ejpn.2013.11.006 · 2.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-m-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 muta-tions in CMT2 were mainly loss-of-function nonsense in the 5 0 region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.
    The American Journal of Human Genetics 11/2014; DOI:10.1016/j.ajhg.2014.10.002 · 11.20 Impact Factor