Commentary

Gebhardt reports the tragic circumstances of a sperm donor who fathered 18 children in 13 women, who subsequently was diagnosed with autosomal dominant cerebellar ataxia (ADCA).¹ The ADCAs are a genetically heterogeneous group of conditions that overall affect fewer than one in ten thousand people.² Currently 16 locations on chromosomes have been found where genes reside that have mutations resulting in ADCAs. Testing is generally available for 5 (SCA 1, 2, 3, 6, and 7). Testing for the common CAG expansion (the type of mutation in these five genes that lead to ADCAs is the presence of three bases C, A, and G that repeat over and over, CAG CAG CAG etc) in these five genes will identify the genetic cause in about half of all families affected by ADCA.³ The offspring of the sperm donor are at 50% risk to inherit the mutation and therefore go on to develop the condition. Autosomal dominant cerebellar ataxia usually has its onset in adulthood and causes progressive unsteadiness (ataxia) with the sufferer generally becoming wheelchair-bound and ultimately dying from the condition around 10–30 years after the onset.²

Could this episode have been prevented? In all donor gamete programes, a thorough family history should be taken to detect the risk of such occurrences. In the case described, it is possible that the gentleman was unaware of the family history—for example, because he was adopted, or that his family history was apparently negative due to the genetic mechanism of anticipation. Anticipation is well described for some of the ADCAs and refers to the phenomenon whereby the age of symptom onset is earlier in successive generations. The chances of an individual having a mutation in one of these genes and not knowing of his family history is extremely small and does not justify routine testing in gamete donors. In 1995 when the last of his donor offspring were conceived, only SCA 1 and 3 had been discovered to be the cause of ADCA.

In my view it was entirely appropriate to let the families of the children conceived through the sperm donor know about their children's risk. The three year delay is unlikely to have resulted in harm but if the information had been leaked to the media prior to the families being notified, it could have caused considerable anxiety to many couples who utilised that clinic's donor sperm service. Whilst there are no treatments that are currently known to delay the onset or slow the progression of ADCAs, this may change over the coming years. The oldest child is now 13 years, meaning that the children will be of an age where they may reproduce over the coming five years and beyond. They may wish to have predictive genetic testing to assist with reproductive decision making if a causative mutation has been found in the gentleman. Similarly the children may avail themselves of predictive testing to assist in lifestyle decisions. This testing should in my view, only be undertaken if the child wishes to have this information and is at an age that he or she can make an informed choice about this.⁴

There is general agreement that gamete donors should be screened for recessive conditions that are common in that population as well as a chromosome study being performed. Examples of recessive conditions that should be screened for are cystic fibrosis in the white population, thalassaemia in Asian and Mediterranean groups, and Tay Sachs disease in those of Ashkenazi Jewish background.⁵ Tizzano and colleagues described a situation which reinforces the importance of these recommendations.⁶ This involved a condition known as spinal muscular atrophy (SMA) which causes a child to progressively lose muscle strength due to deterioration of the nerves that supply the muscles. It is often fatal before the second birthday. The condition is recessively inherited which means that a gene mutation is inherited from each parent. It affects about one in 10 000 people. In the situation described by Tizzano and colleagues, a woman conceived using donor sperm and the resultant child was affected by SMA. She then conceived again with sperm from a different donor and tragically the second child was also affected by SMA. The authors recommend that consideration should be given to routine screening for carrier status (about 1:50 whites are carriers of SMA) for SMA in gamete donors by undertaking a cost-benefit analysis.

What should happen in the coming years when DNA technology becomes faster and cheaper, meaning that gamete donors may be able to be screened for numerous genetic mutations? For recessive disorders, carrier testing is associated with a low risk of significant sequelae for a positive result which generally has no implications for the gamete donor's own health. This is because in recessive inheritance the parents have one mutation in the pair of genes but the second unaffected gene compensates, meaning that person's health is in no way affected by carrying that mutation. It is estimated that all people have 5–10 recessive mutations and they are only a problem if that person's partner carries a mutation in the same gene. If the gamete donor is a carrier of a recessive mutation then the recipient can be tested and if they are a carrier of a mutation in the same gene, then clearly that donor's gametes should not be used.

To find that one is going to develop a fatal neurodegenerative condition whilst undertaking a selfless act such as gamete donation is another matter entirely. This is the situation if a dominant mutation is found. In dominant conditions, having a mutation in one of a pair of genes is sufficient to result in the disease occurring, as is the case with ADCAs. I expect that improved technology will result in a broad range of recessive conditions being screened for in gamete donors. However, the low chance of finding a severe dominant condition in the absence of a family history together with the potential harm to the donor, not to mention the fact that it may well discourage people coming forward as donors, should mean that conditions such as the ADCAs will not be screened for, even if tests are available. Time will tell!