Introduction
Sphingomyelinase deficiency, also called Niemann-Pick disease, is a rare congenital lipid storage disorder. It is a serious medical condition that results in cognitive impairments interfering with the development of the child and is most often a fatal one. It affects several body parts due to abnormal or defective lipid metabolism resulting in fat deposition in various vital organs and tissues, including the brain and bone marrow.
The main reason for this disease is the deficiency of the enzyme sphingomyelinase, which plays a significant role in the lipid metabolism of the body. Sphingomyelinase deficiency is classified into four major variants depending on the severity, type A, B, C, and E.
How Are Sphingomyelinase Deficiencies Classified?
Sphingomyelinase deficiencies are classified into four major types depending on the disease severity.
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Type A: Type A sphingomyelinase deficiency is also known as infantile neurovisceral disease. It is characterized by very low levels of the enzyme sphingomyelinase and is considered the most severe variant. As it is fatal, the maximum life expectancy is three years.
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Type B: It is less severe compared to type A, with minimal disease symptoms and neurological problems.
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Type C: Type C sphingomyelinase deficiency is seen in adults.
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Type E: It is the least common variant commonly encountered during adulthood.
What Is the Incidence of This Disease?
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Niemann-Pick disease is a rare disorder commonly affecting children.
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Type A and B are the most common variants, with an incidence of 1 in 250,000 births.
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The highest prevalence rate is seen in the Ashkenazi Jewish population, with an incidence of 1 in 40,000 births.
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Type C is commonly seen in the french Acadian populations in Nova Scotia, with an incidence of 1 in 150,000.
What Is the Inheritance Pattern of This Disease?
Sphingomyelinase deficiency disorder has an autosomal recessive pattern of inheritance. There should be two copies of mutated genes in autosomal recessive conditions to cause the defect. So if either of the parents has a mutated gene (carriers of the disease), they can pass on the defect to their children. So the probability is as follows:
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A 25 % chance of having a healthy baby.
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50 % chance of having an unaffected child with one defective gene serving as a disease carrier.
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25 % chance for a child to have a genetic defect.
What Is the Cause of Sphingomyelinase Deficiency?
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Niemann-Pick disease types A and B are caused primarily due to the mutation of the gene sphingomyelin phosphodiesterase 1 (SMPD1). It results in decreased activity of the enzyme acid sphingomyelinase (the enzyme seen in the lysosomes).
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The cell organelles produce lysosomes, where the sphingomyelin is converted to ceramide and phosphocholine. But in the case of Niemann Pick disease, due to the deficiency of the enzyme sphingomyelinase, there is no conversion of sphingomyelin resulting in the accumulation of lipids in the lysosomes itself and causing cellular damage in the vital organs like the brain, lungs, spleen, liver, etc.
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Type C is further sub-classified as C1 and C2. Any mutations in the NPC1 and NPC2 genes are responsible for type C sphingomyelinase deficiency.
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The NPC1 and NPC2 proteins present in the lysosomes and endosomes are involved in the intracellular transportation of cholesterol and sterols. So defective proteins of NPC1 and NPC2 may obstruct cholesterol mobilization, resulting in the accumulation of lipids in the lysosomes.
What Are the Signs and Symptoms?
The symptoms of type A are evident within a few months of life. The most common presentations seen in sphingomyelinase deficiency are:
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Enlargement of the spleen and liver.
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Growth retardation and delay in the development of milestones.
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Elevated cholesterol levels.
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Decreased bone growth and mineralization.
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Mental retardation.
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Difficulty in walking.
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Jaundice due to impaired liver functions.
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Tremors.
Symptoms of Type A:
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Hepatomegaly and splenomegaly.
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Growth retardation.
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Neurological disorders.
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Decreased muscle tone.
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Feeding difficulties in children.
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Failure to thrive.
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Recurrent respiratory infections.
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The feature specific to type A disease is the presence of cherry-red spots in the eye.
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These affected children die before they complete two to three years of age.
Symptoms of Type B:
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Enlargement of the spleen and liver.
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Mild pulmonary problems. Pneumonia is seen in rare cases.
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Cirrhosis and ascites (liver disease and fluid accumulation in the abdomen).
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Lipid levels are seen elevated in the blood.
Symptoms of Type C:
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The symptoms appear around five years of age.
