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 ... 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 a single entity with a clinical spectrum (summary by Schuchman, 2007). Schuchman (2007) provided a detailed review of Niemann-Pick disease type B, including clinical management.
Simonaro et al. (2002) commented that type B Niemann-Pick disease is a particularly difficult disorder to diagnose clinically. They suggested that it might be useful to screen in heart disease clinics for patients with very low HDL cholesterol ... Simonaro et al. (2002) commented that type B Niemann-Pick disease is a particularly difficult disorder to diagnose clinically. They suggested that it might be useful to screen in heart disease clinics for patients with very low HDL cholesterol levels, since this is a common finding in almost all patients with type B Niemann-Pick disease, or in endocrinology clinics where patients may be seen for growth retardation.
In contrast to patients with Niemann-Pick disease type A, patients with type B have involvement of the spleen, liver, and lungs, and remain free of neurologic manifestations despite the massive visceral involvement. Patients with type B often survive ... In contrast to patients with Niemann-Pick disease type A, patients with type B have involvement of the spleen, liver, and lungs, and remain free of neurologic manifestations despite the massive visceral involvement. Patients with type B often survive into adulthood. Pfaendler (1953) described non-Jewish Swiss brothers (out of 14 sibs) with Niemann-Pick disease who died at ages 29 and 33 years; they most likely had type B. Blankenship et al. (1973) reported a family with sea-blue histiocytosis with acid phosphatemia and suggested that it represented a syndrome similar to Gaucher disease (230800). Golde et al. (1975) described a second family with sea-blue histiocytosis, lamellar inclusions, and decreased sphingomyelinase activity. Fried et al. (1978) presented evidence that primary sea-blue histiocyte disease (269600) and Niemann-Pick disease type B are the same. Deficiency of sphingomyelinase could be demonstrated in leukocytes and an intermediate level in heterozygotes. Despite the lack of neurologic symptoms in type B, Wenger et al. (1981) were unable to demonstrate lysosomal sphingomyelinase in brain tissue of a fetus affected with type B. Landas et al. (1985) reported a 48-year-old woman with debilitating and eventually fatal coronary artery disease and hepatosplenomegaly in whom multiorgan infiltration by sea-blue histiocytes was the consequence of Niemann-Pick disease type B. Strisciuglio et al. (1987) found evidence of involvement of multiple endocrine glands in a patient with type B Niemann-Pick disease and growth failure. Viana et al. (1990) reported a Brazilian family in which 4 sibs had sea-blue histiocytosis and nonneuropathic Niemann-Pick disease, presumably type B. The kindred was ascertained through a 7-year-old boy who was found to have massive hepatosplenomegaly since infancy. Four of 12 sibs were similarly affected with short stature, bilateral interstitial pulmonary infiltration, and high levels of serum acid phosphatase. Leukocyte acid sphingomyelinase activity ranged from 3.6 to 6.5% of mean control values, and fibroblast activity from 9 to 13% of mean controls. The parents had low-normal levels. The 4 sibs also had very low levels of low density lipoprotein (LDL) cholesterol, very low levels of high density lipoprotein (HDL) cholesterol, and low levels of apoAI. Viana et al. (1990) pointed out that low levels of serum HDL cholesterol have been reported in other patients with Niemann-Pick disease and may be a secondary manifestation of the lysosomal storage disease since low serum HDL cholesterol has been found in at least 2 other diseases in this category, namely, Gaucher disease and cholesteryl ester storage disease. Volders et al. (2002) reported a unique case of a 55-year-old woman who presented with a clinical picture of Parkinson disease, severe back pain, splenomegaly, and pronounced dyspnea. Radiographic examination of the spine showed multiple vertebral fractures. Niemann-Pick disease type B was diagnosed by the finding of lipid-loaded histiocytes and strongly reduced sphingomyelinase activity. She was found to be homozygous for a mutation in the SMPD1 gene (607608.0002); see MOLECULAR GENETICS. In this patient, Volders et al. (2002) screened for polymorphisms previously described as possibly associated with increased risk for osteoporosis and fractures and found that the patient was heterozygous for polymorphisms of the vitamin D receptor gene (VDR; 601769), the estrogen receptor gene (ESR1; 133430), and the alpha-1 chain of type I collagen (COL1A1; 120150). The dramatic presentation of the patient was thought to be explained by increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening of the disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that can inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed. McGovern et al. (2013) performed a systematic evaluation of morbidity and mortality in Niemann-Pick type B disease in a total of 103 patients (49 males, 54 females, age range 1-72 years) studied between 1992 and 2012. Serious morbidities included significant neurologic, hepatic, and cardiac disease. Thirteen patients had some degree of neurologic impairment. Nine had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart disease were present in 9 patients. Of note, only 4 patients were oxygen-dependent, although progressive pulmonary disease is a well-described feature of Niemann-Pick disease. During the follow-up period 18 deaths occurred. Median age of death was 15.5 years (range 1-72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of the 18) occurred in patients younger than 21 years, yielding a mortality rate of 19% in the pediatric population. - 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. - Niemann-Pick Disease, Types E and F Terry et al. (1954) and Lynn and Terry (1964) described an indeterminate adult form of Niemann-Pick disease, type E. Type E patients are adults with moderate hepatosplenomegaly and some increase in sphingomyelin in the liver, spleen, and bone marrow. Schneider et al. (1978) used the designation type F for a form characterized in 2 patients by childhood onset of splenomegaly, lack of neurologic involvement, diminished sphingomyelinase activity, and thermolabile enzyme. Niemann-Pick disease types E and F have not been well-characterized.
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 ... 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.
In an Ashkenazi Jewish patient with Niemann-Pick disease type B, Levran et al. (1991) identified a mutation in the acid lysosomal sphingomyelinase phosphodiesterase-1 gene (607608.0002). Takahashi et al. (1992) identified 3 SMPD1 mutations (607608.0008-607608.0009) causing Niemann-Pick disease type ... In an Ashkenazi Jewish patient with Niemann-Pick disease type B, Levran et al. (1991) identified a mutation in the acid lysosomal sphingomyelinase phosphodiesterase-1 gene (607608.0002). Takahashi et al. (1992) identified 3 SMPD1 mutations (607608.0008-607608.0009) causing Niemann-Pick disease type B. 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.
Simonaro et al. (2002) collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease. They found that the disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, ... Simonaro et al. (2002) collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease. They found that the disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, and North African descent. Only 5 of the 394 patients were Ashkenazi Jewish, revealing that, unlike the type A form of Niemann-Pick disease, type B does not occur frequently within this population. Mutation analysis of the SMPD1 gene was performed on 228 patients and several novel 'common' mutations were found. The previously reported arg608-to-del mutation (607608.0002) occurred in approximately 12% of the alleles studied. Overall, a total of 45 novel mutations were found, and several new genotype/phenotype correlations were identified.