Abstract
Abstract Proximal spinal muscular atrophy (SMA) is an autosomal-recessive inherited neuromuscular disorder caused by the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Patients show hypotonia, muscular atrophy and weakness of voluntary proximal muscles. SMA is one of the most common genetic diseases, with a frequency of about 1 in 7,000 newborns in Germany. The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1. The severity of the disease is mainly influenced by the copy number of the highly homologous SMN2. Since the discovery of the underlying genetic defect 25 years ago, both the diagnostics of SMA and its treatment have undergone constant and in recent times rapid improvements. SMA has become one of the first neuromuscular disorders with effective therapies based on gene targeted strategies such as splice correction of SMN2 via antisense oligonucleotides or small molecules or gene replacement therapy with a self-complementary adeno-associated virus 9 expressing the SMN1-cDNA. With the availability of treatment options, which are most effective when therapy starts at a pre-symptomatic stage, a newborn screening is indispensable and about to be introduced in Germany. New challenges for diagnostic labs as well as for genetic counsellors are inevitable. This article aims at summarising the current state of SMA diagnostics, treatment and perspectives for this disorder and offering best practice testing guidelines to diagnostic labs.
Highlights
Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN) 1 gene, while the disease severity is mainly determined by the number of SMN2 copies
The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1
We suggest using the MLPA kit MRC-P021-B1, which provides a maximum of information
Summary
Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN) 1 gene, while the disease severity is mainly determined by the number of SMN2 copies (reviewed in [1]). SMN1 and its copy gene SMN2 are localized within a copy number variation (CNV) on chromosome 5q13.2. The CNV is highly polymorphic with respect to orientation, length and structure; individuals may carry zero to four segments per chromosome, resulting in different numbers of SMN1 and SMN2 per genome. The majority of healthy individuals carry two SMN1 and two SMN2 genes per genome; both SMN1 and SMN2 genes may vary from zero to four copies per chromosome. Individuals with SMA usually harbour a homozygous deletion of SMN1, while the SMN2 copy number varies between one and six. The SMA carrier frequency is 1:51 worldwide and 1:41 in Europe (Table 1) [2]
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