New ASAH1 Mutations Linked to Rare Case of SMA and Farber Disease

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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ASAH1 mutations report

A rare instance of a child with both spinal muscular atrophy (SMA) and Farber disease, associated with two new mutations in the ASAH1 gene, is detailed in a case report.

Its team suggested that Farber, a rare disorder caused by ASAH1 mutations, should be considered and tested for in patients with SMA symptoms but no mutations in its main associated gene, SMN1.

The case report, “Spinal muscular atrophy and Farber disease due to ASAH1 variants: A case report,” was published in the American Journal of Medical Genetics – Part A.

Mutations in the ASAH1 gene lead to low levels of acid ceramidase, the enzyme responsible for breaking down fatty molecules called ceramides. This deficiency leads to the toxic accumulation of ceramides and a drop in its byproducts, which are recycled to produce new ceramides.

Evidence suggests that the level of reduction in acid ceramidase determines which condition a person will develop in a spectrum of rare disorders ranging from a slowly progressive form of SMA and SMA with progressive myoclonic epilepsy (SMA‐PME) to severe and early-onset Farber disease.

People with SMA-PME have progressive muscle weakness and wasting beginning in childhood, followed by seizures, uncontrollable muscle jerks, and sensorineural hearing loss.

In classic Farber disease, a severe acid ceramidase deficiency leads to the dangerous accumulation of fat in joints, tissues, and organs. It is characterized by abnormal small lumps of fat under the skin, swollen and painful joints, and a weak cry or a hoarse voice beginning in the first months of life. Developmental delay and lung disease are also known.

While SMA (with or without seizures) and Farber disease are considered distinct conditions, a previous case study described for a first time a 9-year-old girl who developed signs of Farber disease at 3 years old, followed by SMA symptoms without seizures.

Researchers at the University of Rochester, in New York, now described the case of a 4-year-old boy presenting symptoms of both SMA and Farber disease associated with two previously unidentified ASAH1 mutations.

The boy was admitted to the hospital at age 3 due to walking difficulties, trembling, and leg pain. Born to parents who are not blood relatives, he had met his early motor milestones at expected times but did not walk until age 17 months.

A neurologic examination found tongue twitching and tremors, muscle weakness, and poorer reflexes in the arms and legs on both sides of the body. Additional analyses supported the presence of a motor neuron disease, particularly SMA.

He was tested for the presence of mutations in the SMN1 gene, SMA’s main cause, but the test came back negative. An expanded SMA gene panel was then used for genetic testing, indicating two new ASAH1 mutations.

One of the mutations (c.966-2A>G) was predicted to be disease-causative, while the other (c.1127C>T) was likely damaging. Functional studies would have been helpful to confirm the mutation’s disease-causing nature, but they were not performed due to lack of clinical availability, the researchers noted.

Given his joint complaints, the boy underwent further evaluation for the presence of Farber disease.

He had swelling and restricted range of motion of the joints, small lumps in several fingers, a mild defect situated above the vocal cords, and a marked deficiency in acid ceramidase activity, consistent with Farber disease.

His brain activity was normal, and he had not experienced seizures to date, favoring SMA over an SMA-PME diagnosis. However, since seizures can start later in childhood, it may be early for a definitive diagnosis.

While the boy had profound acid ceramidase deficiency, he did not have classic Farber disease, the researchers noted. This suggests that other factors, besides enzyme levels, may determine the development of different forms of ASAH1­-associated diseases.

Clinicians should measure acid ceramidase activity in patients presenting with SMA that is not related to SMN1 mutations, “especially if there are symptoms of arthritis, nodules of the fingers or toes, or voice hoarseness,” the researchers suggested.