title: Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells.
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.
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Electronic address: mjedrzejowska@imdik.pan.pl.
authors.forename: Maria
authors.initials: M
authors.lastname: Jędrzejowska
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Madej-Pilarczyk
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Fidziańska
authors.affiliation: Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mierzewska
authors.affiliation: Department of Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Obersztyn
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Gos
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pronicki
authors.affiliation: Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kmieć
authors.affiliation: Department of Anaesthesiology and Intensive Care, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Migdał
authors.affiliation: Department of Paediatric Anaesthesiology and Intensive Care, Medical University of Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mierzewska-Schmidt
authors.affiliation: Department of Paediatric Anaesthesiology and Intensive Care, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Walczak-Wojtkowska
authors.affiliation: Department of Paediatric Anaesthesiology and Intensive Care, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Konopka
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Hausmanowa-Petrusewicz
mesh_terms: D002467:Cell Nucleus / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000473:pathology*; D012583:Schwann Cells / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C489892:IGHMBP2 protein, human; D014157:Transcription Factors
keywords: Diaphragmatic paralysis; Distal SMA; IGHMBP2; Nuclear degeneration; SMARD1