Clinical Spectrum and Diagnostic Criteria of Infantile Spinal Muscular Atrophy: Further Delineation on the Basis of SMN Gene Deletion Findings

Abstract

With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background.

Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene

“…The possibility of misdiagnosis is unlikely given that all patients fulWlled the clinical diagnosis criteria and have at least one null SMN1 allele. However, given the high frequency of SMA carriers in the population, we cannot totally rule out the possibility that one or a few of these cases were SMA carriers with another similar disorder aVecting motor neurons (Camu and Billiard 1993;Rudnik-Schöneborn et al 1996;Bingham et al 1997).…”

Genetic testing and risk assessment for spinal muscular atrophy (SMA)

“…However, SMARD affects distal muscles more severely, causing diaphragmatic paralysis and life-threatening respiratory distress (Bertini et al 1989;Grohmann et al 1999). In addition, SMARD is unlinked to chromosome 5q11.2-13 (Novelli et al 1995;Rudnik-Schöneborn et al 1996). Recently, Grohmann et al (2001) have shown that mutations in the gene encoding immunoglobulin µ-binding protein 2 cause SMARD type I.…”

Survival Motor Neuron (SMN) Protein Interacts with Transcription Corepressor mSin3A

“…SMA occurs with a frequency of 1 in 10,000 individuals and is the most common genetic cause of infant mortality (1,2). SMA is classically subdivided into three types based on the age of onset and clinical severity (3). Type I SMA is characterized by severe muscular problems in infancy, whereas type II and type III SMA are characterized by minor muscle weakness in adulthood.…”