Niemann-Pick carrier status, and which of the three Niemann-Pick diseases your file looked at
Three different diseases share the name Niemann-Pick. Two of them are one gene, and the third is a different gene with a different mechanism that is not on our panel at all. Before you interpret a carrier result, it is worth knowing which one you were tested for.
Also known as: SMPD1 carrier, acid sphingomyelinase deficiency, ASMD, Niemann-Pick disease type A, Niemann-Pick disease type B.
- Gene
- SMPD1
- Inheritance
- Autosomal recessive
- Carrier frequency
- higher in Ashkenazi Jewish ancestry; uncommon in the general population
What it is
Niemann-Pick types A and B are both caused by changes in SMPD1, the gene for an enzyme called acid sphingomyelinase. The enzyme breaks down a fatty substance inside cells. When both copies of SMPD1 are altered, the enzyme runs at a fraction of its normal rate, the substance accumulates, and the liver, spleen and lungs are affected first. The modern name for the whole picture is acid sphingomyelinase deficiency, and clinicians increasingly use it in preference to the older type labels, for a reason that matters here.
The reason is that A and B are not two diseases. They are the ends of one continuum, and where a person sits along it tracks how much working enzyme they have left. The severe early-onset form with neurological involvement was historically called type A. The later-onset form that spares the central nervous system was called type B. Cases that sit between the two have needed a third label, type A/B, which is a fair sign that the original two were describing a spectrum rather than two distinct conditions. There is also now an enzyme replacement therapy, olipudase alfa, approved by the FDA and by the EMA in Europe for the manifestations outside the central nervous system, whichever label a patient carries. It does not act on the central nervous system, so it does not address the neurological features of the severe form.
Type C is the one that causes the confusion. It is not caused by SMPD1 and it is not an enzyme deficiency. It comes from changes in NPC1 or NPC2, genes for proteins that move cholesterol and other lipids around inside the cell, and it has its own neurological course and its own treatments. It shares the name for historical reasons, because the cases looked similar under a microscope a century ago. GeneReviews lists it in the differential diagnosis for acid sphingomyelinase deficiency, which is the clearest signal available that these are separate diseases that need telling apart. Neither NPC1 nor NPC2 is on the Aimosti carrier panel.
How it is inherited
All forms of acid sphingomyelinase deficiency are autosomal recessive. A carrier has one changed copy of SMPD1 and one working copy, makes enough enzyme, and stays healthy. The result is reproductive information: if a partner also carries an SMPD1 change, each pregnancy has a one in four chance of an affected child, and testing the partner is the useful next step.
Because A and B are one gene, being told you are a carrier of type A rather than type B is slightly misleading, and consumer products encourage the confusion. The list a vendor screens against is usually built from the founder variants seen in a particular population, and those variants happen to be associated with particular ends of the spectrum. Three SMPD1 changes account for around ninety percent of the disease-causing alleles found in the Ashkenazi Jewish population, and they are associated with the severe early-onset form. A different single change accounts for most alleles in populations across the Maghreb and around ninety to one hundred percent in Gran Canaria, and it is associated with the later-onset form. What a carrier result tells you is which change you carry, not which type of disease a future child would have, because that depends on what the other parent contributes as well.
One practical trap is worth knowing if you go looking up your own variant. SMPD1 has two numbering systems in circulation that differ by two amino acids, because of a length polymorphism in the gene itself. The same change is written p.Arg498Leu in one paper and p.Arg496Leu in another, and the common later-onset variant appears as both p.Arg610del and p.Arg608del. They are the same variants under two names, and mistaking them for different ones is an easy way to misread your own result.
What your raw DNA file can and cannot tell you
Start with the chip file. 23andMe's published carrier list includes an entry called Niemann-Pick Disease Type A, and nothing for type B or type C. That entry is doing what array-based screening does: typing a small set of founder positions, in this case the Ashkenazi ones. Inside that ancestry it is a real signal worth confirming. Outside it, a clear result covers only the positions on the list and says close to nothing, and it says nothing at all about type C, which lives in different genes that no part of that report examines. Aimosti does not issue carrier status from a chip file, for this gene or any other.
A whole-genome VCF or gVCF is what our carrier module reads, and it looks across SMPD1 rather than at pre-chosen positions, which is what lets it see changes outside any population's founder set. Its limits here are narrower than for some other conditions on this panel, and the difference is worth stating rather than glossing. A short-variant file does not represent large deletions, which for some genes is a serious blind spot. For SMPD1 it is a smaller one: deletions and duplications have not been established as a cause of this condition, and GeneReviews notes that if such variants exist their detection rate is unknown and probably very low. The blind spot that does matter is the boundary of the gene itself. A clear SMPD1 result is not information about NPC1 or NPC2, so it neither raises nor lowers the odds for Niemann-Pick type C.
This product is not carrier screening, and for this condition there is a specific reason to say so. Diagnosis of acid sphingomyelinase deficiency rests on measuring the enzyme, where affected people typically run below ten percent of normal activity, and the measured values vary between laboratories. That is a diagnostic test rather than a carrier test, and a re-analysis of a file you already own is neither. It can tell you that a change is present in a gene worth taking seriously. It is not a substitute for a validated carrier test, and if the answer matters for a pregnancy, the clinical test is the one that should carry the weight.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
Does a Niemann-Pick carrier result cover type C?
No, and this is the most important thing on the page. Types A and B come from the SMPD1 gene, which our carrier panel includes. Type C comes from NPC1 or NPC2, different genes with a different mechanism, and neither is on the panel. A clear SMPD1 result tells you nothing about type C in either direction. The three conditions share a name because of how they looked to pathologists a century ago, not because they are variations of one disease.
23andMe told me about Niemann-Pick type A. What about type B?
Same gene. Types A and B are both SMPD1, and they describe positions along one spectrum of how much working enzyme a person has, rather than two separate diseases. Array-based screening lists type A because the variants it types are the Ashkenazi founder ones, which are associated with the severe early-onset end. A whole-genome file re-analysed against the gene can find changes anywhere in SMPD1, including ones associated with the later-onset form and ones not associated with any population's founder set.
My whole-genome file shows no SMPD1 variant. Am I definitely not a carrier?
No, though for this gene a clear result is worth somewhat more than it is for some others. Large deletions are the usual blind spot of a short-variant file, and they have not been established as a cause of this condition, so that particular gap is small here. Residual risk still remains after any negative carrier result, our panel is not clinical carrier screening, and if the answer matters for a pregnancy the clinical test is the one to rely on.
Why do I see two different names for the same SMPD1 variant?
Because the gene has a length polymorphism, and two numbering systems that differ by two amino acids are both still in use. p.Arg498Leu and p.Arg496Leu are the same change, and so are p.Arg610del and p.Arg608del. If you are comparing a result against a paper or a database entry, check which numbering it uses before concluding that you are looking at different variants.
I am a carrier. What does that mean for my health?
Nothing, in the ordinary case. One working copy of SMPD1 makes enough enzyme and carriers do not develop the condition. The finding is reproductive information, so the useful next step is testing a reproductive partner. If you are both carriers, that is the point where a genetic counselor earns their keep and where a re-analysis result should be confirmed with a validated clinical test before anything is decided.