Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells.

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.

Jędrzejowska M ，Madej-Pilarczyk A ，Fidziańska A ，Mierzewska H ，Pronicka E ，Obersztyn E ，Gos M ，Pronicki M ，Kmieć T ，Migdał M ，Mierzewska-Schmidt M ，Walczak-Wojtkowska I ，Konopka E ，Hausmanowa-Petrusewicz I ... -  《-》

The Clinical Heterogeneity of Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)-A Report of Three Cases, Including Twins.

Leśniak A ，Glińska M ，Patalan M ，Ostrowska I ，Świrska-Sobolewska M ，Giżewska-Kacprzak K ，Kotkowiak A ，Leśniak A ，Walczak M ，Śmigiel R ，Giżewska M ... -  《Genes》

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

Grohmann K ，Schuelke M ，Diers A ，Hoffmann K ，Lucke B ，Adams C ，Bertini E ，Leonhardt-Horti H ，Muntoni F ，Ouvrier R ，Pfeufer A ，Rossi R ，Van Maldergem L ，Wilmshurst JM ，Wienker TF ，Sendtner M ，Rudnik-Schöneborn S ，Zerres K ，Hübner C ... -  《NATURE GENETICS》

The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Diers A ，Kaczinski M ，Grohmann K ，Hübner C ，Stoltenburg-Didinger G ... -  《ACTA NEUROPATHOLOGICA》

Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis.

Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.

Guenther UP ，Varon R ，Schlicke M ，Dutrannoy V ，Volk A ，Hübner C ，von Au K ，Schuelke M ... -  《-》