title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Metabolic Center, University of Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: University of California San Francisco, San Francisco, CA, United States.
authors.forename: Seymour
authors.initials: S
authors.lastname: Packman
authors.affiliation: Academic Medical Centre Hospital of Udine, Udine, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.affiliation: La Rabta Hospital, Tunis, Tunisia.
authors.forename: Hadhami Ben
authors.initials: HB
authors.lastname: Turkia
authors.affiliation: King Faisal Specialist Hospital& Research Center, Riyadh, Saudi Arabia.
authors.forename: Moeenaldeen
authors.initials: M
authors.lastname: Al-Sayed
authors.affiliation: University of Paris-Diderot, APHP and INSERM U1141, Reference Center for Inborn Errors of Metabolism, Robert-Debré Hospital, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: Niemann-Pick Disease Group (UK), Tyne and Wear, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Imrie
authors.affiliation: Hospital Dr. Exequiel González Cortés, Santiago, Chile.
authors.forename: Paulina
authors.initials: P
authors.lastname: Mabe
authors.affiliation: Akita University School of Medicine, Akita, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Villa Metabolica, Center of Pediatric and Adolescents Medicine, University Medical Center, Mainz, Germany.
authors.forename: Karl Eugen
authors.initials: KE
authors.lastname: Mengel
authors.affiliation: Medical Genetics Service, HCPA, Dep. Genetics, UFRGS and INAGEMP, Porto Alegre, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Clinical Development, Sanofi Genzyme, Cambridge, MA, United States. Electronic address: gerald.cox@genzyme.com.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002423:Cause of Death; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D052536:Niemann-Pick Disease, Type A / Q000401:mortality*; D052537:Niemann-Pick Disease, Type B / Q000401:mortality*; D012307:Risk Factors; D055815:Young Adult
keywords: Acid sphingomyelinase deficiency; Liver failure; Niemann-Pick disease; Respiratory failure