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Ataxia (a condition that affects coordination, balance, and speech).
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Dysphagia (difficulty in swallowing).
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Severe lung and liver diseases.
Symptoms of Type E:
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The symptoms are often encountered in adults.
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There is swelling of the spleen, brain, and other tissues of the brain.
What Are the Possible Complications?
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Hepatic failure.
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Respiratory dysfunction.
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Heart diseases.
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Bleeding due to decreased platelet count in the body.
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Coxa vara (a rare hip deformity).
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Seizures and other psychotic disorders.
What Are the Other Similar Conditions?
Certain disorders may show similar signs and symptoms that mimic the sphingomyelinase deficiency disorder, such as:
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Gaucher Disease: It is also a lysosomal storage disorder that results in the accumulation of lipids in the body tissues.
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Tay-Sachs Disease: It is a neurodegenerative disorder occurring due to an enzyme deficiency resulting in abnormal fat metabolism.
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Metachromatic Leukodystrophy: Another rare disorder due to impaired fat metabolism resulting in the deposition of sulfatides in the body cells.
How to Diagnose Sphingomyelinase Deficiency?
Niemann-Pick disease is usually diagnosed from laboratory findings. Although common signs such as growth retardation and enlargement of the spleen may be visible, special tests may be required to confirm the diagnosis of the disease.
A blood investigation is mandatory for the diagnosis of types A and B.
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Blood Picture: Blood investigation is mandatory for measuring the activity of the enzyme acid sphingomyelinase. In sphingomyelinase deficiency disorder, elevated levels of acid sphingomyelinase are seen in the leukocytes. If the levels are low, then genetic testing may be required.
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Skin Biopsy: A skin biopsy is done to diagnose type C. It measures the acid sphingomyelinase activity. Furthermore, DNA testing can also be done.
Other diagnostics procedures are:
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Liver Biopsy or Elastography: This test is done to check for the presence of liver fibrosis and indicates severe liver disease.
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Complete Blood Picture: This test is performed to measure the platelet count and the volume of the spleen.
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Lipid Profile: Blood investigation that measures the abnormalities in the lipids and the value of high-density and low-density lipoproteins.
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Eye Examination: Fundoscopy of the eye is performed to assess the presence of cherry-red spots.
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High-Resolution Computed Tomography of the Lungs (HRCT): The presence of any lung disease or interstitial lung disorder is ruled out from the CT imaging.
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Magnetic Resonance Imaging of the Brain: It shows the loss of brain cells which is evident in the final stages of the disease condition.
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Genetic Testing: The genetic material (DNA) present in the blood is obtained to rule out the abnormalities in the gene that causes Niemann-Pick disease. It also shows the carrier state if the defective gene is present in the child.
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Prenatal Ultrasounds: Enlarged spleen and liver may be evident during the ultrasounds performed in routine prenatal assessments. Although they do not confirm the diagnosis of this disease, they help to assess the medical condition of the baby.
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Amniocentesis and Chorionic Villi Sampling: This procedure may be performed to rule out the presence of sphingomyelinase deficiency. The amniotic fluid and a portion of the placental cells are removed and examined for any genetic abnormalities.
How Are They Treated?
There is no definite treatment modality or cure for Niemann-Pick disease. Therefore, supportive therapy and palliative treatment are rendered for survival.
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Medications such as Statins are given to maintain the lipid profile.
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A blood transfusion may be necessary if there is bleeding due to platelet deficiency. This is because it improves the platelet count.
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Oxygen therapy is indicated in patients with interstitial lung disease (ILD). In some cases, organ transplant is also done, but it has a low success rate.
What Is the Prognosis?
The prognosis depends on the type of disease. Type B has a better prognosis compared to type A. They survive till adulthood with several health complications and compromised quality of life.
Conclusion
Like any other genetic condition, Niemann-Pick disease is a fatal and unpreventable condition with neither a specific treatment nor a cure. Supportive treatment is the only option that can be offered to improve the life expectancy of the affected children. The healthcare team provides parents counseling to support their children with this disease. Although it is unpreventable, genetic tests are conducted with a positive family history. It can help to identify the genetic disorder's presence and preventive measures early. Pregnant women are advised to have regular prenatal checkups as the ultrasounds and prenatal tests allow us to identify several health conditions in the baby.
