Spinal muscular atrophy: molecular genetics and diagnostics

Abstract

Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future.

Parental attitudes toward newborn screening for Duchenne/Becker muscular dystrophy and spinal muscular atrophy

“…Diagnosis relies on clinical observation and molecular genetic testing (Ogino, 2004;D'Amico, 2011). SMA should be on the list of differential diagnoses when a severely weak child or hypotonic baby presents with normal attentiveness and cognitive function (Menezes, 2011;D'Amico, 2011).…”

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

“…Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease with a carrier frequency of 1 in 50 unrelated individuals and is distinguished by degeneration of spinal motor neurons and severe atrophy of skeletal muscle (Pearn et al, 1978;Ogino and Wilson, 2004). The Survival Motor Neuron 1 gene (SMN1) was identified by positional cloning as the gene responsible for ϳ95% of SMA cases (Lefebvre et al, 1995).…”

“…The Survival Motor Neuron 1 gene (SMN1) was identified by positional cloning as the gene responsible for ϳ95% of SMA cases (Lefebvre et al, 1995). Because of the observed variability in phenotypic severity, at least three classes of SMA have been established (Pearn, 1980;Ogino and Wilson, 2004). SMA type I, also known as Werdnig-Hoffman disease, is the most common and the most severe form of the disease, with an age of onset at Ͻ6 mo.…”

Atrofia muscular espinal: Caracterización clínica, electrofisiológica y molecular de 26 pacientes

“…Esta proteína normal no logra compensar la pérdida de la proteína por mutación del gen SMN1 3,5 . Deleciones del exón 7 y 8 o sólo del 7 del gen SMN1 son responsables de más de 95% de los casos de AME 6 . De este modo, la detección de una deleción homocigota de al menos el exón 7 de SMN1, constituye una herramienta para el diagnóstico de AME que alcanza una sensibilidad cercana a 95% y una especifi cidad de 99% 6 .…”

“…Deleciones del exón 7 y 8 o sólo del 7 del gen SMN1 son responsables de más de 95% de los casos de AME 6 . De este modo, la detección de una deleción homocigota de al menos el exón 7 de SMN1, constituye una herramienta para el diagnóstico de AME que alcanza una sensibilidad cercana a 95% y una especifi cidad de 99% 6 . Los diversos subtipos clínicos de AME se han clasifi cado según la edad de aparición de los síntomas y su evolución 2 y se muestran en la Tabla 1.…”