A Turkish Family with a Familial ALS-positive UBQLN2-S340I Mutation

We observed a family with a new and rarely encountered ubiquitin-associated genetic mutation seven months ago.Herein we would like to comment about this rare case.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motor neurons in the motor cortex of the brain, brainstem, and spinal cord.Because of the progressive degeneration of motor neurons, ALS eventually leads to their death.Degenerating motor neurons develop protein-rich inclusions in their cell bodies and axons, which may be due to, at least in part, defects in protein degradation.Recently, focus on RNA metabolism and protein degradation disorders in familial ALS has intensified.The most frequently encountered disorders involve ubiquitin, superoxidase dismutase (SOD1), TAR DNA-binding protein (TDP-43 or TARDBP), or fused in sarcoma (FUS) (1).In recent years, ALS has been thought to not be a monotypic disease but a syndrome consisting of diseases caused by a series of non-overlapping mechanisms.Multiple genetic and environmental factors have been implicated in ALS pathogenesis (1,2).Several theories related to the etiopathogenesis of ALS have been proposed, including oxidative stress, mitochondrial dysfunction, excitotoxicity, defective axonal transport, and abnormal protein aggregation; however, the true etiopathogenesis is not known with certainty (3).Majority of ALS cases are sporadic.Genetic testing of sporadic cases has shown that genetic transmission occurs in 5% of all ALS cases (familial ALS).SOD1 was the first best studied gene responsible of approximately 20% of familial cases.In recent years, numerous genes other than SOD1 have been identified that are responsible for familial forms of ALS.Today, hexanucleotide expansion in the C9orf72 gene is the most common mutation (20-40%) in all populations studied.Genetic transmission in familial ALS is usually autosomal dominant with differing degrees of penetrance (4,5).