What is Acid Sphingomyelinase Deficiency?
Acid sphingomyelinase deficiency (ASMD) is a genetic condition where the body does not produce enough of an enzyme called acid sphingomyelinase. The enzyme’s function is to break down a fatty substance within cells called sphingomyelin. When functional acid is insufficient, sphingomyelinase, an abnormal accumulation of sphingomyelin inside cells, eventually damages or kills the cells. The disorder affects various parts of the body, most often the liver, spleen, lungs, and brain.
Historically, Niemann-Pick disease has been classified into three different types, types A, B, and C. However, scientists have recently concluded that types A and B have separate causes and effects than type C and therefore consider them distinct disorders. Therefore, types A and B are often called ASMD.
Niemann-Pick disease Type A (NPD-A) begins in infancy and typically affects the brain and lungs, resulting in severe complications that are usually fatal by early childhood. Niemann-Pick disease Type B (NPD-B) begins later. Its symptoms are typically less severe, and children with NPD-B often survive into adulthood. In general, NPD-B is not considered to be a neurological disorder.
Symptoms of NPD-A
Common symptoms of NPD-A include:
- Enlarged liver and/or spleen
- A distinctive red spot on the retina inside the eye
- Accumulation of fluid in the abdomen
- Feeding difficulties
- Acid reflux
- Loss of reflexes
- Weak muscle tone
- Slow growth
- Developmental delays and loss of skills already acquired. Infants with NPD-A may develop normally for their first few months before skill loss begins.
What Causes Acid Sphingomyelinase Deficiency?
ASMD is caused by abnormal changes (mutations) in a gene called the SMPD1 gene. This gene carries instructions for the enzyme acid sphingomyelinase, which is responsible for the normal breakdown of a fatty substance called sphingomyelin inside cell structures called lysosomes. The mutations impair enzyme production and, consequently, sphingomyelin accumulates inside cells, leading to cell damage and cell death.
In NPD-A, gene mutations cause a complete absence of acid sphingomyelinase. In NPD-B, some acid sphingomyelinase is produced, but not in sufficient quantities.
Is Acid Sphingomyelinase Deficiency Hereditary?
ASMD is an inherited disorder. The disorder-causing gene mutations are inherited in an autosomal recessive pattern. This means that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop ASMD but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with ASMD with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.
NPD-A is especially prevalent among people with Ashkenazi Jewish ancestry.
How Is Acid Sphingomyelinase Deficiency Detected?
Early intervention may be able to slow or prevent some complications of ASMD that can be life-threatening. For example, in some states, tests to detect NPD-A and NPD-B are part of the routine screening given to all newborns.
How Is Acid Sphingomyelinase Deficiency Diagnosed?
A doctor may suspect ASMD if a patient presents multiple symptoms such as liver disease, enlarged spleen, and neurological symptoms. The diagnostic process may include:
- Physical exams
- Neurological exams
- Blood tests and/or skin biopsies to measure the levels of acid sphingomyelinase inside cells
- Magnetic resonance imaging (MRI) to look for brain damage characteristic of ASMD. This exam may be normal in the early stages of the disorder.
- Eye exams to look for the cherry-red spot on the retina characteristic of NPD-A
- Genetic testing to look for the gene mutations that cause ASMD
PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.
How Is Acid Sphingomyelinase Deficiency Treated?
ASMD has no cure. Treatment options aim to prevent complications and improve quality of life. Common treatments for NPD-A include:
- Feeding assistance, including a feeding tube
- Sedatives for sleep disruptions
- Monitoring for complications such as liver or lung disease
- Physical therapy
- Occupational therapy
Treatments for NPD-B may include:
- Nutritional guidance and supplements
- Supplemental oxygen if lung disease develops
- Blood transfusions if the patient develops low blood platelet counts
- Monitoring for conditions such as liver disease or abnormal cholesterol levels
How Does Acid Sphingomyelinase Deficiency Progress?
