Inna Valentinovna SharkovaResearch Center of Medical Genetics, Russia
Title: An algorithm for the clinical diagnosis of spinal muscular atrophy 5q
Spinal muscular atrophy (SMA) is one of a group of hereditary neuromuscular diseases resulting from degeneration of cells in the anterior horns of the spinal cord and motor nuclei in the lower part of the brainstem. The most common variant is proximal SMA, caused by mutations in the survival motor neuron gene, SMN1, located on chromosome 5q13 (5qSMA). The diversity of phenotypic manifestations of 5qSMA, which debuts in a wide age range from prenatal to adulthood, the significant clinical and genetic heterogeneity of hereditary neuromuscular diseases with similar symptoms, may complicate the timely diagnosis of 5qSMA and access to therapy or clinical trials.
Determination of the main clinical manifestations and symptoms characteristic of 5qSMA with a debut in different age periods, and the development of a clinical diagnostic algorithm that can help in making decisions regarding the need for testing the SMN1 gene by primary care physicians and hospitals.
Materials and methods:
A retrospective analysis of the case histories of patients observed at the Research Center of Medical Genetics with a confirmed diagnosis of 5qCMA was carried out.
The presence and diagnostic significance of 27 signs and symptoms in 315 (173 with type I, 95 and 47 with types II and III) patients with 5qSMA were analysed depending on the age of disease manifestation. Some signs (such as progressive muscle hypotension, fasciculations/tremor of the tongue or other muscle groups, tremor of outstretched fingers in the absence of sensory impairment) were detected in the analysed group regardless of the age of manifestation, and some only when manifested in a certain age period. This allowed us to systematize them according to their occurrence and significance in two periods of the onset of the disease: before and after 18 months of life. Each feature was assigned a value from 0.25 to 2 points.
An attempt was made to create a clinical diagnostic algorithm based on a simple scoring system for the presence of major symptoms that would help suspect 5qSMA in the early stages of the disease, order testing for SMN1 gene deletions, and, if necessary, continue molecular genetic search by direct Sanger sequencing to find small mutations in symptomatic heterozygous carriers. However, if there is an unusual clinical presentation or only some of the listed symptoms are present, if SMA5q is clinically suspected, genetic testing for the disease should still be performed.