Abstract
Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.
Highlights
GENETICS OF SMAProximal spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide, alongside cystic fibrosis
Because survival motor neuron 2 (SMN2) copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA
It is a rare and sporadic disorder that is clinically distinct from amyotrophic lateral sclerosis (ALS) even though subclinical involvement of upper motor neuron (UMN) has been observed in many progressive muscular atrophy (PMA) patients
Summary
Proximal spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide, alongside cystic fibrosis. Type I SMA [listed in the Online Inheritance in Man (OMIM) database under accession number 253300; http://www.omim.org/entry/ 253300] patients have an age of onset before 6 months. They show hypotonia and weakness in limbs; they are unable to sit independently. Type II SMA (http://www.omim.org/entry/253500) patients have an age of onset before 18 months. They are poor crawlers and weak sitters; most of these patients can rarely stand and only with support. Adult-onset (type IV) SMA (http://www.omim.org/entry/271150) patients have an age of onset of 18–21 years.
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