Mild SMA Poses Diagnostic Difficulties for Clinicians

A new case report highlights the difficulties in pinning down spinal muscular atrophy (SMA) when it presents in a mild form.

Symptoms of spinal muscular atrophy (SMA) often appear early and with significant mobility impairment, but patients with milder phenotypes can often present a diagnostic challenge.

In a new case report published in Journal of Neurological Sciences, the authors recalled one such case involving a 32-year-old woman whose initial symptoms were relatively minor: mild limb-girdle weakness and increased fatigue when climbing stairs.

“While the severe presentation is much more distinct in infancy, the milder phenotype observed in adulthood (type III or IV SMA) may be misleading for adult neurologists and radiologists who are generally less familiar with the disorder,” they said.

The patient in the case report had a family history that was negative for neuromuscular conditions, and besides her muscle weakness, her only other notable health condition was hypothyroidism, the authors explained. At age 31, the patient underwent a neurological examination, which revealed mild symmetrical, proximal weakness in both limbs and a lack of deep tendon reflexes in her lower extremities. She also had elevated serum creatine kinase activity. Other assessments, such as cranial nerve and sensory examinations, were normal, the authors said.

The patient’s pelvic-girdle and thigh muscles were examined using MRI. The scan showed diffuse and severe fatty transformation and atrophy in MOST of the muscle groups, which initially prompted investigators to believe her issues were myopathic. However, when THEY performed electromyography (EMG), they found chronic neurogenic changes in every muscle they investigated, as well as “occasional” fasciculations. The authors said this was a crucial diagnostic clue pointing toward a neurogenic cause.

They decided to do genetic testing, and targeted SMN1 gene analysis confirmed a diagnosis of 5q SMA (so named because the deletions are present on the long arm [q] of chromosome 5). The patient qualified for gene therapy but opted against it due to her mild disease course and a desire to become pregnant.

The investigators said the case highlights a number of diagnostic “pitfalls” in milder cases of SMA, such as the risk of mistakenly assuming muscle weakness is myopathic in nature.

Another potential problem, they said, can come at the genetic-testing phase. In this case, exome sequencing initially yielded a negative result, and SMA was only confirmed once the investigators performed targeted testing of the SMN1 gene.

The authors said it is common to use next-generation sequencing (NGS) to search for potential neuromuscular disorders, since those disorders can be genetically heterogeneous. Yet, they added that NGS often misses 5q SMA “due to the extremely high sequence homology between SMN1 and its paralog SMN2.

“Therefore, more specific methods such as multiplex ligation-dependent probe amplification or qualitative polymerase chain reaction need to be applied,” they said.

For this reason, the study authors said conventional tools such as EMG might still be necessary before moving on to genetic testing. They said a muscle biopsy could have also proven valuable had diagnostic uncertainty remained.

In their conclusion, the investigators said the case highlights the challenges of diagnosing milder cases of SMA in adults and other patients.

“Most notably, it further emphasizes the need to consider SMA among the differential diagnoses in ambulatory patients with a limb-girdle pattern of weakness and elevated CK activity levels, especially in view of possible therapeutic consequences in the era of gene-based therapies,” they wrote.


Krenn M, Jengojan S, Grisold W. Spinal muscular atrophy presenting with mild limb-girdle weakness in adulthood: Diagnostic pitfalls in the era of disease-modifying therapies. J Neurol Sci. Published online July 25, 2022. doi:10.1016/j.jns.2022.120347

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