Sphingomyelinase Deficiency 

Updated: May 29, 2020
Author: Jaimin M Patel, MD, MBBS, MS; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Practice Essentials

Acid sphingomyelinase deficiency (ASMD) is a rare lipid storage disorder with a genetic etiology. It is commonly known as Niemann-Pick disease (NPD) type A, type B, or type A/B. 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 (chronic visceral ASMD) is a milder, non-neuronopathic form with later onset and longer survival, sometimes into adulthood. NPD types A and B are inherited as autosomal recessive traits.

NPD type A/B is an overlapping disease entity that is also known as chronic neurovisceral ASMD or NPD B variant. It has later symptom onset compared with type A and slower neurologic and visceral disease progression compared with type A and type B.

NPD type C, a rarer form, results from defects in cholesterol metabolism, specifically defects in two distinct cholesterol-binding proteins (NPC1 and NPC2),[1] rather than from ASMD. Hence, type C will not be discussed here.

Signs and symptoms of sphingomyelinase deficiency

Niemann-Pick disease (NPD) type A

The first sign detected is usually the presence of hepatosplenomegaly, which is evident at age 3 months and becomes progressively greater.

Psychomotor development does not progress beyond the 12-month level, and in later stages, the affected child is completely unable to interact with the environment.

Mild hypotonia may be evident by age 6 months, followed by progressive loss of tone and deep tendon reflexes. With disease progression, loss of motor function occurs, and in the final stages, spasticity and rigidity are evident.

Affected infants exhibit feeding problems, failure to thrive, recurrent respiratory tract infections, and irritability. Most children with NPD type A die before age 2-3 years, often from respiratory failure following pulmonary infection.

Niemann-Pick disease (NPD) type B

The condition is diagnosed in most patients in infancy or childhood when enlargement of the liver, spleen, or both is detected during routine physical examination. At diagnosis, patients with NPD type B also have evidence of mild pulmonary involvement.

Recurrent pneumonia and life-threatening bronchopneumonias may occur, and cor pulmonale has been described. Severely affected patients may also have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites.

Workup in sphingomyelinase deficiency

The diagnosis of NPD is confirmed with measurement of enzyme activity in peripheral white blood cells or in cultured fibroblasts.

Targeted mutation analysis for four common SMPD1 mutations is available in clinical laboratories.

The pathologic hallmark in NPD types A and B is the histochemically characteristic lipid-laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination.

Pancytopenia may be present secondary to the enlarged spleen in patients with NPD, and reduced high-density–lipoprotein cholesterol (HDL-C) fraction is common in NPD type B.

Chest radiography in NPD type B reveals a typical reticulonodular pattern of infiltration, even in patients with no overt pulmonary symptoms. Calcified pulmonary nodules may be seen. Skeletal imaging in NPD type B often shows delayed bone age.

Computed tomography (CT) scanning or magnetic resonance imaging (MRI) in NPD type B can be used to quantify liver and spleen volumes. MRI of the brain in NPD type A may be normal or may show signs of white matter involvement.

Management of sphingomyelinase deficiency

At present, medical and surgical care for NPD types A and B are mainly focused on supportive care.

No specific treatment is currently available for patients with any NPD type A, and treatment is symptomatic.

Adult patients with elevated serum cholesterol due to NPD type B should be treated to bring serum cholesterol concentration into the normal range. Liver function should be monitored in patients treated with statins.

Transfusion of blood products may be necessary for acute episodes of bleeding secondary to hypersplenism and thrombocytopenia in NPD type B patients.

Supplemental oxygen may be used for NPD type B patients with symptomatic interstitial lung disease. Bronchopulmonary lavage has had variable results.

Pathophysiology

Niemann-Pick disease (NPD) types A and B result from genetic mutations in the SMPD1 gene, producing in a deficiency of acid sphingomyelinase (ASM) and lysosomal accumulation of sphingomyelin.

