Compound Heterozygote Mutation in the SMPD1 Gene Leading to Nieman-Pick Disease Type A.

BACKGROUND Niemann-Pick disease (NPD) type A is an autosomal recessive lipid storage disorder caused by acid sphingomyelinase deficiency due to a mutation in the SMPD1 gene. Type A is the most severe phenotype of NPD, with early onset in infancy and unfavorable outcome in early childhood. CASE REPORT An 11-month-old boy with hepatosplenomegaly, elevated liver transaminases, and faltering growth was admitted to our hospital for further assessment of potential liver disease. He had severe generalized muscular hypotonia, muscular hypotrophy, reduced muscular strenght, joint laxity, weak deep tendon reflexes, and severe motor developmental delay. Leukodystrophy was seen on the brain MRI, and brainstem auditory evoked potentials were characteristic for auditory neuropathy. A chest X-ray showed signs of interstitial lung disease, which was not further evaluated due to absence of respiratory distress. Liver biopsy histopathologic findings were indicative for lipid storage disease. Genetic analysis showed that the patient is a compound heterozygote in the SMPD1 gene - (NM_000543.5): c.573delT p.(Ser192Alafs*65), which was inherited from the mother and c.1267C>T p.(His423Tyr) was inherited from the father. Both variants were previously individually reported in NPD type A and B. The clinical phenotype in our patient was characteristic of NPD type A, with an early onset and a rapidly progresive neurodegeneration. The patient was included in multidisciplinary follow-up, providing him symptomatic treatment and support. CONCLUSIONS We present a case of NPD type A caused by a rare compound heterozygote mutation in the SMPD1 gene. Most clinical findings and the disease course were typical for NPD type A, except for bilateral auditory neuropathy, which seems to be an uncommon finding in this phenotype and could be underestimated due to infrequent testing for auditory dysfunction.

Therapy-type related long-term outcomes in mucopolysaccaridosis type II (Hunter syndrome) - Case series.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, X-linked recessive multisystem lysosomal storage disease due to iduronate-2-sulfatase enzyme deficiency. We presented three unrelated Slovenian patients with the severe form of MPS II that received three different management approaches: natural course of the disease without received specific treatment, enzyme replacement therapy (ERT), and hematopoietic stem cell transplantation (HSCT). The decision on the management depended on disease severity, degree of cognitive impairment, and parent's informed decision. The current benefits of MPS II treatments are limited. The lifelong costly intravenous ERT brings significant benefits but the patients with severe phenotypes and neurological involvement progress to cognitive decline and disability regardless of ERT, as demonstrated in published reviews and our case series. The patient after HSCT was the only one of the three cases reported to show a slowly progressing cognitive development. The type of information from the case series is insufficient for generalized conclusions, but with advanced myeloablative conditioning, HSCT may be a preferred treatment option in early diagnosed MPS II patients with the severe form of the disease and low disease burden at the time of presentation.