Acid sphingomyelinase ( ASM ) deficient Niemann-Pick disease ( NPD ) is caused by SMPD1 gene mutations and subsequent acid sphingomyelinase deficiency. It is a rare autosomal recessive disorder, usually categorized as either neuropathic type A, non-neuropathic type B, or clinically intermediate type.
Affected individuals, with the neuropathic type A, present with grossly enlarged spleens and livers, and disease onset approximately 3 months of age. These individuals also suffer psychomotor development retardation, as evidenced by only achieving milestones of less than a 1-year developmental level, and death occurring at around three years of age.
Individuals with type B usually have normal neurological development, and onset of the disease can occur from infancy to late adulthood.
In addition to types A and B, an intermediate form exists, this form is differentiated by presence of mental abnormality and onset at 2 to 7 years of age.
Occurrence of Niemann-Pick disease type B ( NPD-B ) is pan-ethnic, while the people of Ashkenazi Jewish descent have a high incidence of NPD-A. The genotype and phenotype correlation for some mutations are consistent, e.g., three common mutations, p.Arg498Leu ( p.R496L ), p.Leu304Pro ( p.L302P ), and p.Phe333SerfsX52 ( 990delC ), account for approximately 90% of Niemann-Pick disease type A alleles in the Ashkenazi Jewish population.
A common NPD type B mutation, p.Arg610del ( R608del ), has been reported to be the predominant mutant allele ( 87% ) in Maghreb region of North Africa. A high frequency of this mutation has also been found in Spain ( 38% ), and in a report including patients from European countries, USA and Brazil ( 25% ). In a worldwide study this mutation accounted for 12% of allelic variation. In another study the p.Gln294Lys ( Q292K ) mutation was associated with severe and progressive neurological involvement in an intermediate type group.
Finally, the p.Trp32X mutation was the most frequent allele identified in an Italian NPD-B cohort study.
Currently, the mainstay treatment for Niemann-Pick disease type A/B is symptomatic. Bone marrow transplantation has been performed on a small number of NPD patients and found to be beneficial only to NPD-B individuals.
Enzyme replacement therapy in type B has completed phase I clinical trial. A phase II clinical trial should start in the near future.
Accurate prediction of disease type from genotype would be critical for optimal treatment choices when a clinical phenotype cannot be determined based on patients’ disease presentation.
Data from hundreds of North American, Western European, and Ashkenazi Jewish patients are available. Conversely, data from Chinese patients is rare.
In the past 5 years, 27 patients with acid sphingomyelinase deficiency were diagnosed at Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai ( China ). ( Xagena )
Zhang H et al, Orphanet Journal of Rare Diseases 2013, 8:15 doi:10.1186/1750-1172-8-15