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Other entities represented in this entry:
SNOMEDCT: 52165006; ICD10CM: E75.240; ORPHA: 77292; DO: 0070111;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.4 | Niemann-Pick disease, type A | 257200 | Autosomal recessive | 3 | SMPD1 | 607608 |
A number sign (#) is used with this entry because Niemann-Pick disease type A is caused by homozygous or compound heterozygous mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1; 607608), which encodes acid sphingomyelinase (ASM), on chromosome 11p15.
Niemann-Pick disease type B (607616) is an allelic disorder characterized by visceral involvement only and survival into adulthood.
Niemann-Pick disease types A and B are caused by an inherited deficiency of acid sphingomyelinase activity. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A) to a later-onset nonneurologic form (type B) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded as a single entity with a clinical spectrum (summary by Schuchman, 2007).
Knudson and Kaplan (1962) suggested that 3 types of the disorder can be distinguished: infantile cerebral, juvenile cerebral, and noncerebral. Later, 5 forms of Niemann-Pick disease were distinguished. Four were delineated by Crocker (1961): the classical infantile form (type A), the visceral form (type B), the subacute or juvenile form (type C; 257220), and the Nova Scotian variant (type D; see 257220). The fifth, the adult form (type E; see 607616), was described by Terry et al. (1954) and Lynn and Terry (1964). Schneider et al. (1978) used the designation type F (see 607616) for a form characterized in 2 patients by a thermolabile enzyme. Most patients fall into Crocker's group A, with death before age 3 years.
Schuchman (2007) provided a detailed review of Niemann-Pick disease type A, including clinical management.
In Niemann-Pick disease, lipid, mainly sphingomyelin, accumulates in reticuloendothelial and other cell types throughout the body. The accumulation in ganglion cells of the central nervous system leads to cell death. Crocker and Farber (1958) presented a detailed clinical and pathologic account of 18 patients with Niemann-Pick disease. Persistent early jaundice, enlarging abdomen, and poor nutritional and developmental progress were the most common initial complaints. Hepatosplenomegaly, retarded physical and mental growth and severe neurologic disturbances, including hypotonia, rigidity, and mental retardation, were features. Symptoms usually developed by 6 months and death occurred by 3 years of age. Crocker and Farber (1958), Forsythe et al. (1959), and others suggested that the biologic behavior can be widely variable.
Wiedemann et al. (1965) found large storage cells in the bone marrow of both clinically normal parents of a sibship with several affected children. The parents were first cousins. The authors noted that about 40% of cases were Jewish. Heterogeneity was emphasized by Lowden et al. (1967) who described non-Jewish sibs with both clinical and chemical differences from the usual disease.
In addition to a cherry red spot, Walton et al. (1978) found corneal opacification and brown discoloration of the anterior lens capsule in all of 4 infants with type A Niemann-Pick disease who were studied in their first year.
Barness et al. (1987) presented a well-studied case of Niemann-Pick disease type A at a clinicopathologic conference.
McGovern et al. (2006) reported the natural history of 10 unrelated patients with type A Niemann-Pick disease. All affected infants had a normal neonatal course and early development. The presenting symptom in all patients was hepatosplenomegaly, and the median age at diagnosis was 6 months. Median developmental age for all 10 did not progress beyond 12 months for developmental milestones. None achieved independent sitting, crawling, or walking; most had progressive hypotonia with loss of deep tendon reflexes. All patients had cherry red spots by age 12 months. Nonneurologic symptoms included vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbances. The median time from diagnosis to death was 21 months. McGovern et al. (2006) concluded that type A Niemann-Pick disease shows a homogeneous, relentless, neurodegenerative clinical course with death within 3 years of onset.
Clinical Variability
Pavlu-Pereira et al. (2005) described 25 Czech and Slovak patients with acid sphingomyelinase deficiency. Five could be clearly classified as having Niemann-Pick disease type A and 4 as having type B. However, 16 (64%) of 25 patients showed variable features, which the authors considered to be an intermediate form of the disease. Twelve of these patients had a combination of visceral storage with a protracted course of neurologic involvement and a general protracted disease course. Three patients had prominent visceral involvement with a rapid course and discrete neuronal storage observed at autopsy. One patient had a rapidly fatal course of visceral involvement without neuronal involvement; he died at age 8 years. The Q292K mutation (607608.0015) was strongly associated with a protracted neurovisceral phenotype in 10 of 12 patients. Pavlu-Pereira et al. (2005) concluded that a phenotypic continuum exists between the basic neurovisceral (type A) and purely visceral (type B) forms of Niemann-Pick disease, and that the intermediate type encompasses a cluster of variants combining clinical features of both types A and B.
