TYPES OF ALBINISM IN THE BLACK SOUTHERN AFRICA POPULATION.

BACKGROUND: Oculocutaneous albinism (OCA) is the most common inherited disorder in Southern African blacks and several types have been described. Molecular techniques, where available, can be used to confirm a clinical diagnosis and the type of OCA, if necessary, and for prenatal diagnosis. OBJECTIVES: To investigate and classify the different types of albinism commonly found and to determine the clinical implications for each type. DESIGN: A descriptive survey. SETTING: Gauteng province, South Africa, and Lesotho. SUBJECTS: Three groups of subjects with OCA (96 from a genetics clinic, 62 from a dermatology clinic, and 31 from community surveys) from the black African population participated. MAIN OUTCOME MEASURES: Subjects underwent clinical and/or dermatological examinations and were then classified according to type of OCA. RESULTS: Four forms of OCA were identified: most (82%) subjects had OCA2 (a tyrosinase- positive type) with three sub-types: those without large freckles (ephelides) on exposed areas (named OCA 2a in this study), those with such freckles (named OCA 2b), and those with brown albinism (BOCA); the remainder had red/rufous albinism, ROCA (OCA 3). The four forms could be distinguished from each other clinically without using molecular genetic testing. CONCLUSION: The most common types of albinism found in the black population of Southern Africa are OCA2 and OCA3. Given the high prevalence of the disorder, together with the high risk of skin cancer, and the recent persecution of affected individuals in certain East African countries, these findings and their clinical implications have significance in terms of both education and awareness for health professionals and lay people caring for those with albinism.

Children with intellectual disability in rural South Africa: prevalence and associated disability.

The objective of the present study was to determine the prevalence of intellectual disability (ID) and its associated disabilities in rural South African children aged 2-9 years. It was undertaken in eight villages in the district of Bushbuckridge, Northern Province, South Africa. A two-phase design was utilized. The first phase involved screening children on a house-to-house basis by interviewing mothers or caregivers using an internationally validated questionnaire for detecting childhood disability in developing countries. The second phase consisted of a paediatric/neurodevelopmental assessment of the children who screened positive. A total of 6692 children were screened; 722 (10.8%) had a paediatric evaluation and 238 children were diagnosed with ID, giving a minimum observed prevalence of 35.6 per 1000 children in this population. The prevalence of severe and mild ID was 0.64 per 1000 and 29.1 per 1000 children, respectively. The male:female ratio of children with ID was 3:2. In the affected children, a congenital aetiology for the ID was determined in 49 subjects (20.6%), an acquired aetiology in 15 (6.3%) and the aetiology was undetermined in 174 children (73.1%). Epilepsy (15.5%) and cerebral palsy (8.4%) were the commonest associated disabilities. The present study represents the first data on the prevalence of ID and associated disabilities in rural South African children. The prevalence of ID was comparable with results from a study performed in one other African country (Zambia) as well as those from other developing countries. The data provide an initial factual insight into ID and its associated disabilities for healthcare, social service and educational policy planners. This study provides a basis for the initiation and development of appropriate and integrated services for the best possible care of individuals affected with these disabilities, and for their possible prevention.

Epilepsy in rural South African children--prevalence, associated disability and management.

OBJECTIVE: To determine the prevalence of epilepsy and its associated disabilities in rural South African children aged 2-9 years. SETTING: Eight villages in the district of Bushbuckridge, Northern Province, South Africa. DESIGN: A two-phase design was used. The first phase involved screening children on a house-to-house basis by interviewing mothers or caregivers using an internationally validated questionnaire for detecting childhood disability in developing countries. The second phase consisted of a paediatric/neurodevelopmental assessment of the children who screened positive. RESULTS: A total of 6,692 children were screened; 722 (10.8%) had a paediatric evaluation and 49 (0.73%) had epilepsy. The lifetime and active prevalences of epilepsy in these children were 7.3/1,000 and 6.7/1,000 respectively. Associated developmental disability was recorded in 35 affected children (71.4%), including 8 (16.3%) in whom this was moderate to severe. More than a half of the children with epilepsy (57.1%) did not receive anticonvulsant medication. CONCLUSION: The prevalence of epilepsy in the rural childhood population investigated is higher than that recorded in most similar studies from sub-Saharan Africa, and the poor utilisation of appropriate anticonvulsant treatment is cause for concern. This study highlights the paucity of relevant information on the epidemiology of epilepsy in South Africa and that the system available for its management, especially in rural areas, appears to have functional deficiencies. Appropriate research is needed to identify the problems in service delivery and to enable the planning and implementation of an appropriate primary health care-based system for the diagnosis and management of epilepsy in children.

