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  • Updated 08.11.2022
  • Released 11.15.1997
  • Expires For CME 08.11.2025

Acid sphingomyelinase deficiency (Niemann-Pick disease types A and B)



The term "acid sphingomyelinase deficiency (ASMD)“ or "acid sphingomyelinase-deficient Niemann-Pick disease” should now be preferred to collectively designate Niemann-Pick disease types A and B. Acid sphingomyelinase deficiency is a rare autosomal recessive lysosomal lipid storage disease resulting from mutations in the acid sphingomyelinase SMPD1 gene. This name allows inclusion of cases intermediate between the historical severe infantile neuronopathic type A and the non-neuronopathic type B; it also clearly differentiates this group from Niemann-Pick disease type C, a distinct entity. In this article, the author updates clinical knowledge from surveys in large cohorts of patients, methods for laboratory diagnosis, and genotype/phenotype correlations. She also discusses the progress towards enzyme replacement therapy in type B patients and summarizes other experimental therapeutic approaches.

Key points

• Niemann-Pick disease type A and type B are rare autosomal recessive lysosomal lipid storage diseases corresponding to the acid sphingomyelinase-deficient forms of Niemann-Pick disease (ASMD).

• Infantile neurovisceral acid sphingomyelinase deficiency (classical type A) is a severe neurovisceral form associated with very poor prognosis and limited survival.

• The more frequent chronic visceral acid sphingomyelinase deficiency (type B) typically shows only visceral, mainly spleen, liver, lung involvement, and may be diagnosed from infancy to late adulthood.

• Chronic neurovisceral acid sphingomyelinase deficiency refers to intermediate forms with mild or late onset neurologic involvement.

• Status of enzyme replacement therapy by recombinant acid sphingomyelinase: 12-month results of clinical trials have been published for adults and children with chronic visceral acid sphingomyelinase deficiency. Treatment with olipudase alfa of noncentral nervous system manifestations of acid sphingomyelinase deficiency in pediatric and adult patients is now approved in the European Union, Japan, and the United States.

Historical note and terminology

Niemann-Pick diseases constitute a heterogeneous group of genetic disorders that share the general clinical and biochemical features of hepatosplenomegaly, with varying degrees of sphingomyelin and cholesterol accumulation in tissues. Their recognition had its genesis in Albert Niemann's report of an 18-month-old girl who had died of a neurodegenerative disorder accompanied by massive hepatosplenomegaly, which was followed by the pathological studies of Ludwig Pick (51; 56). Klenk later (1933) demonstrated that the predominant stored lipid in those patients was sphingomyelin. In 1946, Pfändler and Dusendschon described 2 adult brothers with similar pathologic findings, but distinct from Niemann’s patients by a later onset of disease symptoms and the lack of central nervous system (CNS) manifestations. In 1958, Crocker and Farber published a review of 18 cases of “Niemann-Pick disease,” showing that there was a wide variability in age of onset and clinical expression as well as in the level of sphingomyelin storage in tissues (08). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (07). Type A (corresponding to the original case of Albert Niemann) was characterized by severe, early CNS deterioration and massive visceral and cerebral sphingomyelin storage. Type B showed a chronic course with marked visceral involvement and massive sphingomyelin storage, but with a sparing of the nervous system. Types C and D (the latter corresponding to patients from Nova Scotia) were characterized by a subacute nervous system involvement with a moderate and slower course, as well as milder visceral storage (48). An increasing number of patients intermediate between the A and B forms were also described (53; 84), indicating that the clinical spectrum of acid sphingomyelinase deficiency forms a continuum, much like the situation in Gaucher disease. From 1985 and later, types C and D were defined as a distinct entity, with alterations in trafficking of endocytosed cholesterol and mutations in the NPC1 (including the type D isolate) or the NPC2 gene (see Niemann-Pick disease type C chapter).

The generic name "Niemann-Pick disease” is, thus, ambiguous because it corresponds to 2 distinct disease entities. Furthermore, the historical distinction of 3 types (A, B, C) adds to the confusion. Therefore, the collective term of “acid sphingomyelinase deficiency” (ASMD) has been proposed to specifically designate primary sphingomyelinoses (ie, types A, B, and intermediate forms) (65). In this new nomenclature, which is increasingly used in current literature, infantile neurovisceral acid sphingomyelinase deficiency corresponds to the historical type A, chronic neurovisceral acid sphingomyelinase deficiency to the intermediate forms, and chronic visceral acid sphingomyelinase deficiency to the historical type B.

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