FUS Mutations Cause Most Cases of ALS in Adolescents, Literature Review Finds

When amyotrophic lateral sclerosis (ALS) symptoms emerge during adolescence, mutations in the FUS gene are likely to blame, findings from a case report suggest.

Mutations in this gene also are the cause of some adult-onset ALS cases. However, FUS-associated ALS is more aggressive in children in whom these mutations more profoundly affect the biological mechanisms of the FUS protein, research indicates.

The results, “The Occurrence of FUS Mutations in Pediatric Amyotrophic Lateral Sclerosis: A Case Report and Review of the Literature,” were published in the Journal of Child Neurology.

While ALS affects mostly adults at advanced ages, the disease also can manifest before the age of 25 (juvenile ALS), or even before adulthood (pediatric ALS).

In adults, only about 10% of cases are caused by genetic mutations, but the number of ALS cases caused by known genetic mutations appears to increase significantly in early-onset disease.

FUS is the most commonly mutated gene in juvenile and pedriatric ALS, but it causes only about 5% of cases in adults. It is unclear why younger patients with FUS mutations exhibit a more aggressive disease course than adults.

Researchers in Canada reported the case of 14-year-old boy diagnosed with fast-progressing ALS, and conducted a literature review to better understand the contribution of FUS mutations to pediatric ALS.

The boy had weakness in his right leg that had been progressing in the past month. He had mild intellectual disability and had displayed mild developmental delay in his early years. Brain and spinal cord imaging exams came back normal, but the patient continued to progress, with the disease evolving to postural tremor and weakness in both arms.

The patient had a right foot drop that was affecting gait and had no tendon reflexes in the right leg. An examination of the electrical signals sent from the nervous system into the muscles showed that some muscles were losing connections to motor neurons — the nerve cells controlling movement, which are lost in ALS.

The clinicians first suspected an autoimmune disease, but later a genetic analysis revealed a disease-causing mutation in the FUS gene, which led to a diagnosis of ALS. The disease progressed very rapidly and the boy died nine months after his first symptoms.

A similar mutation in the FUS gene has been reported previously in two other boys, ages 13 and 18, with rapidly progressive disease, researchers said.

The team then examined a total of 31 studies that had reported cases of juvenile (53 cases) or pediatric ALS (29 cases). In both groups, FUS mutations were the most common genetic cause, being found in 43% of juvenile cases and 52% of pediatric cases.

The disease manifested during adolescence in most pediatric patients with FUS mutations, and patients lived on average 25.7 months (range 9 to 76 months) after their first symptoms. These patients sometimes had  intellectual disabilities and developmental delay before their diagnoses. Postural tremor was a unique feature of children with FUS mutations.

Other causes of disease in pediatric patients were SETX mutations (14% of cases), as well as mutations in the SPG11, UBQLN2, SIGMAR1, VRK1, and GNE genes, each described in one patient. In juvenile patients, other causes included mutations in SOD1 (8%), UBQLN2 (4%) and TDP-43, DDHD1 and VRK1 (2%) genes.

FUS protein is involved in transporting RNA molecules, which provide the instructions to make a protein, from the nucleus to the cytoplasm, and is involved in different steps of protein production. The protein is mostly found in the nucleus, but becomes misplaced in the cytoplasm in the motor neurons of ALS patients.

While mutations in adults are located in multiple regions of the gene and affect the protein in different ways, all mutations in pediatric patients disrupt the signal needed for FUS to reach the nucleus.

These mutations “appear to be more toxic for cells,” leading to an earlier onset of disease and more aggressive features in pediatric patients, researchers noted.

This “review of the literature suggests that FUS mutations should be primarily searched in all patients younger than 18 years with a motor neuron disease that may be compatible with ALS,” the researchers wrote.