Utilisation of predictive, prenatal and diagnostic testing for Huntington's disease in Johannesburg.

CONTEXT: Huntington's disease (HD) is a dominantly inherited condition in which the gene defect is known. As such individuals in at-risk families can be tested before symptoms occur, prenatally, or after symptoms appear to confirm the diagnosis. OBJECTIVES: To investigate the utilisation and sequelae of the predictive, prenatal and diagnostic services offered to families with suspected Huntington's disease. DESIGN: A retrospective design was used. The 1975-1997 records of the Department of Human Genetics for all families with a history of HD presenting for genetic counselling and DNA analysis were studied. SETTING: Department of Human Genetics, South African Institute for Medical Research and University of the Witwatersrand, Johannesburg. SUBJECTS: There were 30 at-risk (50% risk) subjects for predictive testing, 7 women (10 pregnancies) for prenatal testing, and 52 subjects for diagnostic testing. OUTCOME MEASURES: These were provided by the results from molecular studies and by the action taken by subjects after a predictive or prenatal result was given. RESULTS: Altogether 15 (50%) subjects for predictive testing had a positive result, but none had serious psychiatric sequelae. Two women were found to be carrying an affected fetus and both requested pregnancy termination. Of 52 diagnostic tests, 33 (63%) were positive. CONCLUSION: The service was used appropriately, and there were no traumatic incidents following positive results. There was no genotypic or sex bias in subjects presenting for testing. Black and white patients were equally likely to be positive for HD on diagnostic testing. The families appreciated the service and found it useful in the detection and prevention of HD.

Trends in the twinning rate in Johannesburg, South Africa, 1969-1989 and estimated twinning rates for 1990.

Birth statistics for the Johannesburg Metropolitan Region were collected for 757 151 confinements from 1969 to 1989 (467513 Black, 194375 White, 67250 Coloured and 28013 Indian confinements). From 1969 to 1978 data on the sexes of twins were also collected for 375 203 of the confinements (203 504 Black, 129 631 White, 28 253 Coloured and 13 815 Indian confinements). A twin confinement was defined as two deliveries during one confinement. Twinning rates (TRs), defined as the number of twin confinements per 1000 total confinements, were calculated per year for each population group and from 1969-1978 estimates of the relative proportions of dizygotic (DZ) and monozygotic (MZ) twins were calculated and thus the relative DZTRs and MZTRs. A significant decline in Black and Coloured TRs was observed between 1969 and 1989. A significant decline in Black DZTR but not Black MZTR was observed between 1969 and 1978, the Coloured twin sample was too small to show significant trends over this period. It is probable that the overall decline in Black twinning may be explained by a decline in the DZTR. An analysis of birth statistics for 159 748 confinements (134 504 Black and 25 244 White confinements) collected as part of a prospective study of TRs in the Johannesburg Metropolitan Region from 1988 to 1990, indicated that the Black TR continued to decline at least until the end of 1990. TRs in the Johannesburg Metropolitan Region calculated from City Health Department birth statistics collected from 1988 to 1990 were: 13.8 and 10.77 for the Black and White populations, respectively. TRs for this period calculated from the combined birth statistics of 14 hospitals, nursing homes and maternity clinics across the region were: 12.4 and 10.88 for the Black and White populations, respectively.

Rufous oculocutaneous albinism in southern African Blacks is caused by mutations in the TYRP1 gene.

Oculocutaneous albinism (OCA) is the most common autosomal recessive disorder among southern African Blacks. There are three forms that account for almost all OCA types in this region. Tyrosinase-positive OCA (OCA2), which is the most common, affects approximately 1/3,900 newborns and has a carrier frequency of approximately 1/33. It is caused by mutations in the P gene on chromosome 15. Brown OCA (BOCA) and rufous OCA (ROCA) account for the majority of the remaining phenotypes. The prevalence of BOCA is unknown, but for ROCA it is approximately 1/8,500. Linkage analysis performed on nine ROCA families showed that ROCA was linked to an intragenic marker at the TYRP1 locus (maximum LOD score = 3.80 at straight theta=.00). Mutation analysis of 19 unrelated ROCA individuals revealed a nonsense mutation at codon 166 (S166X) in 17 (45%) of 38 ROCA chromosomes, and a second mutation (368delA) was found in an additional 19 (50%) of 38 chromosomes; mutations were not identified in the remaining 2 ROCA chromosomes. In one family, two siblings with a phenotypically unclassified form of albinism were found to be compound heterozygotes for mutations (S166X/368delA) at the TYRP1 locus and were heterozygous for a common 2.7-kb deletion in the P gene. These findings have highlighted the influence of genetic background on phenotype, in which the genotype at one locus can be influenced by the genotype at a second locus, leading to a modified phenotype. ROCA, which in southern African Blacks is caused by mutations in the TYRP1 gene, therefore should be referred to as "OCA3," since this is the third locus that has been shown to cause an OCA phenotype in humans.

