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Last updated: 1/2/2025
Years published: 2016, 2019, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Andrew Lieberman, MD, PhD, Abrams Collegiate Professor of Pathology, Director of Neuropathology, University of Michigan Medical School, and Melissa Wasserstein, MD, Chief, Division of Pediatric Genetic Medicine, The Children’s Hospital at Montefiore, Associate Professor of Pediatrics, The University Hospital for Albert Einstein College of Medicine, for assistance in the preparation of this report.
Summary
Acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder that results from a deficiency of the enzyme acid sphingomyelinase, which is required to break down (metabolize) a fatty substance (lipid) called sphingomyelin. Consequently, sphingomyelin and other substances accumulate in various tissues of the body. ASMD is highly variable, and the age of onset, specific symptoms and severity of the disorder can vary dramatically from one person to another, sometimes even among members of the same family. The disorder may be best thought of as a spectrum of disease. At the severe end of the spectrum is a fatal neurodegenerative disorder that presents in infancy (Niemann-Pick disease type A). At the mild end of the spectrum, affected individuals have no or only minimal neurological symptoms and survival into adulthood is common (Niemann-Pick disease type B). Intermediate forms of the disorder exist as well. ASMD is caused by changes (disease-causing variants) of the SMPD1 gene and is inherited in an autosomal recessive manner.
While there is no cure yet, in 2022, an enzyme replacement therapy, olipudase alfa (Xenpozyme), was approved by the FDA to treat the non-central nervous system (CNS) related symptoms of ASMD.
Introduction
There are three disorders known as Niemann-Pick disease (NPD), types A, B, and C. These disorders were initially grouped together because of similar symptoms, but we now know that they are different diseases. NPD types A and B are due to disease-causing variants in the SMPD1 gene, which causes a deficiency of a specific enzyme, acid sphingomyelinase (ASM). NPD type C is due to disease-causing variants in one of two different genes and does not involve a deficient enzyme. NPD type C is now considered a separate disorder, distinct from Niemann-Pick disease types A and B. NORD has an individual report on NPD type C in the Rare Disease Database. ASMD is also known as acid sphingomyelinase-deficient Niemann-Pick disease.
ASMD has traditionally been broken down into two subgroups – neuronopathic (type A) and non-neuronopathic (type B). Neuronopathic refers to disorders that damage brain cells (neurons). Type A generally causes severe neurodegenerative disease during infancy, while type B is generally not considered to be a neurologic disease. However, since cases fall in between these two extremes, such broad designations can be misleading. Some researchers use acid sphingomyelinase disease type B to refer to all mild and intermediate forms, which can include those that have neurological findings.
Because ASMD is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life; others have mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis.
NIEMANN-PICK DISEASE TYPE A
The severe, infantile form of ASMD, known as Niemann-Pick disease type A, can be distinguished from more mild forms, which have later onset. The initial symptom in most infantile cases is abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), which can progressively worsen until the liver and spleen become massive. Significant accumulation of fluid in the abdomen (ascites) can also occur. Yellowing of the skin and whites of the eyes (jaundice) may occur during the newborn period. Additional symptoms during infancy include feeding problems, constipation, nausea, vomiting, significant gastrointestinal reflux, irritability, loss of reflexes, and progressive loss of muscle tone (hypotonia). Feeding difficulties and other abnormalities (e.g. frequent vomiting) can result in failure to thrive. The accumulation of sphingomyelin in the lungs can result in recurrent respiratory infections and difficulty breathing, potentially resulting in life-threatening respiratory failure.
Most infants develop a condition known as cherry red spots in the eyes. A cherry red spot affects the macula, which is the region of the retina that contains light-sensing cells necessary for central vision. It is normally yellow. A cherry red spot is not always present in affected individuals.
The attainment of developmental milestones and overall development may be normal in the first several months. However, often by 9 to 12 months of age, development plateaus and affected infants lose previously acquired motor skills. Affected infants may experience profound neurologic deterioration and increased muscle tone and stiffness of muscles (spasticity), and the disorder is often fatal by 3 years of age.
NIEMANN-PICK DISEASE TYPE B
Individuals with later onset forms of ASMD can develop symptoms from infancy to adulthood. Sometimes, these forms are collectively referred to as Niemann-Pick disease type B; they are, generally, milder than Niemann-Pick disease type A (infantile form). Individuals with mild forms can live until late adulthood and some may go undiagnosed until well into adulthood. Niemann-Pick disease type B is associated with systemic disease that can vary widely in severity and extent.
