Background: Juvenile amyotrophic lateral sclerosis (JALS) refers to a form of amyotrophic lateral sclerosis (ALS) in which a progressive upper and lower motor neuron degeneration begins before 25 years of age. It is generally associated with slow disease progression. During the past decade, a number of genes have been reported to cause JALS. Mutations in the ALSIN gene cause JALS type 2 (ALS2) as well as juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. Mutations in the SETX gene can also sometimes lead to JALS. Conversely, mutations in SOD1, TARDBP, and FUS typically cause pure ALS, with adult onset between 46 and 56 years of age and usually rapid progression over 3 to 5 years. Recently, a few mutations in FUS have been associated with juvenile-onset of ALS characterized by a very rapid progression.
Objective: To investigate the genetics of a patient with juvenile-onset ALS.
Design and patient: We sequenced all the coding exons of SOD1, TARDBP, and FUS in a 19-year-old patient experiencing rapid degeneration of upper and lower motor neurons.
Results: A novel 1-base pair deletion was detected in exon 14 of the FUS gene, leading to a frameshift and the integration of 33 new amino acids. The variant p.R495QfsX527 is located in the highly conserved, extreme C terminal of the FUS protein, where most of the mutations in FUS have been identified. The variant was also identified in the unaffected 47-year-old mother of the patient, who remains asymptomatic.
Conclusions: Our finding, along with other research, further confirms that FUS mutations can lead to an early-onset malignant form of ALS. In addition, our data lend additional support to the notion that disruption of the conserved C terminal of FUS is critical for developing ALS.