Niemann Pick’s disease (NPD) is a rare metabolic disorder, which receives little awareness compared to more prevalent diseases. It is an irreversible autosomal recessive disease, which can be classified into types A, B, and C. Types A and B have a current incidence of 1in 250 000, primarily within the Ashkenazi Jewish population, and type C being 1 in 150 000.
This disease primarily targets 5 organs: the liver, spleen, lungs, brain and bone marrow. Types A and B result from mutations in the SMPD1 gene, causing a deficiency in the lysosomal enzyme, acid sphingomyelinase. Type C results from mutations in the genes NPC1 and NPC2, which code for proteins involved in intracellular cholesterol and lipid trafficking.
Type A is the severest, with symptoms appearing at 4 months of age. As a result of sphingomyelin accumulation, neurologic degeneration, hepatospenomegaly and respiratory infections are prominent, thus life expectancy is only 1.5 to 3 years.
Type B is less severe, with symptoms appearing in late childhood or adolescence and individuals usually survive into adulthood. This type does not affect the central nervous system allowing for normal neurologic and motor development, nevertheless slow skeletal development, lung abnormalities and hepatospenomegaly are still prevalent.
Type C symptoms can appear at any age, and life expectancy varies according to the onset and severity of symptoms; some live into adulthood, while others die in childhood. Unlike Type A and B, Type C results in progressive neurodegeneration, and continuous mobility impairment.
Due to its uncommonness, NPD has no cure. Type A can undergo physiotherapy for better motor control, and tube feeding to meet nutritional requirements, however these treatments aren’t extremely effective. Type B can undergo oxygen therapy for the respiratory issues, and blood transfusions for major bleeding. Type C can undergo physical therapy and take an enzyme inhibitor Miglustat for improved neurologic function.
Though rare, NPD can be diagnosed via a skin assay or genetic tests. The filipin test is a diagnostic assay that utilizes skin fibroblasts to measure the accumulation and movement of un-esterfied cholesterol, thus this test is used to chiefly diagnose for Type C. Fibroblasts are cultured in LDL-enriched medium and stained with filipin, which fluoresces under UV light. This test can distinguish >80% of NPD cases, but such tests can’t reliably distinguish carriers from non-carriers and Types A from B, as these provide intermediate patterns. To discriminate and verify filipin test results, genetic testing must be further undertaken.
Genetic tests tend to be more reliable in detecting carriers and pathogenic variants in both coding and non-coding regions for NPD associated genes. Targeted analysis for pathogenic variants, sequence analysis, and deletion/duplication analysis are just a few options utilized, all having a detection frequency of >90%.
Genetic tests allow individuals to determine if they have hereditary or acquired mutations that may later develop into a disease, or if they’re carriers for disease-associated alleles. This knowledge aids with decisions on parenthood and treatment plans. It also provides information on potential phenotypic variations to expect if their future child inherits the disease. However, genetic tests are limited to the amount of information they can provide and the accuracy of those results. Some variants have not yet been identified making diagnosis difficult; rare polymorphisms can also lead to false positive or false negative results. Additionally, genetic tests don’t indicate the severity of disease symptoms, and inaccurate information on family history can lead to false interpretations on the likelihood of being a carrier.
In my opinion, genetic tests have both disadvantages and benefits depending on who is getting tested.
For a couple that may or may not have family history for the disease, genetic testing holds more consequences. A major disadvantage is psychological and emotional stress. As genetic tests are not 100% accurate, obtaining a negative result doesn’t eliminate the chances of having an affected child. One may have inherited an associated allele that still has not been identified. Furthermore NPD currently has no prenatal treatment or cure; therefore testing positive for being carriers may create a sense of hopelessness for couples.
Positive carrier test results can also lead to extreme changes with decisions on childbirth. Even though Ashkenazi Jews are at a higher risk of being affected, only if both parents are carriers, do they have a 25% chance on having an affected child. But some couples may not take this probability into consideration due to emotional conflicts.
However, newborn screening for NPD is beneficial as an affected child may lack early clinical symptoms. An earlier detection of NPD allows parents to formulate an effective treatment plan alongside specialists to deal with the associated symptoms.