Hepatosplenomegaly is a common initial symptom and can range from mild to massive enlargement. Progressive enlargement of the spleen can cause low levels of white blood cells and platelets. White blood cells help to fight infection and a reduced number of these cells can leave an affected individual susceptible to infection. Platelets are specialized blood cells that allow the body to form clots to stop bleeding. A reduced number of platelets, known as thrombocytopenia, can lead to episodes of prolonged bleeding. Abdominal pain can result from enlargement of the liver and spleen. An enlarged spleen is at risk of rupturing, potentially resulting in life threatening bleeding into the abdominal cavity.
Some degree of liver disease is present in most individuals with type B disease. The majority have abnormal liver blood tests and some scarring in the liver. The scarring can range from mild without symptoms, to severe cirrhosis and liver failure.
Some affected individuals experience a gradual deterioration in lung function. For some individuals, lung involvement may be mild with no noticeable symptoms. Some individuals may develop difficulty breathing upon exertion (dyspnea). Other individuals may experience continued deterioration in breathing (respiratory) function with severe limitations in activity levels and oxygen dependence. Recurrent pneumonia may occur.
Individuals with late-infantile or later onset of ASMD usually do not develop neurological symptoms, but may develop mild symptoms, or, in rare cases, may develop clinically significant neurological symptoms. Some affected children and adolescents may develop rapid, involuntary eye movements (nystagmus) and cerebellar signs, which includes unsteady manner of walking and clumsiness. Intellectual disability and psychiatric disorders have also been reported. Abnormalities of the retina, the nerve-rich membrane lining the back of the eyes, and peripheral neuropathy may occur. Peripheral neuropathy is a general term for any disease affecting the nerves outside the central nervous system. Common symptoms include the loss of sensation or abnormal sensations such as tingling, burning, or pricking along the affected nerves.
Most affected children experience growth delays and low weight, although most eventually reach a near normal adult height. Delayed puberty and skeletal maturation may also occur.
Most individuals have osteopenia (thinning of the bones). Limb and bone pain have been reported.
A common finding in affected individuals is abnormal levels of lipids in the blood serum (dyslipidemia), specifically low levels of high-density lipoprotein (HDL-cholesterol, aka “good cholesterol”), high serum concentrations of low-density lipoprotein-cholesterol (LDL-C) and high triglyceride levels (hypertriglyceridemia). Affected individuals may be at risk for early coronary artery disease.
Acid sphingomyelinase deficiency is caused by disease-causing variants in the sphingomyelin phophodiesterase-1 (SMPD1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When someone has disease-causing variants of a gene, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.
The SMPD1 gene creates (encodes) an enzyme known as acid sphingomyelinase (ASM). The disease-causing variants of this gene lead to deficient levels of functional copies of the ASM enzyme. This enzyme is essential to break down (metabolize) certain fatty substances (lipids) in the body. Reduced or absent activity of the ASM enzyme results in the abnormal accumulation of sphingomyelin in various tissues of the body. Sphingomyelin is a fatty substance that is a component of most cell membranes. The abnormal accumulation of sphingomyelin within certain tissues of the body causes the signs and symptoms of acid sphingomyelinase deficiency.
ASMD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
ASMD affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown but has been estimated at 1 in 250,000 individuals in the general population. However, because some cases go misdiagnosed or undiagnosed, determining the true frequency of ASMD in the general population is difficult. The severe, infantile form (Niemann-Pick type A) can affect different ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. Later-onset forms (Niemann-Pick type B) can affect all ethnic groups.
A diagnosis of ASMD is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Individuals suspected of ASMD can be tested to determine whether the activity of the enzyme, ASM, is reduced or absent. Peripheral blood leukocytes or cultured skin fibroblasts are examined to assess residual ASM activity. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. A diagnosis is confirmed when the ASM activity is less than 10% of a control sample.
The diagnosis of ASMD can also be made with genetic testing identifying variants in the SMPD1 gene. SMPD1 molecular genetic testing is increasingly the preferred test for ASMD but testing that shows a low acid sphingomyelinase enzyme activity is required to confirm the diagnosis.
The treatment of ASMD may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hepatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment. Psychosocial support for the entire family is essential as well.
Genetic counseling is recommended for affected individuals and their families.
