THE SMPD1 GENE MUTATIONS IN TWO SIBLINGS WITH NIEMANN-PEAK TYPE A/B DISEASE

Purpose of work. Niemann–Pick type A/B disease in children was investigated. Niemann–Pick type A disease is the most severe form that begins in infants, characterized by an increase in the hepatosplenomegaly and progressive damage to the nervous system. Type B is characterized by a chronic course, hepatosplenomegaly, the nervous system is usually not involved. Both types are associated with mutations in the SMPD1 gene and sphingomyelinase deficiency. In addition to these, there is an increased level of cholesterol and lipids in the blood and thrombocytopenia. The sphingomyelinase breaks down sphingomyelin into ceramide and phosphocholine in lysosome membranes, and its deficiency leads to excessive accumulation of sphingomyelin. The SMPD1 gene occupies a locus on chromosome 11p15.4-15.1. The disease is inherited as an autosomal recessive trait (1, 2, 3, 4). 

Material and methods. Study materials were collected on DBS cards as dried venous blood spots from Republic Children’s Clinical Hospital departments and Baku Health Center. The method of tandem mass spectrophotometry was used to determine the activity of acid sphingomyelinase in dried blood stains. Using direct automatic sequencing, all 6 coding exons of SMPD1 gene were studied in the ARCHIMED Life laboratory (Austria). General blood analysis and ultrasonic scan were made with common methods.

Patients A.L. (born 2000) and A.Z. (born 2006) live in the city of Ganja. Those born from a blood-related marriage are a cousin of a parallel type. Low activity values of the acid sphingomyelinase enzyme in dry blood spots were obtained for A.L.- 0.29 μmol/liter hour for A.Z.- 0.3 μmol/liter/hour (norm> 0.9 μmol/liter/hour).

Results. Genetic analysis of a DNA sample extracted from the blood of patients A.L. and A.Z., revealed two mutations of the SMPD1 gene: G→A transversion at position 1345 (1345G→A) and cytosine nucleotide duplication at 188 position (188dup. C). Both siblings have a double heterozygous state for two different mutations - 1345 G→A/188 dup. C, which are characteristic of  Niemann–Pick disease type A/B.

The replacement of the guanine nucleotide with the adenine nucleotide at position 1345 in exon 5 of the SMPD1 gene in the heterozygous state leads to the replacement of the glutamine amino acid with lysine at position 449 (Glu449 Lys) in the patient protein.

A mutation of 188 dup. C in the first exon of the SMPD1 gene in the heterozygous state was also identified. Mutation in the protein leads to the replacement of the amino acid leucine with serine at position 64 (Leu 64 Ser).

Conclusion. Thus, both siblings have a double heterozygous state for two different mutations of the SMPD1 gene - 1345 G→A/188 dup. C. Therefore, the identified mutations of the SMPD1 gene indicate Niemann–Pick type A/B disease.