This article includes discussion of Niemann-Pick disease types A and B, acid sphingomyelinase-deficient Niemann-Pick disease, acid sphingomyelinase deficiency, sphingomyelin lipidosis, type A Niemann-Pick disease, type B Niemann-Pick disease, and intermediate type of ASM-deficient Niemann-Pick disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The term “acid sphingomyelinase-deficient Niemann-Pick disease” (“ASM-deficient NPD”) or ASM deficiency (ASMD) is now preferred to collectively designate Niemann-Pick disease types A and B. ASM-deficient NPD 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 neuronopathic type A and the non-neuronopathic type B and 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 other experimental therapeutic approaches.
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• 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.
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• Classical type A is a severe neurovisceral form with very poor prognosis and limited survival; genetic prevention is crucial.
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• The more frequent type B (corresponding to the non-neuronopathic, chronic form with only visceral – mainly spleen, liver, lung – involvement) may be diagnosed from infancy to late adulthood.
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• Intermediate forms with mild or late onset neurologic involvement exist.
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• For type B patients, enzyme replacement therapy by recombinant acid sphingomyelinase is not yet available, but a phase 2/3 clinical trial is well underway in children and adults.
Historical note and terminology
Niemann-Pick diseases are 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 Niemann's report of an 18-month-old girl who had died of a neurodegenerative disorder accompanied by massive hepatosplenomegaly that was followed by the pathological studies of Ludwig Pick (56; 64). Klenk later demonstrated that the predominant stored lipid was sphingomyelin.
In 1958 Crocker and Farber published a review of 18 cases 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 (12). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (11). Type A (corresponding to the original case of A. 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, but with a sparing of the nervous system. Types C and D were characterized by a subacute nervous system involvement with a moderate and slower course as well as milder visceral storage. The rare patients with a non-neurologic adult form, later categorized as the E and F subtypes of Niemann-Pick disease, were ill-defined and most likely corresponded to atypical cases with either type C (E) or type B (F). In 1966 Brady and associates demonstrated a severe deficiency in acid (lysosomal) sphingomyelinase activity in tissues from patients with type A (04), a finding that was soon extended to type B, but not to types C and D.
The next step was the identification of the gene encoding acid sphingomyelinase, SMPD1, and the demonstration of mutations in patients (77; 76), confirming that Niemann-Pick disease types A and B were allelic disorders. Meanwhile, type C was shown to constitute a distinct entity, with alterations in trafficking of endocytosed cholesterol and mutations in the NPC1 or NPC2 genes, type D being an allelic NPC1 form (60; 92). An increasing number of patients intermediate between the A and B forms have been described (61; 101; 46), indicating that the clinical spectrum of sphingomyelinase deficiencies forms a continuum, much like the situation in Gaucher disease. Thus, the nomenclature needed to be amended. One should remember that the generic name "Niemann-Pick disease", without specification of a subgroup, is ambiguous because type A and B on 1 side and type C on the other side refer to 2 very distinct disorders. Considering that Niemann-Pick type C is now established under that name, it has been proposed to use for primary sphingomyelinoses (ie, types A, B, and intermediate forms) the collective term of “acid sphingomyelinase-deficient Niemann-Pick disease” (ASM-deficient NPD) or “ASM deficiency” (73).