The SMPD1 gene spans about 5 kb of chromosome 11 (11p15.1-11p15.4) and consists of six exons. Its 1896 bp frame encodes a 631 amino-acid protein in the endoplasmic reticulum. This pre-pro polypeptide undergoes cleavage and preprocessing in the endoplasmic reticulum and Golgi complex, resulting in the 70 kDa mature form of ASM localized to lysosomes; this is further processed to a 52 kDa form.[2]

ASM enzyme activity is necessary for breaking down sphingomyelin into ceramide and phosphocholine. Most patients with NPD type A typically have less than 5% residual ASM enzyme activity, while those with NPD type B may have over 10% enzyme activity.[3] Certain mutations, such as p.F572L, may result in a residual enzyme activity of about 30%, but due to dramatic reduction of the protein half-life, the condition may phenotypically be type A.[2] Since residual enzyme activity and phenotype are not always correlated, residual enzyme activity should not be used as a predictor of phenotype; rather, it should serve as an adjunct to molecular and clinical assessment in the diagnosis and treatment of NPD.[4]

The enzymatic defect results in the 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.

In addition to sphingomyelin, bis(monoacylglycero)phosphate and lyso-sphingomyelin are also elevated. Cholesterol, glucocerebroside, lactosylceramide, and gangliosides (particularly GM3) are elevated as well, but not to the extent seen in NPD type C.

Sphingomyelin is a major component of cell membranes and the principal phospholipid of the myelin sheath.[1, 5] (See the image below.)

Role of acid sphingomyelinase in metabolism pathwa Role of acid sphingomyelinase in metabolism pathways inside cellular organelles.

Progressive deposition of sphingomyelin in the central nervous system (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—which includes progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia—varies in affected individuals.

Etiology

Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-p15.4.[6, 7] To date, more than 180 mutations have been described.[2]

Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. Large deletions or insertions have not been reported.[2]

Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype.[3, 8] Although, as previously mentioned, the missense mutation pF572L results in 30% enzyme activity, it also dramatically reduces protein half-life and is therefore associated with the type A phenotype.[2]

The complete sphingomyelinase genomic region has been isolated and sequenced. Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. The delta-R608 mutation is a common mutation that results in NPD type B. In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype.[4]

Regional distribution of mutations causing NPD varies. In the Maghreb region of North Africa, delta R608 may account for almost 90% of mutant alleles, resulting in NPD type B, while in the Turkish population, three mutations—L137P, fsP189, and L549P—are responsible for over 70% of cases of type B.[9] In addition, a study reported that the mutations c.409T>C (p.L137P) and c.567delT (p.P189fsX65) were found in 40% and 35% of alleles, respectively, in the entire Turkish population.[3] In the Saudi Arabian population, the H421Y and K576N mutations account for 85% of NPD type B cases. Increased prevalence of distinct mutations has also been described in various other ethnic groups, including Scottish/British and Brazilian/Portuguese populations.[9]

SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.[2]

Epidemiology

Race

Niemann-Pick disease (NPD) is a rare disorder that occurs in persons of all races.[10] Frequency and distribution of mutations are variable in different ethnic groups and even between different families in the same ethnic groups.

NPD type A is more common in persons of Ashkenazi Jewish descent. Guidelines for carrier screening for genetic disorders in this population have been established.[11]

NPD type B occurs worldwide but is more common in the Maghreb region of North Africa, in Saudi Arabia, and in individuals of Turkish descent. NPD type B has various phenotypes, and they are found commonly in Arab, Turkish, and Portuguese populations. In North African patients with NPD type B who originated from Maghreb region, the delta-R608 mutation accounts for almost 90% of mutant alleles.[9]

Sex

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

Patients with NPD type A disease develop symptoms as early as age 3 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.

Prognosis

Mortality/morbidity

In Niemann-Pick disease (NPD) type A, the clinical presentation and course are relatively uniform and characterized by normal appearance at birth and hepatosplenomegaly from age 3 months. Development does not progress beyond age 12 months; a relentless neurodegenerative course then follows.

Patients with NPD type A usually die by age 2-3 years. In contrast, patients with type B disease often survive to adulthood, although most present in childhood with hepatosplenomegaly.

