Sphingomyelinase Deficiency

Updated: Aug 18, 2016
  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Overview

Background

Niemann-Pick disease (NPD) is a lipid storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. The original description of NPD referred to what is currently termed NPD type A, which is a fatal disorder of early childhood characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that leads to death by age 2-3 years.

Since this original description, other forms of NPD have been described. NPD type B is a milder, nonneuronopathic form with later onset and longer survival, sometimes into adulthood. NPD type C, a rarer form, results from defects in cholesterol metabolism. Both NPD types A and B are inherited as autosomal recessive traits.

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Pathophysiology

Niemann-Pick disease (NPD) types A and B result from the deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene located on bands 11p15.1-p15.4. [1, 2] The enzymatic defect results in pathologic accumulation of sphingomyelin (which is a ceramide phospholipid) and other lipids in the monocyte-macrophage system, the primary site of pathology in patients with NPD. Additional progressive deposition of sphingomyelin in the CNS results in the neurodegenerative course observed in NPD type A, which shares systemic disease manifestations with NPD type B. The severity of systemic involvement varies in affected individuals. Systemic involvement includes progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia. [3]

Individuals with NPD types A and B typically have less than 10% residual acid sphingomyelinase enzyme activity. The complete sphingomyelinase genomic region has been isolated and sequenced. Three common mutations (L302P, 1bp del fsP330, R496L) account for approximately 90% of NPD type A alleles in the Ashkenazi Jewish population. The deltaR608 mutation is a common mutation that causes NPD type B.

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Etiology

Niemann-Pick disease (NPD) types A and B result from a deficiency of acid sphingomyelinase and lysosomal accumulation of sphingomyelin.

NPD types A and B

These disorders result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by a gene located on chromosome 11 (11p15.1 to p15.4). Enzymatic defects result in pathologic accumulation of sphingomyelin, a ceramide phospholipid, and other lipids in monocyte-macrophage systems, the primary site of pathology.

NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. Traditionally, NPD type B was considered a milder, later-onset form of the disorder that was non-neuronopathic. However, some overlap exists between these 2 forms of NPD, with a broad range and severity of somatic and neurologic features noted in patients classified as NPD type B. Complete sphingomyelinase genomic regions have been isolated and sequenced, and a number of mutations that cause NPD types A and B are identified, including single base substitutions and small deletions.

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Epidemiology

Racial differences in incidence

Niemann-Pick disease (NPD) is a rare disorder that occurs in persons of all races, [4, 5] although NPD type A is more common in persons of Ashkenazi Jewish descent. Guidelines for carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent have been established. [6] NPD type B occurs worldwide but has a higher frequency in the Maghreb region of North Africa and Saudi Arabia and in individuals of Turkish descent. [7]

Sexual differences in incidence

NPD types A and B are autosomal recessive disorders (see image below), equally affecting males and females.

Autosomal recessive inheritance pattern. Autosomal recessive inheritance pattern.

Age-related differences in incidence

Patients with NPD type A disease develop symptoms as early as age 3 months and die by age 3 years. In contrast, patients with type B disease may survive to adulthood, although most present in childhood with hepatosplenomegaly.

NPD type A is a fatal disorder of infancy. Hepatosplenomegaly develops by age 6 months and development does not progress beyond age 12 months. A relentless neurodegenerative course then follows, with death by age 21 months.

NPD type B has a variable age of presentation but frequently appears early in childhood when hepatosplenomegaly is detected and symptoms of lung involvement may occur. Patients with NPD type B primarily have visceral involvement, sometimes massive, and often survive into adulthood.

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Prognosis

Niemann-Pick disease (NPD) type A disease is fatal in early childhood. The clinical presentation and course of NPD type A is relatively uniform and characterized by normal appearance at birth, followed by progressive hepatosplenomegaly from age 3 months and severe, neurodegenerative course leading to death by age 3 years.

In contrast to the stereotyped type A phenotype, the clinical presentation and the course of patients with NPD type B disease are more variable with respect to clinical findings, age of onset, and severity of symptoms. Most patients are diagnosed in infancy or childhood, when enlargement of the liver and the spleen are detected during routine physical examination. Survival to adulthood is typical.

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Complications

Patients with NPD type B are at risk for splenic rupture and should avoid contact sports.

A small number of patients with NPD type B develop liver failure and may be candidates for liver transplantation.

Pulmonary disease is progressive in patients with NPD type B disease and may result in oxygen dependence.

Mortality/morbidity

Patients with NPD type A develop progressive failure to thrive, sphingomyelin accumulation, liver dysfunction, and neurodegeration beginning at age 3 months and ending with death by age 3 years. Patients with NPD type B may develop extensive involvement of the spleen, liver, and lungs; these patients often survive into adulthood. Mild and progressive neurologic findings may occur in NPD type B; however, progressive neurodegeneration is limited to NPD type A.

A study by Cassiman et al found that in patients with chronic neurovisceral acid sphingomyelinase deficiency (intermediate NPD A/B; NPD B variant), the most frequent causes of death were neurodegenerative disease (23.1%), respiratory disease (23.1%), and liver disease (19.2%). [8]

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Patient Education

Counsel families regarding genetic risk and the availability of prenatal testing.

For patient education resources, see the Cholesterol Center, as well as High Cholesterol, Cholesterol FAQs, and Cholesterol Drugs

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