Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Abstract

A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

Types A and B Niemann-Pick disease

“…[55]. Another mutation, Q292K, is associated with the intermediate neurological phenotype [19]. These and other findings have assisted physicians, genetic counselors and families in predicting the phenotypic outcome in individual NPD patients, and in the future may lead to large-scale screening for this disorder in specific populations.…”

Morbidity and mortality in type B Niemann–Pick disease

“…The Q292K mutation, which has been associated with variant type B NPD, 9 was present in homozygosity in one deceased patient and in the heterozygous state in one deceased and one alive patient. Both of these deceased patients had variant NP-B, but the patient who is alive has no neurological involvement.…”

“…[2][3][4][5][6][7] In addition, there is a subset of variant patients who survive early childhood but have progressive neurologic findings including ataxia, variable degrees of developmental delay, and peripheral neuropathy. 8,9 Accompanying this marked phenotypic variability among patients with NP-B is a broad range of disease severity. For example, age at clinical presentation can range from early childhood to the fourth or fifth decades of life.…”

Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann–Pick disease type B

“…2,4,5 Patients with intermediate phenotypes between types A and B NPD have also been described. 6,7 These patients represent the expected continuum caused by inheriting different variants in the ASM gene. 2 More than 100 pathogenic variants in the SMPD1 gene have been identified throughout the gene, albeit most are located in exon 2.…”