Patients with NPD type B primarily have visceral involvement, sometimes massive. In contrast to the stereotyped type A phenotype, the clinical presentation and 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.

A study by Cassiman et al found that in patients with chronic neurovisceral ASMD (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%). Death in patients with chronic visceral ASMD (ASMD type B), however, mainly resulted from respiratory disease (30.9%), liver disease (29.1%), and bleeding (12.7%).[12]

Complications

Complications of Niemann-Pick disease (NPD) include the following:

  • 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 and may result in oxygen dependence
  • Coronary artery or valvular heart disease can occur in NPD types B and A/B

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

 

Presentation

History

Niemann-Pick disease (NPD) type A

The clinical presentation and course of NPD type A is relatively uniform and is characterized by normal appearance at birth. Some patients may have neonatal edema, and hydrops fetalis may occur. The first sign detected is usually the presence of hepatosplenomegaly, which is evident at age 3 months and becomes progressively greater. The liver is usually enlarged out of proportion to the spleen.

The patient's development seems to progress normally until about age 6 months, followed by a plateau phase from 6 months until about age 15 months. Lastly, rapidly progressive psychomotor and intellectual deterioration occur. Psychomotor development does not progress beyond the 12-month level, and in later stages, the affected child is completely unable to interact with the environment.

Mild hypotonia may be evident by age 6 months, followed by progressive loss of tone and deep tendon reflexes. With disease progression, loss of motor function occurs, and in the final stages, spasticity and rigidity are evident.

Affected infants exhibit feeding problems, failure to thrive, recurrent respiratory tract infections, and irritability. Most children with NPD type A die before age 2-3 years, often from respiratory failure following pulmonary infection.

Atypical presentations of NPD type A have been reported, including unilateral tremors and ipsilateral hemiparesis, with regression of milestones, followed by the development of hepatosplenomegaly.[13]

NPD type B

The clinical presentation and course in patients with NPD type B disease is milder and more variable. The condition is diagnosed in most patients in infancy or childhood when enlargement of the liver, spleen, or both is detected during routine physical examination.

At diagnosis, patients with NPD type B also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest radiograph films.

In many patients, hepatosplenomegaly is particularly prominent in childhood; however, with increasing linear growth, the abdominal protuberance decreases and becomes less conspicuous.

In mildly affected patients, splenomegaly may not be noted until adulthood, and disease manifestations may be minimal.

In most patients with NPD type B, decreased pulmonary diffusion caused by storage of sphingomyelin in pulmonary macrophages becomes evident in childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15-20 years. Such patients have low PO2 values and dyspnea on exertion.

Recurrent pneumonia and life-threatening bronchopneumonias may occur, and cor pulmonale has been described. Severely affected patients may also have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites.

Clinically significant pancytopenia caused by secondary hypersplenism may require partial or complete splenectomy, although removal of the spleen should be avoided because it results in rapid progression of the pulmonary disease.

Patients with NPD type B disease who undergo splenectomy frequently have worsening of pulmonary symptoms. Hepatosplenomegaly is prominent in childhood, but with increasing linear growth, abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients, splenomegaly may not be noted until adulthood and disease manifestations may be minimal.

NPD type A/B

Patients with NPD type A/B (also known as intermediate phenotype, or chronic neurovisceral, ASMD) have symptom onset in early childhood and slower progression of mild neurologic symptoms than do patients with NPD type A, following a period of normal development. Neurologic symptom progression may last from 2-7 years. Neurologic symptoms may include peripheral neuropathy, extrapyramidal signs, psychiatric symptoms, learning disabilities, and ataxia. Patients also develop an ocular “cherry-red spot,” also known as a macular halo.

The liver and spleen are usually affected, with hepatosplenomegaly occurring. Liver disease may progress to portal hypertension and fibrosis, with liver function tests elevated. Patients may also develop diarrhea.

Lung involvement is similar to that in type A, and patients may develop interstitial lung disease and a restrictive pattern on pulmonary function testing. Radiographic findings may be marked in the absence of apparent clinical lung symptoms.

