Overview

Acid sphingomyelinase deficiency (ASMD) is a devastating disease which affects a small proportion of the world’s population, approximately ranging from 1 in 40,000-1,000,000, depending on ethnic origins. 

In the following article, we will take a closer look at how it can be diagnosed earlier and what types of genetic counselling are available for the lives touched by this disease. 

But first, let’s take a closer look at what acid sphingomyelinase deficiency is.

What is acid sphingomyelinase deficiency?

Acid sphingomyelinase deficiency (ASMD) is a genetic condition caused by a problem with the enzyme called acid sphingomyelinase. This enzyme can be completely absent within the body, it can be present, but dysfunctional, due to anomalies in its structure, or it can be present in abnormally low quantities, meaning there isn’t enough enzyme to properly carry out its role.¹ 

Because of this, a substance called sphingomyelin can accumulate in different cell types, thus causing a vast array of symptoms. There are three main types of disease caused by this deficiency, but all can be classified as types of Niemann-Pick Disease (NPD).⁴ 

They can be categorised as follows:⁴

• NPD-A: Early onset disease with neurological defects caused by NPD
• NPD-A/B (intermediate NPD): Neurological and visceral defects caused by ASMD with varying presentation
• NPD-B: Late-onset disease with only visceral organs affected, no neurological deficits

In all these types of ASMD presentation can differ depending on which specific mutation has caused the disease.⁴ Several types have been identified which has led to a greater understanding of what type of sequencing is required when genetic sequencing is performed, as well as what treatments are available to help manage the likely symptoms which will occur.⁴ 

Based on this information, parents and other family members can decide how to best bolster their lives. 

For example, a DNA nucleotide change from a thymine to a cytosine in position 416 on chromosome 18 typically leads to NPD-B without neurological involvement, and even then, only a mild form of the disease will likely manifest.¹ This is because this mutation will probably change the leucine amino acid which is normally in acid sphingomyelinase to a proline which can alter the shape of the enzyme, thus rendering it less efficient, but still permitting it to carry out some function.

On the other hand, a DNA base change in position 874 on the same chromosome can change a glutamine amino acid into a lysine amino acid.¹ Consequently, NPD-A/B is likely with neurological side-effects not observed from birth but later in life; this mutation is more prominently seen in those of Slovak heritage. 

Currently, over 300 different kinds of mutations have been noted, with many causing some form of ASMD.⁴ 

Not only can sequencing help provide information about who is at a higher risk of having ASMD, but the specific guidance about severity, onset and range of symptoms can help plan whether parents may want to continue with pregnancies as well as which types of specialist care should be allotted to treat the patients postnatally (after birth). 

Genetic counsellors can help direct you about your specific situation and aid in coordinating postnatal care for the patient with primary-care physicians too. 

Treatment exists in the form of Olipudase alfa, an enzyme replacement for acid sphingomyelinase.¹ The earlier the ASMD is diagnosed, the sooner treatment can begin and the better quality of life will be experienced. 

However, this treatment only impacts NPD-A/B and NPD-B as it doesn’t impact the nervous system. No cure exists. 

How can samples be collected for genetic testing?

If your physician suspects that your child may have ASMD before birth or if you would like to carry out a genetic test during your pregnancy to check whether your child may have a genetic condition such as ASMD, an amniocentesis or chorionic villus sampling may be carried out to collect cells which can be used for genetic testing.² 

An amniocentesis is when a thin needle is guided into the uterus using an ultrasound scan, and then some of the loose embryonic cells are collected through the amniotic fluid that the foetus (baby) is floating in.² The needle is then removed through the abdomen and the cells can then be used to test the foetal DNA for ASMD (or other genetic conditions). Ordinarily, this is carried out in the latter part of the first trimester to limit complications from the procedure but can be carried out when necessary. 

