Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD), [Niemann-Pick Disease Types A and B (NPD A and B)], is an inherited metabolic disorder resulting from deficiency of the lysosomal enzyme acid sphingomyelinase. Accumulation of sphingomyelin in hepatocytes, reticuloendothelial cells, and in some cases neurons, results in a progressive multisystem disease that encompasses a broad clinical spectrum of neurological and visceral involvement, including: infantile neurovisceral ASMD (NPD A) that is uniformly fatal by 3years of age; chronic neurovisceral ASMD (intermediate NPD A/B; NPD B variant) that has later symptom onset and slower neurological and visceral disease progression; and chronic visceral ASMD (NPD B) that lacks neurological symptoms but has significant disease-related morbidities in multiple organ systems. The purpose of this study was to characterize disease-related morbidities and causes of death in patients with the chronic visceral and chronic neurovisceral forms of ASMD. METHODS: Data for 85 patients who had died or received liver transplant were collected by treating physicians (n=27), or abstracted from previously published case studies (n=58). Ages at symptom onset, diagnosis, and death; cause of death; organ involvement, and morbidity were analyzed. RESULTS: Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%). The overall leading causes of death were respiratory failure and liver failure (27.7% each) irrespective of age. For patients with chronic neurovisceral ASMD (31.8%), progression of neurodegenerative disease was a leading cause of death along with respiratory disease (both 23.1%) and liver disease (19.2%). Patients with chronic neurovisceral disease died at younger ages than those with chronic visceral disease (median age at death 8 vs. 23.5years). CONCLUSIONS: The analysis emphasizes that treatment goals for patients with chronic visceral and chronic neurovisceral ASMD should include reducing splenomegaly and improving liver function and respiratory status, with the ultimate goal of decreasing serious morbidity and mortality.

Morbidity and mortality in type B Niemann-Pick disease.

PURPOSE: The purpose of this study was to perform a systematic evaluation of morbidity and mortality in type B Niemann-Pick disease. METHODS: A total of 103 patients with Niemann-Pick disease (49 males, 54 females, age range: 1-72 years) participated in natural history studies through Mount Sinai's International Center for Types A and B Niemann-Pick Disease between 1992 and 2012. RESULTS: Serious morbidities included significant neurological, hepatic, and cardiac disease. Thirteen patients had some degree of neurological impairment. Nine patients had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart disease were present in nine patients. Of note, only four 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. The 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 18) occurred in patients <21 years, yielding a mortality rate of 19% in the pediatric population. CONCLUSION: This study demonstrates that Niemann-Pick disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. The information collected in this series highlights the need for safe, effective therapy for Niemann-Pick disease.

A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.

OBJECTIVE: The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. METHODS: Fifty-nine patients who had Niemann-Pick disease type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. RESULTS: Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. CONCLUSIONS: This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.