Some patients with NPD type A/B may have associated neurologic findings, including cerebellar signs, nystagmus, extrapyramidal involvement, and intellectual disability.

In some cases, patients with NPD type A/B also have cardiac involvement, in the form of valve disease and early onset coronary artery disease. Mixed dyslipidemia and low high-density–lipoprotein cholesterol (HDL-C) levels may develop.

Skeletal manifestations include delayed bone growth, growth restriction, and osteopenia, along with bone and joint pain and pathologic fractures.

Thrombocytopenia and bleeding tendencies, recurrent ear infections, and headaches are also noted in these patients.

Physical Examination

Ocular findings

Patients with NPD type A disease usually have a cherry-red spot on ophthalmologic examination. In NPD type A patients, deposition of excess gangliosides occurs in the retina surrounding the macula. This results in opacification of a retina-sparing, cherry-red macula, thus resulting in a distinct appearance known as a cherry-red spot or macular halo.

Hepatosplenomegaly

Hepatosplenomegaly is a common feature in NPD. In NPD type A, the condition typically becomes massive, while in NPD type B, it can widely vary. Some patients with NPD type B have massive enlargement, whereas others have milder enlargement that may remain unnoticed for years.

Neurologic findings

Patients with NPD type A have progressive neurodegeneration, and attainment of milestones does not progress beyond 10 months in any domain. Motor milestone attainment rarely progresses beyond the ability to sit with assistance. Progressive hypotonia and loss of deep tendon reflexes result in loss of previously achieved milestones. The neurologic degeneration is relentless, leading to a spastic state. Seizures are not common.

Most patients with type B disease have normal findings on neurologic examination, although some patients have been described with peripheral neuropathy, extrapyramidal signs, psychiatric symptoms, and learning disabilities. In addition, some patients reportedly have normal early development but loss of language skills and onset of ataxia beginning around the third year of life.

Growth findings

Patients with moderate-to-severe NPD type B typically experience growth retardation in childhood and attain a final adult height that is less than expected based on familial heights.

Other

Examination of the skin in patients with NPD type B disease may reveal extensive bruising. Patients with severe hypersplenism may also have petechiae.

Findings on auscultation of the lungs are usually normal in the absence of an intercurrent respiratory tract infection in all types of NPD.

Cardiac examination findings are usually normal in the absence of valvular dysfunction. The valvular dysfunction may be present in NPD types B and A/B.

 

DDx

Differential Diagnoses

 

Workup

Approach Considerations

During infancy, patients presenting with hepatosplenomegaly and one or more features suggestive of ASMD, such as cherry-red macules, developmental delay and/or regression, hypotonia, and/or low HDL-C, should be evaluated for ASM activity. In patients with hepatosplenomegaly without other features of ASMD, infections and hematologic-oncologic etiology should first be ruled out, followed by assessment of ASM activity.

When lysosomal storage disease is suspected, enzyme assays for ASM can be performed, along with evaluation of glucocerebrosidase activity, to distinguish between ASMD and Gaucher disease.

For diagnosis of ASMD, enzyme assay is preferred over gene sequencing. There are a wide variety of mutations, leading to different combinations of alleles and resulting in varying levels of enzyme activity; hence, genetic mutation results are difficult to interpret unless two known pathogenic mutations are present. For assessment of ASM activity, tandem mass spectrometry is considered the method of choice.[4]

A diagnostic algorithm for the infantile neurovisceral form of ASMD and for ASMD presenting after childhood has been developed.[4]

Acid Sphingomyelinase

Activity

The diagnosis of Niemann-Pick disease (NPD) is confirmed with measurement of enzyme activity in peripheral white blood cells or in cultured fibroblasts.

