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Last updated: 09/01/2022
Years published: 2016, 2019
NORD gratefully acknowledges 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 Childrenโs 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 mutations in the SMPD1 gene and is inherited in an autosomal recessive manner.
Introduction
There are three disorders known as Niemann-Pick disease, types A, B, and C. These disorders were initially grouped together because similar symptoms, but we now know that they are different diseases. NPD types A and B are due to mutations in the SMPD1 gene, which causes a deficiency of a specific enzyme, acid sphingomyelinase (ASM). NPD type C is due to mutations 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 โ 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 childโs 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 platelets and white blood cells. 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 frank 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, or thinning of the bones. (Wasserstein et al, JIMD, 2013). 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 โgood cholesterolโ), high serum concentrations of low density lipoprotein-cholesterol (LDL-C) and high triglyceride levels (hypertriglyceridemia). Affected individuals may be at risk early coronary artery disease.
Acid sphingomyelinase deficiency is caused by a mutation 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 a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The SMPD1 gene is located on the short arm (p) of chromosome 11 (11p15.4). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated โpโ and a long arm designated โqโ.
The SMPD1 gene creates (encodes) an enzyme known as acid sphingomyelinase (ASM). A mutation in this gene leads 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 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 a genetic disease, which means that it is inherited from the parents and might be present in other family members. In general, human beings receive two copies of most genes, one inherited from the mother, and one from the father. Recessive genetic disorders such as ASMD occur when an individual inherits changes, or mutations, in both copies of a particular gene (in this case, the SMPD1 gene.). If an individual receives one normal copy of a gene and one altered copy, 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 defective copy of the gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal copies of the gene from both parents and be neither affected nor a carrier for that particular trait 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.
Clinical Testing and Workup
Individuals suspected of ASMD will 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. A diagnosis is confirmed when a suspected sample demonstrates less than 10% that of a control sample. 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.
Molecular genetic testing can confirm a diagnosis of ASMD. Molecular genetic testing can detect mutations in the SMPD1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
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 childโs treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.
Current therapies are directed toward the specific symptoms that are apparent in each individual. In Niemann-Pick type A, physical and occupational therapy and periodic nutritional assessment may be recommended. Ensuring proper nutritional intake may require the implantation of a feeding (gastronomy) tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for direct intake of food and/or medicine. The sleep issues associated with the disorder can be treated with nocturnal sedatives.
Treatment for dyslipidemia may be required in some adults with type B disease. Nutritional support is also encouraged for individuals with type B disease to guide sufficient high quality caloric intake, ensure proper calcium and vitamin D intake because of the risk of osteopenia, and reduce the risk of dyslipidemia in adults. Blood transfusions may be required for individuals with Niemann-Pick type B who experience prolonged bleeding due to thrombocytopenia. Individuals with lung disease may require supplemental oxygen. Individuals with an enlarged spleen are advised to avoid contact sports to prevent the spleen from rupturing. Adults with hyperlipidemia should be treatment to correct cholesterol levels. Liver transplantation has been reported in some adults with liver failure due to Niemann-Pick B.
In 2022, Olipudase alfa (Xenpozyme) was approved by the U.S Food and Drug Administration (FDA) to treat pediatric and adult patients with ASMD. This is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. Olipudase is an enzyme replacement therapy (ERT) that replaces the missing enzyme, acid sphingomyelinase, with a genetically engineered (recombinant) form and helps reduce sphingomyelin accumulation in the liver, spleen and lung.
Gene therapy is also being studied as another approach to therapy for individuals with lysosomal storage diseases like ASMD. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy may theoretically lead to a โcure.โ However, at this time, there remain technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
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.
TEXTBOOKS
Vanier MT. Niemann-Pick Diseases. In: Handbook of Clinical Neurology. Dulac O, Lassonde M, Sarnat HB, eds. 2013 Elsevier, Cambridge, MA. pp. 795-802
JOURNAL ARTICLES
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
Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. 2006 Dec 7 [Updated 2015 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1370/ Accessed January 8, 2019.
Patterson MC. Overview of Niemann-Pick Disease. UpToDate, Inc. Apr 20, 2018.. Available at: https://www.uptodate.com/contents/overview-of-niemann-pick-disease Accessed January 8, 2019.
Ierardi-Curto LA. Sphingomyelinase Deficiency. Medscape. Sep 10, 2018. Available at: https://emedicine.medscape.com/article/951564-overview Accessed January 8, 2019.
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