Babies with NPD-A typically develop liver and spleen enlargement within the first few months after birth, and they usually fail to grow at an average rate. Later progressive symptoms include:
- Loss of motor and intellectual skills
- Lung damage
- Recurrent lung infections
- Fatal respiratory failure
People with NPD-B may experience long-term complications such as:
- Enlarged liver and/or spleen
- Lung infections
- Abnormally low level of platelets, blood cells responsible for clotting when a blood vessel is damaged
- Impaired bone development
- Slow growth and short stature
How Is Acid Sphingomyelinase Deficiency Prevented?
There is no known way to prevent ASMD when the disorder-causing gene mutations are present. Therefore, parents with a family history of the disorder or who have had another child with ASMD are advised to consult a genetic counselor to assess their risk if they plan to have another child.
Acid Sphingomyelinase Deficiency Caregiver Tips
Caregivers for children or adults who are experiencing symptoms of ASMD should keep these tips in mind:
- Learn as much as you can about the disorder. Then, work to understand how NPC affects your child or loved one so you can be the best possible caregiver.
- Find support from other NPC families. The National Niemann-Pick Disease Foundation provides resources for families living with the disorder, including connections to online support groups.
Acid Sphingomyelinase Deficiency Brain Science
The gene mutations associated with ASMD result in deficient levels of acid sphingomyelinase (ASM) in cells’ lysosomes and, consequently, elevated sphingomyelin levels, a fatty substance that ASM helps break down. Sphingomyelin is found in cell membranes, and it is particularly abundant in myelin, the fatty sheath that surrounds some nerve cells in the brain and central nervous system.
Some scientists believe that an abnormal level of sphingomyelin in brain cells may lead to a loss of myelin, a process called demyelination. Without myelin, the nerve cells are unable to communicate effectively with each other and eventually die. Research suggests that problems with sphingomyelin may be responsible for the neurological symptoms of ASMD and other demyelinating disorders such as multiple sclerosis.
Acid Sphingomyelinase Deficiency Research
Title: Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency (ASCEND)
The primary objective of this phase 2/3 study is to evaluate the efficacy of olipudase alfa (recombinant human acid sphingomyelinase) administered intravenously once every two weeks for 52 weeks in adult patients with acid sphingomyelinase deficiency (ASMD) by assessing changes in 1) spleen volume as measured by abdominal magnetic resonance imaging (MRI) (and, for the United States [US] only, in association with patient perception related to spleen volume as measured by splenomegaly related score [SRS]); and 2) infiltrative lung disease as measured by the pulmonary function test, diffusing capacity of the lung for carbon monoxide (DLCO).
- To confirm the safety of olipudase alfa administered intravenously once every two weeks for 52 weeks
- To characterize the effect of olipudase alfa on the patient perception related to spleen volume as measured by the SRS after 52 weeks of study drug administration. (For the US, the effect of olipudase alfa on the splenomegaly related score is part of the primary objective)
- To characterize the effect of olipudase alfa after 52 weeks of study drug administration on the following endpoints assessed sequentially:
- The effect of olipudase alfa on:
- liver volume
- platelet count
The total duration per patient is at least three years and up to 5 years and three months. This includes up to approximately two months of screening, 52 weeks of the primary analysis period, up to 4 years and three months of the extension treatment period, an end-of-study visit within two weeks of the last treatment, and a safety follow-up 30 to 37 days after the last treatment.
Title: Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
Stage: Has Results
Principal investigator: Paul Orchard, MD
University of Minnesota Medical Center
The primary objective of this clinical trial is to evaluate the ability to achieve and sustain donor engraftment in patients with lysosomal and peroxisomal inborn errors of metabolism undergoing hematopoietic stem cell transplantation (HCT).
This has been an ongoing area of interest by our group at the University of Minnesota, but this is a new protocol to take the place of several older protocols. While survival has been very good on the prior protocols over the past decade, incomplete engraftment has remained somewhat problematic. Therefore, we have modified the preparative regimen somewhat to increase engraftment by replacing anti-thymocyte globulin (ATG) with Campath-1H, a drug that is more immune suppressive. In addition, we have modified the supportive care regimen. Based on this, we will monitor antioxidant therapy (N-acetylcysteine) levels and biomarkers of inflammation and oxidative stress for the families that consent to these research studies.