Ashkenazi Jews are at a higher risk of
being diagnosed with the severe metabolic disorder Niemann-Pick Type A disease
(NP-A). Lacking a necessary enzyme, fatty substances, or lipids, accumulate in
the spleen, liver, lungs, bone marrow,
to a point where the organs falter and fail. There is no cure. There is no
NP-A is autosomal recessive. Both
parents would need to carry defective copies or alleles of the gene to cause
the disease. If this were the case, the
expected outcome for each pregnancy would include 50% carrier and 25% at risk
for the disease. Prospective carrier
parents thus face a devastating medical health life course for their child if
they choose to conceive.
Infants with NP-A usually develop hepatosplenomegaly, the simultaneous
enlargement of both the liver and spleen, by age 3 months, and fail to gain
weight and grow at the expected rate. With the central nervous system also
affected, psychomotor regression is evident by age 1 year. Children appear
clumsy and have difficulty walking. Widespread
lung damage can cause recurrent infections and eventual respiratory failure. Cherry-red
macular spots can be identified on eyes. Most devastating is the life expectancy
– typically not past two to five years of age.
Potential parents may be wondering why this is happening within the Ashkenazi
Jewish community, and what is the frequency. The former is primarily owing to
historical founder effects that have occurred over the past two millennia. As
for frequency, according to the Handbook of Genetic Counseling, NP-A is estimated to affect between 1:20,000 and
1:30,000 Ashkenazi Jews with a carrier frequency at 1:90 to 1:100.
Before conception, those interested can
get savvy about NP-A biochemistry to better understand any future dialogue with
medical staff. There are terms to consider such as sphingomyelinase. In classic
infantile type-A Niemann-Pick, a missense mutation causes significant
deficiency of the enzyme, acid sphinomyelinase (ASM). ASM is
responsible for the conversion of sphingomyelin into another type of lipid called
ceramide. Therefore, mutations in SMPD1,
a protein encoded gene that gives directions, causes the fat to
accumulate in cells leading to eventually cell death.
Carrier testing helps determine the
probability of children inheriting Niemann-Pick and to plan accordingly. A skin
assay test will examine white blood cells to reliably assess residual ASM
activity. A diagnosis is confirmed when a sample demonstrates less than 1% of
what is normal. While this test will identify persons with Type A, it is not
very reliable for detecting persons who are carriers. Further, the test will
show decreased activity of ASM, but it cannot always predict NP type.
To confirm the enzymatic diagnosis, a patient’s
DNA is tested. According to The Sick Kids Hospital in Toronto, the accuracy of
detecting Ashkenazi Jewish NP carriers genetically is 95% once the mutations
are determined. The Mount Sinai
Department of Human Genetics has identified mutations R496L, fsP330 and L302P
accounting for over 95% of genetic changes causing NP-A in the Ashkenazi Jewish
population. Genetic testing is used to detect any of these common mutations.
testing has its limitations, therefore, notably with unidentified mutations and
the classification of new variants. Moving away from the scientific aspect,
results from genetic testing can also have a psychological impact. When
tested positive for being a NP-A carrier parents may feel guilty or angry
regarding their future children’s health. Within families, there may be
derision on acceptance for caregiver roles. Will there enough physical and
emotional stamina required to care for a child with NP-A, and accept the early
death of a beloved child?
On the plus side, there is time to organize support for a
potential outcome. Canada’s Bill S-201 now prevents genetic tests results from
be disclosed to employers and insurance companies for specific policies. The
clinical data bank for NP-A can be expanded for future research.
If you are an Ashkenazi Jewish community member, get
genetic testing before procreation. There are many pros, and the cons are
really pros. Contact the Hospital for Sick Children (Toronto) for screening
which currently consists of testing for seven diseases common in this
population including NP-A.
palatable but also viable in limiting the risk of NP-A is cross cultural
parenting between Ashkenazi Jews and those from the general population with an
occurrence rate of 1 in 250 000. Is the incorporation of a reproductive
partner worth the cultural and religious risk in comparison to the odds value
of a healthy child?