Mutation analysis

Targeted mutation analysis for 4 common SMPD1 mutations is available in clinical laboratories. Three common type A mutations (L302P, R496L, fsP330) predict the severe infantile form of the disease common in the Ashkenazi Jewish population. One common type B allele (delta R608) is associated with the non-neuronopathic, milder form of disease. Individuals with the Gln294Lys mutation, often associated with NPD type B with progressive neurologic findings, may have apparently normal enzymatic activity when artificial substrate is used.[14]

Sequence and deletion/duplication analysis of SMPD1 are available in clinical laboratories and permit identification of rare and private gene mutations. This information is useful for genotype-phenotype correlation. In addition, genotype information allows identification of carriers among at-risk family members and permits prenatal diagnosis using fetal DNA analysis.

Histologic Findings

The pathologic hallmark in Niemann-Pick disease (NPD) types A and B is the histochemically characteristic lipid-laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination.

These cells, which can be readily distinguished from Gaucher cells by histologic and histochemical characteristics, are not pathognomonic for NPD. Histologically similar lipid-laden foam cells are found in patients with Wolman disease, cholesterol ester storage disease, lipoprotein lipase deficiency, NPD type C, and, in some patients, GM1 gangliosidosis type 2.

Bone marrow examination is not necessary for the diagnosis of NPD.

Laboratory Studies

Complete blood count (CBC)

Pancytopenia may be present secondary to the enlarged spleen in patients with Niemann-Pick disease (NPD).

Serum chemistry

Transaminase levels may be elevated.

Cholesterol

Reduced HDL-C fraction is common in NPD type B. In most patients, this is accompanied by elevated total cholesterol and low-density–lipoprotein cholesterol (LDL-C) levels.

Triglycerides

Most patients with NPD type B and low serum HDL-C levels also have hypertriglyceridemia.

Imaging Studies

Radiography

Chest radiography in Niemann-Pick disease (NPD) type B reveals a typical reticulonodular pattern of infiltration, even in patients with no overt pulmonary symptoms. Calcified pulmonary nodules may be seen.

Skeletal imaging in NPD type B often shows delayed bone age. Indeed, bone age can lag on average 2.5 years behind chronologic age.[15] Many patients have significant osteopenia, which can be quantified using dual-energy x-ray absorptiometry (DEXA) scanning. In adults with NPD type B, DEXA Z-scores are often in the osteopenic or osteoporotic ranges.

CT scanning and MRI

Computed tomography (CT) scanning of the lungs in NPD type B may reveal a reticulonodular pattern of pulmonary involvement, with interlobular septal thickening, ground-glass density, and, sometimes, calcified nodules (which are usually less than a centimeter in diameter). These findings are typically located initially in the lung bases and may appear cranially in the lungs over time.[5, 16, 17]

CT scanning or magnetic resonance imaging (MRI) in NPD type B can be used to quantify liver and spleen volumes. Splenic masses are often detected, representing accumulated storage material. These masses are echogenic on ultrasonography and low resolution on CT scan.[5, 17, 18]

MRI of the brain in NPD type A may be normal or may show signs of white matter involvement, as evidenced by hyperintensity on T2-weighted imaging. It may also reveal cerebral or cerebellar atrophy.[5]

Other Tests

Pulmonary function testing

Testing typically reveals decreased oxygen diffusion, restrictive lung disease, and decreased maximal exercise tolerance.

Echocardiogram (ECHO)

ECHO may reveal valve dysfunction in patients with valvular heart disease and myocardial dysfunction in those with underlying coronary artery disease.

Electrocardiography (ECG) and stress testing

Testing may be abnormal in patients with hyperlipidemia and evidence of coronary artery disease.

Biomarkers for ASMD

Once ASMD has been diagnosed, a biomarker assay may be useful to monitor disease progression. The following biomarkers have been under investigation.[4]

Plasma chitotriosidase

This is a biomarker of macrophage activation and is markedly increased in several lysosomal storage diseases, including Gaucher disease and chronic ASMD. In up to 6% patients who may have inherited deficiency in chitotriosidase, plasma chemokine ligand 18 (CCL18) may serve as surrogate marker for disease activity.[4]

Plasma lysosphingolipids

Plasma lysosphingolipids, such as lysosphingomyelin, are increased in patients with ASMD and may serve as biomarkers to monitor disease activity. Additional studies are needed, however.[4]

 

Treatment

Medical Care

At present, medical and surgical care for Niemann-Pick disease (NPD) types A and B are mainly focused on supportive care.

