Infantile spasms in early-onset Niemann-Pick disease with a novel compound heterozygous mutations in SMPD1 gene

Niemann-Pick diseases are a group of rare autosomal recessive disorders caused by an inherited deficiency of lysosomal storage with similar clinical presentations. At least three different Niemann-Pick (NP) diseases have been described, with NPA and NPB occurring as a result of a deficiency of the acid sphingomyelinase (ASM) enzyme, while NPC as a disorder that cause misregulation in cholesterol and lipids turnover, causing their accumulation in various tissues, including brain. The resulting phenotypic spectrum ranges from a severe infantile type with neurologic degeneration and death, usually by 3 years of age (NPA), to a non-neurologic adult onset form compatible with survival into adulthood (NPB) and a neurovisceral disorder with symptoms that occur at different times and progress independently (NPC).Here, we report on an Italian child born from non-consanguineous healthy parents, with a negative family history, who developed infantile spasms at the age of 5 months and clinical signs of potential storage disease. The genetic screening, performed by means of whole exome sequencing, revealed compound heterozygous mutations in the Sphingomyelin Phosphodiesterase 1 gene (SMPD1), comprising both a homozygous polymorphism (p.V36A) in exon 1 and a new frameshift heterozygous deletion (c.1187delT) in exon 3 generating a premature stop (TAA) at codon 424 (p.L395fsX29).This result appears to corroborate the phenotypic heterogeneity of the symptoms and suggests a correlation between the presence of a truncated SMPD1 polypeptide and the very early onset of the disease. Focal points•Benchside: The comprehension of genotype-phenotype correlations in patients affected by Niemann-Pick disease will accelerate the accuracy of the diagnosis and permit to ameliorate patient follow-up. •Bedside: The coexistence of a homozygous polymorphism and of a new heterozygous frameshift deletion in exon 3 of the SMPD1 gene reveals the presence of infantile spasms, not previously related to mutations in SMPD1 gene. Elucidating the mechanisms associated to this altered gene product could open novel approaches in therapy.