Acid Sphingomyelinase Deficiency (ASMD): Causes, Symptoms, Complications, And Treatment

ASMD or ( mainly known as Niemann-Pick disease) also known as acid sphingomyelinase-deficient Niemann-Pick disease, can be described as a rare progressive genetic disorder that develops a deficiency of the enzyme acid sphingomyelinase in the body. The key function of acid sphingomyelinase is to digest the lipid called sphingomyelin which can be described as a fatty substance found in the animal cell membrane.

Niemann-Pick disease can be subcategorized into three types, A, B, and C. due to the identical signs and symptoms, these three types were grouped together, but as the scientists research the types more further, they realize that all the types are different and now they all known as separated conditions.

The root cause of the Niemann-Pick disease type A (NPD-A) and Niemann-Pick disease type B (NPD-B) is the mutation of the gene called SMPD1 gene. The key role of the SMPD1 gene is to design a blueprint making an enzyme called acid sphingomyelinase or lipase, which is produced in the lumen of lysosomes ( known as small compartments in the cell that digest and recycle molecules).

What makes type A and type B different is their impact on the brain cells of an individual. Type A is generally known as a neuronopathic one as it causes severe neurodegenerative conditions in the early stages of life. But on the other hand type B is the non-neuronopathic one as its mutation does not cause any damage to brain cells.

Since NPD type C does not involve a deficient enzyme in its nature due to mutations in one of two different genes, it is considered a separate disorder from NPD type A and NPD type B.

Since ASMD accumulates in various tissues of the body, it is very fluid in nature and can be different in each case. It has been seen that even amongst the members of the same family can have different variants of the same mutation. Type A can be a fatal neurodegenerative disorder that presents in infancy. On the contrary, Niemann-Pick disease type B is survivable and only reflects minimal neurological symptoms in an individual which can be seen throughout life.

The common cause of Acid Sphingomyelinase Deficiency is the mutation in the sphingomyelin phophodiesterase-1 (SMPD1) gene. The SMPD1 gene creates instructions to generate a protein that plays a critical role in the overall functioning of the body. Any mutation in the gene can cause imbalance or inefficiency in the production of the protein.

The SMPD1 gene encodes ASM (acid sphingomyelinase), its mutation can create a deficiency in the overall functional production of the ASM enzyme. The key role of the ASM enzyme is to break down lipids in the chromosome’s short arm, which is present in the nucleus of human cells.

The absence or diminished level of ASM enzyme leads to abnormal accumulation of sphingomyelin in various tissues of the body.

Since ASMD is a recessive genetic disease, the mutation of the gene which causes the disorder has to be inherited from the parents. Even though your parents don't have the default genetic trait, it can transfer from any of their family members.

The design of the genetic pattern of a human is a combination of genetics inherited by the parents, that is one from the father and one from the mother. Recessive genetic disorders such as ASMD developed only when a person received an SMPD1 mutated gene from both of the parents. The chances can vary from case to case, like:

• If one of the parents has a faulty gene and another has a normal copy of a gene, the offspring generally becomes the carrier with no effects of the default on the body.
• If both of your parents have faulty genes, there is a 25% chance that you have the genetic mutation.
• If one of the grandparents along with your parents has been a carrier of the faulty gene, there is a 50% chance that you might get affected.
• If any of the parents don't have any genetic mutation, and never have been a carrier of the mutation, there is a 25% chance that you might have it. It is quite rare but few cases have been detected.

Considering the fact that the nature of the ASMD is highly variable, its effect on each individual will be non-identical compared to each other, therefore symptoms mentioned below may or may not relate to your actual case. From a real stage of life-threatening complications to mild illness, these symptoms may vary in adults and children.

Severe symptoms may that can be seen in the case of Niemann-Pick disease type A is:

• Hepatosplenomegaly - Abnormal enlargement of the liver and/or spleen
• Ascites - Accumulation of fluid in the abdomen
• Jaundice- Yellowing of the skin and whites of the eyes ( mostly seen in newborns)
• Cherry red spots in the eyes
• Accumulation of sphingomyelin in the lungs
• Feeding Problems
• Frequent Vomiting
• Significant Gastrointestinal Reflux
• Constipation
• Nausea
• Progressive Loss Of Muscle Tone (Hypotonia)
• Irritability
• Loss Of Reflexes

These symptoms in an infant can further create more complications, like frequent vomiting, Constipation, and Feeding difficulties will eventually lead to failure to thrive ( FTT) or accumulation of sphingomyelin in the lungs can lead to potential respiratory infections, breathing difficulties, and lung collapse.

Other than the physical symptoms, the overall psychological and neurological progress of an infant also hampers. It will be difficult for the child by 9 to 12 months of age to achieve the general milestones. They lose control of their motor skills which they acquired before and may experience profound neurologic deterioration followed by stiffness of muscles (spasticity) and increased muscle tone.

