The first-ever case of someone in Romania with spinal muscular atrophy (SMA) caused by a mutation in the ASAH1 gene was described in a recent report.

The study, “Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency,” was published in the Journal of Medicine and Life.

In more than 95% of cases, SMA is caused by mutations in the gene SMN1, which sometimes is referred to as 5q-SMA. For the remaining 5% of cases (non-5q-SMA), disease-causing mutations in at least 16 different genes have been described.

In this report, researchers in Romania shared the story of a 13-year-old boy who was admitted to their hospital in autumn of 2018.

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As an infant, the boy had been hypotonic (abnormally low muscle tone), and as he grew there were marked delays in motor development. He was able to sit up at age 1, and walk at age 2 (most children can sit by 9 months, and walk by 18 months). He had never been able to run, climb stairs, or jump on one foot.

At his first neurological examination when he was 4 years old, motor deficits, muscle atrophy (shrinkage), and abnormal reflexes were noted. His arms were generally less affected than his legs.

From the ages of 5 to 10, muscle weakness became gradually more severe, leading to difficulties with swallowing and breathing. He was a wheelchair user by age 10.

By the time he was brought to the hospital at age 13, the researchers said he had severe breathing difficulty and muscle atrophy. He had body-wide movement difficulties, including poor head control, though his arms remained comparatively stronger than his legs.

The boy underwent gastrostomy (when an opening is made in the stomach for food to be put in directly) in 2019, and he had spine surgery earlier this year. After the surgery, “muscular atrophy became extreme and the weakness was generalized,” the researchers wrote. “The patient lost head control and only presented a few active movements in the upper limbs.”

The boy’s symptoms led his care team to suspect SMA. So, they performed genetic testing of the SMN1 gene. The results were negative.

This led the team to perform whole-exome sequencing, a technique that determines the sequence of all the parts of the genome — an organism’s entire set of genetic information — that provide instructions for making proteins. This revealed three mutations in the gene ASAH1, which is known to cause SMA in rare cases.

“Cases of non-5q SMA caused by ASAH1 mutations are sporadic, with only 45 patients reported worldwide so far,” the researchers wrote, noting this case is the first patient reported in Romania.

Notably, ASAH1 usually is associated with a specific form of SMA called SMA with progressive myoclonic epilepsy, or SMA-PME. In addition to muscle atrophy and motor weakness, this type of SMA is often characterized by seizures. While the boy in this case had no history of seizures, he did have some atypical activity on measures of brain electrical activity.

Mutations in the ASAH1 gene also are known to cause a related condition called Farber disease. The researchers noted that, in addition to showing symptoms typical of SMA, the boy also had some symptoms more commonly associated with Farber disease, such as an abnormally hoarse voice.

“We presented the first case ever reported in Romania of overlapping symptoms from SMA-PME and Farber disease caused by ASAH1 mutations. We believe our presentation is useful in furthering the knowledge about the SMA-PME/Farber disease spectrum,” the researchers concluded.

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