No specific treatment is currently available for patients with any NPD type A, and treatment is symptomatic.

Adult patients with elevated serum cholesterol due to NPD type B should be treated to bring serum cholesterol concentration into the normal range. Liver function should be monitored in patients treated with statins.

Transfusion of blood products may be necessary for acute episodes of bleeding secondary to hypersplenism and thrombocytopenia in NPD type B patients.

Supplemental oxygen may be used for NPD type B patients with symptomatic interstitial lung disease. Bronchopulmonary lavage has had variable results.

Surgical Care

Orthotopic liver transplantation in an infant with Niemann-Pick disease (NPD) type A and amniotic cell transplantation in several patients with NPD type B have been attempted with little or no success.

Bone marrow transplantation has been attempted in patients with NPD type B with variable results, including reduction in spleen and liver volumes, increased peripheral blood cell counts, and decreased infiltration of the lungs. It is not considered appropriate for treatment of NPD with neurologic involvement.

Histocompatible hematopoietic stem cell transplantation conducted on a 4-year-old girl with NPD type B was successful in improving sphingomyelinase enzyme levels and improving severe pulmonary disease.[19]

To date, lung transplantation has not been performed in any patient with type B disease who was severely compromised.

Although patients may have massive splenomegaly, splenectomy should be avoided whenever possible. Removal of the spleen is accompanied by deterioration of pulmonary status and increased morbidity since it eliminates an important reservoir for substrate accumulation that leads to acceleration of disease in other organs such as the lung.[20]

Further Care

Pulmonary infections occur frequently in patients with Niemann-Pick disease (NPD) types A and B.

Patients with type A disease may develop respiratory decompensation, requiring inpatient care for stabilization during severe episodes.

Diet

Pediatric patients with NPD type B require frequent meals to promote growth. Many patients have early satiety because of organomegaly. For some patients, supplements with high levels of kilojoules are useful.

In patients with NPD type A, feeding becomes a major difficulty as the disease progresses. Discussion with the family to determine a strategy for providing calories should occur.

Activity

Patients with NPD type B disease and splenomegaly should avoid contact sports because of the risk of splenic rupture. Immediate medical attention should be obtained after trauma, owing to the risk of splenic rupture and intracranial bleeding due to hypersplenism.

Consultations

Evaluation and ongoing care by a trained metabolic geneticist should occur.

Patients with NPD type B should undergo annual pulmonary function testing and evaluation.

 

Medication

Medication Summary

Currently, there are no targeted therapies available for Niemann-Pick disease (NPD) type A. Gene therapies, enzyme replacement therapies, and bone marrow transplantations have been studied in animal models, but the challenge is to deliver treatments directly into the central nervous system (CNS) before the onset of neurologic symptoms. Safety assessment of intracranial injection of biologic vectors into the brain is still under discussion.[2]

For NPD type B, recombinant human ASM (rhASM) treatment for non-neurologic manifestations is undergoing clinical trial.[21, 22, 23]  Recombinant human ASM has been successfully produced in Chinese hamster ovary cells. Initial treatment studies were conducted in animal models, specifically, in ASM knockout mice. Treatment with rhASM in these animals resulted in dose-dependent toxicity. Such toxicity could be prevented by dose escalation to debulk stored sphingomyelin and thus maintain a low level of ceramide release.

Subsequent studies have begun in humans. In a phase 1 study in adult patients, single administrations of rhASM (olipudase alfa) in increasing doses once every 2 weeks were undertaken, without adverse events. A 0.6 mg/kg maximum starting dose was determined. Transient elevation of cytokines and bilirubin was observed in this cohort.[22] In Phase 1b, a dose escalation scheme was used in five adult patients, first with low doses to debulk sphingomyelin in tissues, then with dose escalations of up to 3 mg/kg, for a total of 26 weeks. No serious adverse events were encountered.[21] A randomized phase 2/3 trial is underway.

Miglustat is first and only targeted therapy approved for NPD type C.[24]