Severe symptoms may that can be seen in the case of Niemann-pick Disease Type B are:

• Hepatosplenomegaly
• Progressive enlargement of the spleen can cause thrombocytopenia
• Abdominal pain
• Some degree of liver disease ( very from mild to serious medical illness like frank cirrhosis and liver failure)
• Deterioration in lung function
• Dyspnea - Difficulty breathing upon exertion
• Early coronary artery disease
• Recurrent pneumonia
• Osteopenia - Thinning and weakening of the bones
• Limb and bone pain

Along with the physical symptoms, neurological and psychological abnormalities may include:

• Nystagmus - involuntary eye movements
• Unknown cerebellar signs like unsteady manner of walking and clumsiness
• Peripheral neuropathy ( may include loss of sensation or addition of abnormal sensations like burning, tingling, or pricking along the affected nerves)

Other common symptoms may include:

• Growth delays
• Low body mass index
• Skeletal maturation
• Dyslipidemia - abnormal levels of lipids in the blood serum
• low levels of high-density lipoprotein ( commonly known as HDL-cholesterol or good cholesterol)
• High serum concentrations of low-density lipoprotein-cholesterol (LDL-C)
• Hypertriglyceridemia - High triglyceride levels

Since type B ASMD develops symptoms from infancy to adulthood, the probability of these symptoms being diagnosed in the early stages of life is diminishing. The symptoms of type B of ASMD may also include symptoms of type A but in a less effective manner.

Other than type A and B some cases show related illnesses that may replicate Type C or do not replicate any of the cases at all. These symptoms may include:

• Several types of metabolic disorders like mucopolysaccharidoses and other lysosomal storage disorders
• Galactosemia
• Sialidosis
• Gaucher disease
• Galactosialidosis
• Wolman disease
• Cholesteryl ester storage deficiency

The medical condition does not discriminate between its effects in males and females, which makes it more prone to mutate. Even though the main tale of the disorder is still unknown, researchers were successful in looking for some shreds of the genetic mutation in different ethnic groups like Ashkenazi Jewish descent ( both type A and Type B ).

Furthermore, the frequency rate of ASMD is still unknown due to its complex genetic mutations, Acid Sphingomyelinase Deficiency generally gets misdiagnosed or undiagnosed. However, the frequency rate of the cases that have been successfully diagnosed can be estimated at 1 in 2,50,000 individuals around the globe.

Depending upon your medical history and combination of symptoms your medical healthcare professional will prescribe the accurate series of testing that need to be required to identify the root cause of the symptoms. Some of the elements that are commonly diagnosed in this case are:

• ASM enzyme activity
• Peripheral blood leukocytes (white blood cells)
• Cultured skin fibroblasts ( connective tissue cells of the skin)

If the diagnosis of the above shows less than 10% results, in that case only your doctor will further move the diagnosis with the molecular genetic testing. This test actually confirms the presence of ASMD as it detects mutations in the SMPD1 gene. molecular genetic testing needs specialized laboratories and settings, which may be hard to locate.

After the diagnosis, your doctor will coordinate with a team of specialists to deal with every associated symptom. This team may include neurologists, pediatricians, hepatologists, ophthalmologists, genetic counselors, and other healthcare professionals that will design a systematic and comprehensive plan for the patient. This team will also include a psychiatrist or a general counselor to ensure overall mental health by providing psychosocial support for the patient and their family.

Current methods of treatment are designed as per the symptoms reflected by the patient.

Treatment for Niemann-Pick type A may include:

• Physical and occupational therapy
• Periodic nutritional assessment
• Gastronomy - Implantation of a feeding tube ( to ensure proper nutritional intake)
• Nocturnal sedatives - To cure sleep-associated disorders

Treatment for Niemann-Pick type B may include:

• Dyslipidemia and hyperlipidemia treatment
• Osteopenia treatment
• Nutritional support
• Blood transfusions ( for thrombocytopenia )
• Supplemental oxygen ( in case of serious lung disease )
• Liver transplantation ( in case of liver failure )

Since the presence of sphingomyelin in the human body is in abundance, Acid Sphingomyelinase Deficiency can make an individual body fragile and more vulnerable to fatal damage.

For infants, it is important to keep track of their nutritional value and hygiene. Keep a close eye on any new symptoms as they can damage the internal body at a fast pace.

Physical activity for both adults and infants is restricted, they are advised to avoid contact sports to prevent any internal damage, especially spleen rupture in adults.

Maintain social distancing, and keeping oneself covered with personal protective gear may save the person from external bacteria and viruses entering the body.

Summary: ASMD or acid sphingomyelinase-deficient Niemann-Pick disease, is a rare progressive genetic disorder that develops a deficiency of the enzyme acid sphingomyelinase in the body. Caused by the sphingomyelin phosphodiesterase-1 (SMPD1) gene, depending upon the type the symptoms can be mild or life-threatening.