There is still no cure but, in 2022, olipudase alfa (Xenpozyme) became the first FDA-approved enzyme replacement therapy (ERT) for ASMD, addressing non-central nervous system (CNS) symptoms. Olipudase replaces the missing enzyme, acid sphingomyelinase, with a genetically engineered (recombinant) form and helps reduce sphingomyelin accumulation in the liver, spleen, and lung. It improves hepatosplenomegaly (reduces the size of the liver and the spleen) and lung function and raises platelet counts, which result in less bleeding episodes. It also improves growth in children.Olipudase is not expected to cross the blood-brain barrier or to impact any CNS manifestations of ASMD. Families of people with neuronopathic ASMD should be counseled on the limitations of olipudase alfa, particularly its inability to prevent or treat neurologic involvement. Alternatives, such as palliative care and supportive management, should be part of these discussions.
Therapy is recommended for all people who have severe systemic manifestations of ASMD, with treatment decisions individualized based on clinical evaluation.
Regular evaluations should track liver and spleen volume, lung function, lipid profiles, hematological markers, and disease biomarkers. In children, growth monitoring is also essential.
Recommendations for Niemann-Pick type A may include:
Recommendations for Niemann-Pick type B:
Published guidelines for ASMD management emphasize structured monitoring and preventive care, targeting both systemic and specific complications. These recommendations aim to standardize care across all age groups and healthcare settings.
Other general recommendations include:
All at-risk family members should undergo diagnostic testing for SMPD1 pathogenic variants if a case of ASMD is identified. Early diagnosis allows for proactive monitoring and intervention. Families should work with specialist centers to develop holistic, individualized management plans, ensuring a designated point of contact throughout the person’s care journey.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
JOURNAL ARTICLES
Geberhiwot T, Wasserstein M, Wanninayake S, et al. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B). Orphanet J Rare Dis. 2023;18(1):85. Published 2023 Apr 17. doi:10.1186/s13023-023-02686-6
Wasserstein MP, Jones SA, Soran H, et al. Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab. 2015; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/26049896
Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin Endocrinol Metab. 2015;29:237-247. https://www.ncbi.nlm.nih.gov/pubmed/25987176
McGovern MM, Wasserstein MP, Kirmse B, et al. Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann-Pick disease type B (acid sphingomyelinase deficiency). Genet Med. 2015; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/25834946
Lidove O, Sedel F, Charlotte F, Froissart R, Vanier MT. Cirrhosis and liver failure: expanding phenotype of acid sphingomyelinase-deficient Niemann-Pick disease in adulthood. JIMD Rep. 2014;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/24718843
Irun P, Mallen M, Dominguez C, et al. Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B. Clin Genet. 2013;84:356-361. https://www.ncbi.nlm.nih.gov/pubmed/23252888
Zhang H, Wang Y, Gong Z, et al. Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease. Orphanet J Rare Dis. 2013;8:15. https://www.ncbi.nlm.nih.gov/pubmed/23356216
Wasserstein M, Godbold J, McGovern MM. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J Inherit Metab Dis. 2013;36:123-127. https://www.ncbi.nlm.nih.gov/pubmed/22718274
Aneja A, Sharma A, Dalal A, Sondhi V. R542X mutation in SMPD1 gene: genetically novel mutation with phenotypic features intermediate between type A and type B Niemann-Pick disease. BMJ Case Rep. 2012;2012. https://www.ncbi.nlm.nih.gov/pubmed/23188845
Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. Int J Clin Pharmacol Ther. 2009;47:S48-S57. https://www.ncbi.nlm.nih.gov/pubmed/20040312
INTERNET
Patel, JM. Sphingomyelinase Deficiency Treatment & Management: Medical Care, Surgical Care, Further Care. Medscape.com. July 12, 2024. https://emedicine.medscape.com/article/951564-treatment Accessed December 20, 2024.
Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. 2006 Dec 7 [Updated 2023 Apr 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1370/ Accessed December 20, 2024.
Patterson MC. Overview of Niemann-Pick Disease. UpToDate, Inc. Apr 20, 2018 [Updated 2024 Nov 20]. Available at: https://www.uptodate.com/contents/overview-of-niemann-pick-disease Accessed December 20, 2024.
Ierardi-Curto LA. Sphingomyelinase Deficiency. Medscape. Sep 10, 2018 [Updated 2024 July 12]. Available at: https://emedicine.medscape.com/article/951564-overview Accessed December 20, 2024.
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