Chorionic villus sampling is when some cells are removed from the placenta whilst the baby is in its 11th to 14th week of gestation.³ This can be done in a similar way to an amniocentesis using a needle through the abdomen, or it can be done using thin forceps through the vagina and cervix, although this is less commonly done.³

Alternatively, if symptoms of ASMD are suspected after birth then blood can be taken or skin cells can be collected for fibroblast culture to test for ASMD. Here, the peripheral blood lymphocytes (white blood cells like T cells, B cells and natural killer cells) or the fibroblasts may show acid sphingomyelinase activity which is less than 10% of that seen in healthy individuals.¹ This can also prompt genetic testing for confirmation.

What types of genetic testing are carried out?

Sequencing for patient diagnosis

When radiographic evidence, abnormal newborn screening or skin/ blood tests for ASMD come back indicative of ASMD a single gene may be tested to diagnose ASMD.¹ The patient’s DNA, and specifically the SMPD1 gene which codes for acid sphingomyelinase, can be checked to see if a few extra base(s) have been inserted into the DNA sequence, deleted from the DNA sequence, or switched with existing base pairs, either in the exon (protein-coding part) or at the splice site (which decides where protein chain will finish).⁴ 

All of these may change at least one of the amino acids in the protein sequence for acid sphingomyelinase which can lead to a less functional or completely dysfunctional enzyme. 

Because of the way the DNA is sequenced, duplication of the entire exon, duplication of multiple exons or of the entire gene may not be detected. Therefore, if the initial results come back negative despite positive skin or blood or radiographic findings, further investigation in the form of gene-targeted duplication or deletion analysis to unveil any genetic abnormalities in this area. This can also be performed if only a single abnormal allele has been found in the sequence.¹ 

This is because the person may not have typical ASMD as this is an autosomal recessive inherited disease requiring two copies of abnormal alleles for the disorder to manifest. It should be noted that gene or whole-exon duplication has not previously caused ASMD so further investigation may be required to ascertain what is causing the clinical signs.

Alternatively, if a symptomatic patient needs testing (with key symptoms like neurological signs, enlarged liver or spleen, etc.) then a multigene panel which tests all the different genes of interest can be run to ascertain which gene is responsible for the patient’s condition.¹

It is important to note that not all changes in the DNA base sequence may result in ASMD, for example, a base change may lead to the same amino acid in the protein sequence so the acid sphingomyelinase would remain functional.⁴ In this case, other avenues of illness may need to be unearthed. 

Sequencing of family members

Parents of a diagnosed patient will be heterozygous for ASMD, meaning that they both will carry at least one disease-causing version of the SMPD1 gene. In some cases, one parent may not have a disease-causing copy of the SMPD1 gene, which means that the second one occurred spontaneously in the new embryo before the patient was born.⁵ An alternative explanation may be sought in uniparental isodisomy, where all the genes in a child come from one parent instead of both. Sequencing the genes of the parents can permit healthcare specialists to reliably inform you of the likelihood of another child being born with the condition in the same family. 

Siblings of those diagnosed with ASMD will also be sequenced to determine whether they have ASMD too, and perhaps it has not yet manifested. Sequencing will also provide information such as if they are carriers for the disease and whether their children will be more likely to have ASMD. Only ¼ of children born to all parents who are both heterozygous for ASMD will not inherit at least one copy of the disease-causing version of SMPD1.⁴ The rest will either have ASMD (¼) or likely carry the disease-causing variant (½).

This information can also aid in medical care for family members beyond family planning as some heterozygous for ASMD have low high-density lipoprotein (HDL) which can increase the risk of other health issues like cardiovascular disease.³

Can those with ASMD have children?

Patients who have ASMD: type NPD-A will not have children. 

Those with NPD-A/B or NPD-B may have children but they will all be carriers of the disease-causing SMDP1 variant.⁴ This means that any grandchildren may be more likely to have ASMD. It is also possible that children will have ASMD depending on the other parent’s genetic composition. 

Summary

ASMD is a recessive disorder which can cause one of three phenotypes (forms): NPD-A, NPD-A/B and NPD-B. These manifest as those with neurological conditions, those with neurological and visceral symptoms and those with visceral symptoms alone respectively. 

Treatment exists in the form of enzyme-replacement therapy for NPD-A/B and NPD-B, and genetic counselling alongside physicians can provide guidance and support to help you make informed decisions about your future.