Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.

Acerca de ciertas variaciones estructurales del genoma humano / About certain structural variations of the human genome

En el genoma humano aparecen variaciones que aparentemente no implican cambios deletéreos, y que se diagnostican mediante técnicas de citogenética convencional o molecular. Sin embargo, está demostrado que en ocasiones estas variaciones son causa de serias alteraciones fenotípicas. El presente trabajo tiene como objetivo realizar una actualización sobre los avances en el diagnóstico de las variaciones genómicas y evaluar los resultados que pueden explicar la correlación entre el fenotipo anormal del paciente con el genotipo aparentemente balanceado en una aberración estructural o con variaciones en el número de copias que aparecen de novo en los individuos. Se realizó una revisión del tema a través de la búsqueda de artículos científicos en Pubmed y Research Gate, seleccionando los disponibles a texto completo y con información novedosa. Dentro de las aberraciones estructurales balanceadas se describen las alteraciones que involucran los puntos de ruptura implícitos en este tipo de reordenamiento. Se refiere el efecto adverso que pueden tener las variaciones en el número de copias en el genoma y su diferente ubicación en el mismo…(AU)