In the classic infantile type (type A), Brady et al. (1966) demonstrated that the biochemical defect is deficient activity of the enzyme that catalyzes cleavage of sphingomyelin to phosphorylcholine and ceramide. Uhlendorf et al. (1967) found the metabolic defect in cell culture. Increased sphingomyelin was demonstrated in cells from bone marrow, skin, and amnion; the last makes prenatal diagnosis possible.
Schneider and Kennedy (1967) found that sphingomyelinase is deficient only in the infantile and visceral forms (type B).
Kirkegaard et al. (2010) showed that Hsp70 (140550) stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively reverted the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease A and B (607616), severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase-1 gene (SMPD1; 607616) encoding ASM, is also associated with a marked decrease in lysosomal stability, and this phenotype could be effectively corrected by treatment with recombinant Hsp70. Kirkegaard et al. (2010) concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.
Due to the phenotypic overlap between Gaucher disease (230800) and Niemann-Pick disease, Oliva et al. (2023) investigated the frequency of patients with Niemann-Pick disease in a cohort of 31,838 patients suspected of having Gaucher disease. Blood spot samples in this cohort were tested for both beta-glucocerebrosidase activity and acid sphingomyelinase activity, and those samples with abnormal enzyme activity were then referred for the appropriate gene sequencing. In the cohort of 31,838 patients, 1,171 blood samples had abnormal acid sphingomyelinase activity, and 551 of 1,171 patients had at least 2 SMPD1 mutations. The frequency of patients with Niemann-Pick disease in the suspected Gaucher disease cohort varied based on geographic region, with the highest frequency (1 in 2) in the Middle East and the lowest frequency (1 in 5) Europe. Oliva et al. (2023) concluded that potentially 1 in 4 patients suspected of having Gaucher disease actually has Niemann-Pick disease.
Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.
Levran et al. (1991) identified a point mutation in the SMPD1 gene (607608.0001) in an Ashkenazi Jewish patient with type A Niemann-Pick disease. Takahashi et al. (1992) characterized 3 SMPD1 mutations (607608.0005-607608.0007) causing Niemann-Pick disease type A. Ida et al. (1996) identified 3 novel mutations in the SMPD1 gene in Japanese patients with type A and B Niemann-Pick disease.
Rodriguez-Pascau et al. (2009) identified 17 different mutations in the SMPD1 gene, including 10 novel mutations (see, e.g., A482E; 608607.0016 and Y467S; 608607.0017), in 19 Spanish patients and 2 patients from Maghreb in Northern Africa with Niemann-Pick disease type A (8 patients) or type B (13 patients). The most common mutations were R608del (607608.0002), found in 38% of alleles, and the A482E mutation, found in 9% of alleles. The R608del mutation was always found in patients with type B disease; the A482E and Y467S mutations were found in type A patients. Functional expression studies of the mutant proteins in COS-7 cells showed decreased enzyme activity.
Takahashi et al. (1992) concluded that small deletions or nonsense mutations that result in truncated ASM polypeptide and missense mutations that render the enzyme noncatalytic cause type A Niemann-Pick disease, whereas missense mutations that produce a defective enzyme with residual catalytic activity cause a milder nonneuronopathic type B phenotype.
Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, Slatkin (2004) considered available genetic data to be consistent with a founder effect resulting from a severe bottleneck in population size between 1100 A.D. and 1400 A.D. and an earlier bottleneck in 75 A.D., at the beginning of the Jewish Diaspora. He concluded that a founder effect can account for the relatively high frequency of alleles causing 4 different lysosomal storage disorders, including Niemann-Pick disease, Tay-Sachs disease (TSD; 272800), and Gaucher disease (230800), if the disease-associated alleles are recessive in their effects on reproductive fitness.
By homologous recombination in embryonic stem cells, Otterbach and Stoffel (1995) achieved targeted disruption of the SMPD1 gene in transgenic mice. Homozygous mice accumulated sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, as well as in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerated completely, leading to severe impairment of neuromotor coordination. The picture resembled that of the neurovisceral form of Niemann-Pick disease (type A). Horinouchi et al. (1995) obtained similar results in Asm knockout mice.
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