Late onset hexosaminidase A deficiency in a young adult

We report the case of a 23-year-old-male patient who was admitted to our hospital with progressive muscular weakness as symptoms of a suspicious early onset amyotrophic lateral sclerosis (ALS). The patient registered the first symptoms at the age of 18 years, when he observed muscular weakness especially of the thighs. Pain or any other symptoms besides the weakness like weight loss or autonomic disorders were not reported. There is no history of muscular disease in his family. His mother died from bowel cancer in her forties. Both his father and his older sister were reported to be healthy. The neurological examination showed 4/5 to 4/5 weakness on the upper and lower limb and atrophic pareses especially on the lower limb. Muscle reflexes were symmetrically increased, Babinski s reflex was positive on the right side. The abdominal reflex was increased and the scapulohumeral reflex, a sign of a possible affection of the upper motoneuron (UMN), was bilaterally positive. Fasciculations were generally observed. Cranial nerves, sensation and co-ordination as well as the physical examination revealed no abnormalities. Overall, lower motoneuron (LMN) seemed to be more affected than UMN. Spinal muscular atrophy and myotonic dystrophy Curschmann Steinert were suspected, but results of genetic testing were negative. Electromyographic examinationshowed complex repetitive discharges, classified as myotonic and pseudomyotonic, and short polyphasic potentials, but no distinct fasciculations indicating a myopathic cause of the weakness. Nerve conduction studies for the right sural sensory nerve revealed normal values (amplitude 15.8 lV, conduction velocity 47 m/s). Therefore, our primarily supported diagnosis of ALS was challenged by these electromyographical findings. For further diagnostic evidence, a muscular biopsy (Fig. 1) of the right quadriceps muscle of the thigh was performed. The biopsy showed severe neurogenic muscular atrophy with secondary additional myopathic changes, but no evidence for a metabolic or myotonic myopathy or an inflammatory cause like a vasculitis or myositis. The lumbar puncture showed no abnormalities, blood analysis revealed an elevated creatine kinase (618 U/l, normal range <171 U/l). An MRI scan of the brain and cervical spine revealed a cerebellar atrophy, but no other significant findings. A pathobiochemical blood test of leukocytes for the enzyme hexosaminidase A showed very low enzyme levels (0.05 U/ 10 cells; normal range >0.4 U), testing for combined hexosaminidase A and B enzymes revealed normal enzyme levels. These results indicated the presence of a late onset GM2 gangliosidose. In case of an early onset, these symptoms would be suitable for the diagnosis of Tay-Sachs disease. Enzyme activity is significantly higher in the late onset disease compared with Tay-Sachs patients [1]. This disease is characterised by an autosomal-recessive inheritance, and is preferably linked to the Jewish population, where one in 2000 is carrier of the responsible deficient gene. However, our patient did not report any Jewish ancestors. As the enzyme activity analysis was sufficient for the diagnosis, no DNA analysis had been performed. Clinical severity is correlated to the enzyme activity, symptoms occur if the enzyme activity is reduced to <10% of the normal range. Spinocerebellar signs related to the atrophy found in brain scans and LMN dysfunction [2] reflected by complex repetitive discharges in the electromyographic examination seem to be characteristic for this GM2 gangliosidose. Therefore this disease mostly presents in two different clinical ways, one like a hereditary cerebellar ataxia, the other like a spinal muscular atrophy or ALS, mostly without cognitive deficits and only slightly reduced life-expectancy. Genetic consultation is recommended for the affected families as no therapy is available so far, although pharmaceutical attempts have been made to tackle this disease [3,4]. In conclusion, hexosaminidase A deficiency is a rare occasion, especially in nonJewish populations. Young patients presenting with assumed atypical early onset ALS or late onset myotonic muscle disease should therefore be tested for gangliosidoses [5].