A juvenile sporadic amyotrophic lateral sclerosis case with P525L mutation in the FUS gene: A rare co-occurrence of autism spectrum disorder and tremor

p.P525L mutation in the fused in sarcoma (FUS) gene has been detected in patients with amyotrophic lateral sclerosis (ALS), characterized by early onset and a severely progressive course. We describe a 19-year-old woman who was admitted to our hospital because of rapidly progressive dysarthria and dysphagia, developing over the course of 3 months. She had no family history of neurological diseases including essential tremor and no consanguineous history. Her delivery was non-eventful. In elementary school, her school records were not so bad, but she was not able to get along with her classmates. In addition, she was given a diagnosis of learning disability and autism spectrum disorder by a pediatrician. She therefore went to a special school for handicapped children, instead of junior high school and high school. On admission, she showed dysarthria, a nasal voice, dysphagia, and atrophied tongue with fasciculation. She could not close her eyes perfectly or elevate both corners of the mouth, indicating facial muscle weakness. The muscle strength of the proximal upper limbs and neck were grade 4, and that of the distal upper limb and lower limbs were grade 5 according to the Medical Research Council scale. Deep tendon reflexes were increased, but pathological reflexes were absent. She had showed postural tremor since before onset of any weakness, especially when using a pen or chopsticks. There was no evidence of Parkinsonism, sensory disturbance, or autonomic dysfunction. On laboratory tests, the complete blood count, biochemical screening, lactic acid, and pyruvic acid were all negative for abnormalities. Cerebrospinal fluid tests, MRI of brain and spine were also normal. A spirogram disclosed decreased forced vital capacity (FVC; 54%), while the results of an arterial blood gas test were normal (pH 7.403, PaCO₂ 38.8 mm Hg, PaO₂ 97.5 mm Hg). The results of a nerve conduction study were normal, and needle electromyography showed no acute or chronic denervation in the limbs. A biopsy of the left biceps muscle showed large group atrophy and no vacuoles, suggesting a neurogenic process. The immunohistochemical stains, including p62/SQSTM1, Tau, SMI-31, TDP-43, and FUS, showed no abnormal aggregation in muscle fibers (Fig. 1). After obtaining informed consent, genomic DNA was extracted from peripheral blood. All exons of the SOD1 and FUS genes, whose mutations are popular in familial ALS in Japan, were analyzed by polymerase chain reaction (PCR) followed by direct DNA sequencing. The patient was negative for SOD1 mutation, but had an identical p.P525L (c.1574C>T) variant, resulting in a missense mutation in exon 15 (Fig. 1B). On the basis of these findings, we diagnosed amyotrophic lateral sclerosis caused by FUS gene mutation.