R521C mutation in the FUS/TLS gene presenting as juvenile onset flail leg syndrome

A 24-year-old man presented with painless rapidly progressive lower limb weakness, more severe on the right and more severe distally, resulting in paraplegia within 8 months. His weight dropped from 80 to 70 kg in the absence of bulbar symptoms (e.g., dysphagia or choking episodes). He had no back pain, cramps, dyspnea, or sphincter symptoms. There was no family history suggestive of neuromuscular disease. Examination showed almost complete paraplegia with severe diffuse lower limb atrophy, but without fasciculations. Deep tendon reflexes in the legs were absent and plantar reflexes were downgoing. Strength and deep tendon reflexes in the upper limbs were normal. Cranial nerve and sensory examination findings were normal. There was no cognitive impairment. Elevated creatine kinase (CK) levels (up to 1408 IU/L) before needle electromyography (EMG) were present and were confirmed 1 month later. Motor nerve conduction studies showed absent tibial and fibular motor compound muscle action potentials bilaterally and were normal in the upper limbs. Sensory nerve studies were normal in all 4 limbs. EMG showed abundant fibrillation potentials at rest and decreased recruitment in L3 to S1 myotomes bilaterally. EMG was normal in the upper limbs and in the rectus abdominis, thoracic paraspinal, sternocleidomastoid, genioglossus, and masseter muscles. Brain and total spine MRI were normal. Cerebrospinal fluid analysis was normal. Right quadriceps muscle biopsy revealed small angulated fibers and fiber type grouping, consistent with a neurogenic process. No mutations were found in SMN1, SMN2, or androgen receptor genes. At 10 months after onset, deep tendon reflexes were brisk in the upper limbs, and there was no other change. EMG showed the previous findings plus acute denervation in the left deltoid muscle. Screening for ALS genes, including C9orf72, SOD1, TDP43, FUS, Ataxin 2, Optineurin, and Ubiquitin, identified a R521C missense mutation in the FUS gene. The patient's relatives declined genetic testing. Mutations in the FUS gene cause autosomal dominantly inherited ALS. FUS mutations account for approximately 4% of familial ALS cases and less than 1% of sporadic ALS cases, making them the fourth most common cause of familial ALS after C9orf72, SOD1, and TDP43 mutations.1 FUS mutations are associated with earlier symptom onset (mean age 44 years) and shorter disease survival (mean, 3.4 years) than is typical for ALS.2 FUS mutations are also found in aggressive forms of ALS that begin before age 25 years, termed juvenile-onset ALS. The R521C missense mutation is the most frequent FUS mutation. It is often associated with adult onset symmetrical pelvic and shoulder girdle weakness and predominant lower motor neuron involvement, which has been confirmed pathologically.3, 4 In contrast, other FUS mutations present more frequently with flail arm syndrome or with typical limb or bulbar onset ALS. Our patient with juvenile-onset ALS, an R521C missense mutation, and a flail leg presentation represents an unusual combination. FUS mutations should be assessed in young patients who present with rapidly progressive flail leg syndrome, even in the absence of upper motor neuron signs. Guillaume Taieb, MD1 Pierre Labauge, MD, PhD1 Andre Maues De Paula, MD2 Adelaide Ferraro, MD1 Serge Lumbroso, MD, PhD3 Dimitri Renard, MD1 1Department of Neurology, CHU Nîmes, Hôpital Caremeau, Nîmes, France 2Department of Neuropathology, CHU Marseille, Hopital La Timone, Marseille, France 3Department of Genetics, CHU Nîmes, Hôpital Caremeau, Nîmes, France