Galactosemia, an inborn error of metabolism, has been evident in the South African population for many decades. Only a few reports however, have dealt with the demographics, and clinical / laboratory findings in affected individuals ,,. The recent unravelling of the molecular genetics of galactosemia [for review see ] has prompted a re-examination of this condition in South Africa. This manuscript details the clinical, laboratory and molecular genetic findings of patients from the Cape Metropolitan region.
The diagnosis of galactosemia is usually made early in the neonatal period . In the present study, the mean age at diagnosis of 5.1 months is indicative of considerable delays in detection. While obvious reasons for this are not apparent, a lack of awareness is likely to be an important consideration. In summary then, it is important that the diagnosis be considered in young children with suggestive features including persistent hypoglycaemia, failure to thrive, feeding difficulties, prolonged conjugated hyperbilirubinemia, hepatomegaly, ascites, invasive E. coli infections, neurodevelopmental delay and galactosuria. Another consideration is that mild clinical phenotypes may delay presentation. In contrast to the Q188R mutation, the S135L mutation is associated with a better clinical outcome .
Treatment of Galactosemia involves complete elimination of dietary lactose / galactose. This limits death associated with E. coli infection, reverses growth failure and cataract formation, and prevents severe liver disease. Unfortunately, dietary modification does not moderate the risk of long-term central nervous system dysfunction such as speech defects, mental retardation and ataxia nor premature ovarian failure ,,.
The GALT genotypes defined in our patient cohort conform to reports from other countries, where the Q188R and S135L mutations are commonly encountered in classical galactosemia. Allele prevalences of 60–70% have been found for Q188R in Caucasian patients [16, 17], while prevalences of 48%  and 91% , have been reported in African American and in African Negroid patients, respectively. Of the 18 GALT alleles, from the 9 unrelated patients in our study, only one did not carry either of these two mutations. Although our sample size is small, this finding holds great promise for the genetic diagnosis of galactosemia in South Africa, as these two mutations alone will account for the bulk of the galactosemia burden. While other prominent mutations have been described, such as the K285N substitution in East / Central Europe, the majority of the mutations listed in the GALT database (URL: http://www.ich.bris.ac.uk/galtdb/) are rare and likely to be family specific. All 10 of the black GALT alleles examined in our study carried the S135L amino acid substitution. This finding confirms the earlier report of a >90% association of this mutation with GALT alleles in black South Africans . In contrast, the two unrelated white patients were both homozygous for the Q188R mutation. It is not surprising therefore, that 5 of the 6 GALT alleles from patients of mixed ancestry, manifest one of these two mutations.
The true incidence of galactosemia in South Africa remains difficult to define. Newborn screening and other surveillance programmes in Europe and North America have established newborn rates of 1/30 000 to 1/ 50 000 in Caucasians ,[19, 20]. Similar newborn incidences are probably present in white South Africans. A reliable figure can now be applied to black South Africans as our cord-blood screening programme for the S135L mutation in the GALT gene has yielded a carrier frequency of 1/60 in this population grouping. Given that >90% of galactosemia in this group is associated with this mutation, a newborn incidence of approximately 1/14 400 can be expected in the Cape Metropolitan region. This is in accord with the S135L carrier frequency data from the Northern regions of South Africa, which suggest a similar newborn incidence of approximately 1/22 500 . The South African carrier frequencies for the S135L mutation are the highest reported so far and represent a significant concentration when contrasted with the frequency of 1/505 reported in African Americans .
The projected figure for black newborns for the year 2000, in the Cape Metropole was 25 920 (RE Dorrington, UCT, Director Centre for Actuarial research); with the increasing urbanisation of the Cape Metropole this figure is certain to have increased in the subsequent years. This number translates into expected referrals of at least 1–2 galactosemics every two years; current referral of 1 every 5 yrs is significantly below this projection. Two opposing explanations are likely to account for this diagnostic shortfall. Patients, either go undetected and do not survive the neonatal period, or they do not present in the neonatal period. Some support for the latter explanation comes from the finding that the S135L mutation can be associated with a "mild" phenotype ,, and it is conceivable that only the severe end of the S135L/S135L presentation spectrum, is attracting the attention of the medical fraternity in our region. It is likely that a measure of both possibilities is operative for our black patients.
The association of milder disease phenotypes with residual enzyme activity is now well described in the metabolic diseases literature. There are significant data to suggest that this is also the case with the S135L mutation and galactosemia. Subjects homozygous for the S135L mutation, although deficient in GALT activity in erythrocytes have approx. 10% residual activity and enzyme mass in liver, intestine and leucocytes ,,. This residual activity is also manifest by a whole body galactose oxidative capacity, which overlaps that of normal subjects when given a tracer challenge of 13C-galactose . Clinical parallels would be the finding that S135L homozygotes have survived the neonatal period and have only been detected when later problems such as cataracts, developmental delay and poor school performance have been investigated , and that S135L homozygotes detected in new born screening programs appear to respond very well to dietary restriction of lactose / galactose .