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We refer to the article by Radunović et al 1 and the kindred referred to in this article and in the article by Cleveland et al 2 as the Australian superoxide dismutase (SOD1) Gly37Arg familial amyotrophic lateral sclerosis (FALS) kindred. It did seem extraordinary that the same mutation should produce such different disease phenotypes in two separate continents. Investigations in Australia, subsequent to the publication of the paper by Cleveland et al,2identified the mutation in this family as His43Arg, not Gly37Arg. The mutation was identified as H43R by heterozygote sequencing and sequencing of the single strand conformation polymorphism (SSCP) seen in exon 2 from several affected family members from the kindred. The original designation of the kindred as Gly37Arg must have arisen from a sample mix up between Western Australia, North Carolina, and Chicago. It is a relief to those of us living in Australia that this country may not after all pose an extra hazard to those carrying this SOD1 mutation. The clarification of the mutation in the family adds further weight to the data showing that different mutations may to some extent correlate with different rates of progression of FALS. The kindred has been reported correctly as His43Arg by Juneja et al.3 It is a particularly large kindred with over 500 known family members, There are 20 cases of FALS known to date, and 87 persons at 50% risk of having inherited the family mutation. The family is so large that on its own it represents a significant problem for genetic counselling in Western Australia. Twenty family members have received presymptomatic diagnosis in a Huntington’s-like protocol based on the results of SSCP detection of the exon 2 mutation.
Radunović and Leigh reply:
We are grateful to Drs Laing and Siddique for pointing out the error in the designation of the Australian His43Arg kindred as Gly37Arg. A Gly37Arg kindred with different phenotype to the American one,1-1 however, exists in Turkey.1-2 We are therefore still concerned that it is too early to predict particular ALS phenotypes based on the site of a CuZnSOD gene mutation. We are also worried about the lack of clinical information provided in reports on the CuZnSOD gene mutations, and a lack of evidence as to where these kindreds come from. For example, it is very likely that the Gly37Arg kindred reported by Juneja et al 1-1 is the same one as reported by Cudkowicz et al.1-3All this creates confusion and we would like to see a centralised pedigree database established where detailed but anonymous phenotype and genotype data can be deposited and accessed. It is only by collating all of the available information that comments on prognosis can be made.