About sphingomyelinase deficiency

What is sphingomyelinase deficiency?

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells.

The division of Niemann Pick disease into groups A, B, C and D was proposed by Allan Crocker in 1961 after he and Sidney Farber had expanded the category of Niemann-Pick disease by applying the diagnosis to all patients with "foam cells" and lipid storage in the tissues. This had led to the inclusion of older and less severely affected people than those originally described by Niemann and Pick.

Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits.

What are the symptoms for sphingomyelinase deficiency?

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 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 “good cholesterol”), 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.

What are the causes for sphingomyelinase deficiency?

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 “p” and a long arm designated “q”.

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.

What are the treatments for sphingomyelinase deficiency?

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 an affect child’s 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.

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