Niemann-Pick disease and genetics
Niemann-Pick disease is a group of inherited metabolic disorders characterized by the accumulation of fatty substances in various organs, including the liver, spleen, and sometimes the brain. There are four main types of the disease, each with distinct symptoms and prognoses. Type A typically leads to severe brain damage and early mortality, while Type B causes organ enlargement without brain damage and a better prognosis. Types C1 and C2 are associated with significant neurological decline, with symptoms appearing in childhood or adolescence.
The disease is primarily caused by genetic mutations affecting the SMPD1, NPC1, and NPC2 genes, which play crucial roles in lipid metabolism. Inheritance patterns vary among types, with Types A and B following a unique genomic imprinting mechanism, while Types C are inherited in an autosomal recessive manner. Risk factors include having a family history of Niemann-Pick disease, with certain populations, such as those of Ashkenazi Jewish and North African descent, being more susceptible.
Symptoms generally worsen over time and may include jaundice, enlarged organs, and neurological issues such as difficulty walking or seizures. While there is currently no cure, treatment focuses on managing symptoms and supportive care, with ongoing research into potential therapies like bone marrow transplantation and gene therapy. Families affected by the disease are encouraged to seek genetic counseling for informed family planning.
Niemann-Pick disease and genetics
DEFINITIONNiemann-Pick disease refers to a group of inherited conditions that affect the body’s metabolism. In patients with this rare disorder, fatty material builds up in various vital organs, sometimes including the brain.
There are four main types of Niemann-Pick disease. Type A causes fatty substances to collect in the liver and spleen. Patients have severe brain damage and usually die by age two or three. Type B affects the liver and spleen; these organs enlarge during the preteen years. There is usually no brain damage. Patients usually suffer from breathing problems and die in their teen years or in early adulthood. The prognosis is better for type B than type A. Type C1 produces extensive brain damage. The liver and spleen are moderately enlarged. Type C1 usually starts in childhood and leads to death in the teen years or in early adulthood. Type C2, formerly called Niemann-Pick disease type D, is now recognized as a variation of type C1.
Risk Factors
Individuals who have family members with Niemann-Pick disease are at risk for the condition. Other individuals at risk are those of Ashkenazi Jewish heritage, who have an increased chance of having types A and B. According to 2023 statistics from Niemann-Pick Disease, the incidence of type A within the Ashkenazi population is about 1 in 40,000, while the estimated incidence of types A and B in all other populations is 1 in 250,000 and the estimated incidence of type C is 1 in 150,000. People of Nova Scotian and French Canadian ancestry are at risk for type C, as is the Spanish American population of southern New Mexico and Colorado. Individuals of North African ancestry, who come from the Maghreb region, including Tunisia, Morocco, and Algeria, are at risk for type B.
Etiology and Genetics
Niemann-Pick disease types A and B result from mutations in the SMPD1 gene, which is found on the short arm of chromosome 11 at position 11p15.4–p15.1. This gene encodes a protein known as sphingomyelin phosphodiesterase 1, acid lysosomal, or more simply acid sphingomyelinase. Found in the lysosomes (cellular organelles that digest and recycle molecules), this catalyzes the conversion of sphingomyelin into ceramide (two different lipid molecules). This lipid conversion is essential for normal cell function, since its absence results in the accumulation of sphingomyelin, cholesterol, and other lipids to toxic levels. Those gene mutations that result in a totally inactive enzyme generally cause the more severe form of the disease, type A, whereas mutations that allow the altered protein to retain some small fraction of normal activity are generally associated with the milder type B disease.
Inheritance of Niemann-Pick disease types A and B is quite unusual and follows a pattern known as genomic imprinting. Only the gene inherited from the mother is active; the paternal copy is permanently inactivated. Therefore the child will be healthy or affected depending upon whether the maternal gene copy is normal or mutated.
Type C1 disease is caused by mutations in the NPC1 gene (at position 18q11.2), while type C2 disease results from mutations in the NPC2 gene, located on the long arm of chromosome 14 (at position 14q24.3). Approximately 95 percent of individuals with type C disease have mutations in the NPC1 gene, which encodes a protein found in the membranes of lysosomes. It functions to facilitate the movement of cholesterol across membranes, and its absence as a result of a mutation in the NPC1 gene results in the abnormal accumulation of cholesterol and other lipids. The remaining 5 percent of type C patients have mutations in NPC2, which specifies yet another lysosomal protein that is involved with the of cholesterol and other lipids.
Niemann-Pick type C disease is inherited in a classic autosomal recessive pattern, which means that both copies of the NPC1 or NPC2 gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected.
Symptoms
Symptoms of Niemann-Pick disease may develop during infancy, childhood, or the teen years, depending on the type of the disease. Symptoms vary. Not all patients will develop every symptom. Symptoms usually worsen over time.
Symptoms of type A begin within the first few months of life. They may include yellow skin and eye coloration, an enlarged belly (due to enlarged liver and spleen), intellectual disability, loss of motor skills, difficulty swallowing and feeding, failure to thrive, seizures, visual problems, spastic movements (later in the disease), and rigid muscles (later in the disease).
Type B symptoms start during the preteen years. They may include yellow skin and eye coloration, an enlarged belly (due to enlarged liver and spleen), enlarged lymph nodes, osteoporosis or brittle bones, breathing difficulties, and frequent respiratory infections.
Symptoms of types C may start in infancy, childhood, or the teen years. They may include yellow skin and eye coloration, an unsteady gait, trouble walking, difficulty swallowing, the inability to look up or down, vision loss, hearing loss, and slurred speech. Other symptoms may include enlarged spleen and liver, loss of motor skills, difficulty swallowing, learning problems, a sudden loss of muscle tone, tremors, seizures, and psychosis or dementia.
Screening and Diagnosis
The doctor will ask about a child’s symptoms and medical history and will perform a physical exam. Tests for all types of Niemann-Pick disease may include a complete blood cell count (CBC), the measurement of acid sphingomyelinase activity in white blood cells, and deoxyribonucleic acid (DNA) testing to look for a mutated gene associated with the disease.
A skin biopsy, the removal of a skin sample to check how it transports and stores cholesterol, may be used to test for type C.
Treatment and Therapy
No specific or effective treatment currently exists for Niemann-Pick disease. Patients with type B may be given oxygen to help with lung problems. Research is focusing on the use of bone marrow transplantation, enzyme replacement therapy, and gene therapy.
Prevention and Outcomes
There are no specific guidelines for preventing Niemann-Pick disease. Prevention measures are currently available in the areas of genetic testing and prenatal diagnosis. Individuals who have Niemann-Pick disease or have a family history of the disorder can talk to a genetic counselor when deciding to have children.
Bibliography
Bajwa, Hamza, and Waqas Azhar. Niemann-Pick Disease. StatPearls, National Library of Medicine, 6 Mar. 2023, www.ncbi.nlm.nih.gov/books/NBK556129/. Accessed 5 Sept. 2024.
Goldman, Lee, and Dennis Ausiello, eds. Cecil Medicine. 23d ed. Philadelphia: Saunders, 2008. Print.
Kleigman, Robert M., et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders, 2012. Print.
Kumar, Vinay, Abul K. Abbas, and Jon C. Aster, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia: Elsevier, 2015. Print.
Longo, Dan L., et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw, 2012. Print.
"Niemann-Pick Disease." Medline Plus, 1 Jan. 2015, medlineplus.gov/genetics/condition/niemann-pick-disease/. Accessed 5 Sept. 2024.
Wood, Debra. "Niemann-Pick Disease." Health Library. EBSCO, 11 May 2013. Web. 1 Aug. 2014.