New ASAH1 mutation identified in fetus with severe complications

Case report discusses need for clear diagnosis for those with genetic mutations

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A novel mutation in the ASAH1 gene was identified as the cause of severe fluid buildup with swelling (hydrops fetalis) and cardiac abnormalities in an unborn fetus who later died from the complications in a recent report.

ASAH1 mutations are associated with a spectrum of different genetic rare disorders, including spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease.

“Collectively, these findings provide a better understanding of ASAH1-related disorders during prenatal examination and are expected to guide accurate diagnosis as well as genetic counseling for the family,” the researchers wrote.

Moreover, “improved understanding of the disease will not only enable the identification and accurate diagnosis of more patients, but also effective management of the group.”

The report “Functional analysis of a novel splice site variant in the ASAH1 gene,” was published in Molecular Genetics & Genomic Medicine.

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ASAH1 gene mutations can result in ACDase deficiency

The ASAH1 gene is responsible for producing acid ceramidase (ACDase), an enzyme that breaks down a family of molecules called ceramides. Mutations in this gene can result in an ACDase deficiency, where ceramides and related molecules build to toxic levels inside cells.

This is the cause of SMA-PME, a rare and severe form of SMA characterized by progressive muscle weakness and seizures. While cells of the brain and spinal cord are mostly affected in SMA-PME, symptoms of Farber disease involve the rest of the body and include joint tightening, hoarse voice, and failure to thrive.

To date, only around 200 people with ASAH1-associated disease have been described, about two-thirds of whom had Farber disease, according to the researchers.

“The diagnosis of ASAH1-related disorders is challenging mainly because of the complexity and variations in clinical symptoms,” the researchers wrote, noting some patients may experience severe manifestations and very early death, whereas others may have mild symptoms not diagnosed until adulthood.

The recent case report concerned a 29-year-old woman and her unborn child who had died in utero during the 14th week of pregnancy due to ASAH1-associated disease.

This was the woman’s fourth pregnancy, with her previous pregnancies resulting in a live birth, an induced pregnancy termination for nonmedical reasons, and another child who died in utero after 13 weeks of pregnancy and had fetal hydrops.

During a first trimester ultrasound of the latest pregnancy (13 weeks), it was found that the fetus had increased thickness in the folds of tissue at the back of the neck (nuchal folds), which is associated with fluid buildup in the area. It is particularly common with certain chromosomal abnormalities.

The fetus was found to have severe hydrops fetalis and cardiac abnormalities, but the parents elected not to pursue invasive diagnostic chromosomal testing at that time.

When they next visited the researcher’s clinic, it was found the fetus had died in utero and the pregnancy was terminated. An examination of the male fetus showed severe internal hydrops. The parents did not consent to a full autopsy, but did allow tissue collection for the purpose of genetic analyses.

Testing revealed the fetus had a novel mutation in both copies of the ASAH1 gene. Each parent, who had no symptoms, had a mutation in one copy of the gene.

The mutation, which has never before been reported, was called c.458-2A>T. Additional laboratory experiments found that the mutation caused the insertion of extra genetic material in the ASAH1 gene while also deleting another part of the gene.

Both of these genetic disruptions were predicted to stop the genetic material from being properly translated into a functional ACDase protein.

Altogether, “these findings provide new insights into additional phenotypes [clinical characteristics] and a novel … ASAH1 variant,” the researchers wrote.

The scientists emphasized that reaching a definitive diagnosis in ASAH1-associated disease is “very important,” given the spectrum of conditions, including SMA-PME, that are encompassed by that label.

Genetic testing, biochemical analyses, and other lab analyses are important for helping to make the right diagnosis, “thus aiding genetic counseling for couples who prepare for pregnancy and prenatal diagnosis for the fetuses,” the researchers wrote.