Short reports

Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy

Spinal muscular atrophy (SMA) includes a diverse group of hereditary disorders of the lower motor neuron. The most common form, accounting for 95% of SMA, is a proximal predominant autosomal recessive disease caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene and retention of varying copy number of the SMN2 gene. The combined effects lead to reduced SMN protein levels that are insufficient for normal motor neuron function. In the current era of effective therapies the traditional classification of SMN-related SMA into subtypes (SMA Type 1–4) based on age of onset and achieved maximal motor milestone has largely been replaced by a more clinically pragmatic approach that uses function at the time of evaluation to group individuals into three categories of nonsitters, sitters, and walkers. Diagnostic confirmation is obtained using genetic testing for homozygous deletion or mutation of the SMN1 gene. SMN2 gene copy number, a major disease modifier inversely correlates with disease severity, is routinely obtained to help stratify individuals and guide gene-modifying therapies. This is particularly useful following the recent approval and implementation of newborn screening in some states. Currently, treatment includes aggressive supportive care and the use of the FDA approved antisense oligonucleotide, nusinersen (Spinraza), and the viral-mediated gene therapy, onasemnogene abeparvovec-xioi (Zolgensma).

Spinal muscular atrophy is a genetic neurodegenerative disorder affecting muscle tone and function, primarily in children. Disease onset varies from in utero to adult, and its progression and severity differ significantly among individuals. Clinicians have documented and categorized the disease for over a century, but no cure has been found to date. Recent breakthroughs in the understanding of the disease’s genetic underpinnings and mechanism have ushered in the promise of new treatments for the first time.

Most patients with spinal muscular atrophy lack the survival motor neuron 1 gene (SMN1) in the telomeric region of the spinal muscular atrophy locus on chromosome 5q13. On the other hand, the copy number of SMN2, a centromeric homolog of SMN1, is increased in many of these patients. This study aimed to clarify the mechanism underlying these structural variations.

We determined the copy numbers of telomeric and centromeric genes in the spinal muscular atrophy locus of 86 patients and 22 control subjects using multiplex ligation-dependent probe amplification analysis. Then, we chose 74 patients lacking SMN1 exons 7 and 8, and compared their dataset with that of 22 control subjects retaining SMN1 exons 7 and 8.

The SMN2 copy number was shown to vary widely and to correlate with the disease severity of the patients. Interestingly, telomeric NAIP and telomeric GTF2H2 showed similar tendencies. We also noted positive correlations among the copy number of SMN2 and the telomeric genes of the spinal muscular atrophy locus. However, the copy numbers of centromeric NAIP and centromeric GTF2H2 were stable among the patients, with both approximating a value of two.

Our findings suggested that the telomeric region of the spinal muscular atrophy locus appears to be susceptible to structural variation, whereas the centromeric region is stable. Moreover, according to our results, new SMN2 copies may be generated in the telomeric region of the spinal muscular atrophy locus, supporting the SMN1-to-SMN2 gene conversion theory.

There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients.

Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%–77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage.

Spinal muscular atrophy (SMA) includes a diverse group of hereditary disorders of the lower motor neuron. The most common form, accounting for 95% of SMA, is a proximal predominant autosomal recessive disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene and retention of varying copy number of the SMN2 gene. The combined effects lead to reduced SMN protein levels that are insufficient for normal motor neuron function. SMN-related SMA can be divided into subtypes based on age of onset and maximal motor milestones, and subtype severity correlates with SMN2 gene copy number. Diagnostic confirmation is obtained using genetic testing for homozygous deletion or mutation of the SMN1 gene. Currently treatment is limited to supportive care. Therapeutic development aimed at restoring SMN has been the most successful, and currently gene therapy to replace SMN1 and antisense oligonucleotide therapy to increase SMN production from SMN2 show the most promise.

The aim of our study was to identify point mutations in a group of 606 patients diagnosed for spinal muscular atrophy with excluded biallelic loss of the SMN1 gene. Point missense mutations or small deletions in the SMN1 gene were ultimately identified in 18 patients. Six patients were found to have small deletions, the c.429_435del mutation in 3 cases, the c.431delC mutation in 2 and c.722delC in one. Those mutations, not described previously, were characteristic of patients presenting a severe phenotype. The most frequent missense mutation – p.Thr274Ile, was identified in 9 patients presenting a rather mild phenotype. Three other missense mutations, i.e. p.Ser230Leu, p.Ala111Gly and p.Pro244Leu, were identified in a further 3 SMA3 patients. Mutation p.Pro244Leu, not described so far, was identified in a patient with a mild form of SMA and more distal distribution of muscle weakness. Our results suggest a specific point mutation spectrum in the Polish population. The existence of small deletions not identified thus far could suggest a possible founder effect. In patients with preserved one SMN1 allele without common exon 7 deletion, presenting a mild form of SMA, a special consideration should be given to the p.Thr274Ile mutation.