Maternal non-recognition of Down syndrome in black South African infants.

Down syndrome (DS), one of the commonest causes of mental retardation in Caucasoids, has only rarely been described in Africa. In previous studies it was suggested that there may be clinical difficulties in making the diagnosis in African neonates. In the present study data were collected by means of a questionnaire administered partly before and partly after a genetic counselling session, to 35 mothers of African infants with DS. The results show that 83% of these mothers did not recognise any facial difference between their affected infant and other normal infants and 57% did not observe any other physical differences. After counselling, 40% of the sample still did not accept that their infant was different from other newborns. Only one mother was aware of infants with similar characteristics. These findings suggest that if mothers themselves cannot see the differences between their DS children and normal children, clinical diagnosis based on physical stigmata may be difficult. Furthermore, acceptance of the diagnosis may be retarded until delayed mile-stones can be observed in the affected infants.

Clinical features of Black African neonates with Down's syndrome.

Early reports indicated a low prevalence of Down's syndrome (DS) in black African children. More recent research demonstrates an incidence similar to, or higher than that reported to occur in First World populations. One of the possible reasons for underreporting of DS in Africa, appears to be the lack of recognition of the problem at birth. In this study, the musculoskeletal, central nervous system and craniofacial features are documented in 40 black DS neonates and 50 black control neonates without DS, and the findings are compared with those from a reported series of 37 caucasian DS and 40 healthy newborns. Musculoskeletal and central nervous system features were markedly similar in black and caucasian infants. However, the craniofacial features of the African DS newborns approximated more closely those of the normal African neonates, than was the case in the caucasian DS and normal neonates. This finding may partially explain the underreporting of DS in this population, and it emphasizes the need for a clinical awareness of DS and for complete clinical examination to identify affected infants.

Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs.

The clinical and neurodevelopmental features are presented of four children--two sibling pairs--who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non-verbal ability. He currently attends a school for learning-disabled children.

An ultrastructural study of melanocytes and melanosomes in the skin and hair bulbs of rufous albinos.

We have examined hair bulb and skin melanocytes of rufous albinos from Southern Africa to further characterize this form of albinism. In the skin melanocytes we find both eumelanosomes and pheomelanosomes at various stages of melanization and, in addition, there appeared to be many aberrant incompletely melanized melanosomes. On average, rufous melanosomes are 30% smaller than normal black skin melanosomes. In the keratinocytes, the melanosomes are packaged into distinct aggregations, whereas in normal black skin, they occur singly. We suggest that the reddish skin color of these albinos is a consequence of an increase in the pheomelanin synthesis resulting in a raised pheomelanin/eumelanin ratio and that the aggregation of melanosomes results in a skin color slightly lighter than normal. In hair bulb melanocytes, only eumelanosomes were seen and these were mostly incompletely melanized. These findings correlate with our visual observations that the hair color of Southern African albinos is very pale (light brown or ginger). Based on our observations, we speculate on the possible cause of rufous albinism.

In quest of the tyrosinase-positive oculocutaneous albinism gene.

The gene which causes tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is not known. Forty-seven Bantu-speaking Negroid families with ty-pos OCA were studied in an attempt to find linkage to the gene. Fifteen 'classical' and seven DNA polymorphisms were used in the search for linkage. Close linkage was excluded for the Rh, Gc and beta-globin loci. There is no suggestion of linkage to MNS, ABO, PGM1, 6PGD, ACP1, GPX1, GLO1, GPT1, PEP A, Tf, alpha 1-AT, Hp, DQA, DXA and three arbitrary restriction fragment length polymorphisms (RFLPs). There is a slightly positive lod score for pAW101 (D14S1) (0.591 for theta = 0.2). An 'interesting' lod score was obtained with Bf and a haplotype generated by the markers DQA and DXA (1.575 for theta = 0.1 and 0.979 for theta = 0.2, respectively). Further testing of markers on chromosome 6p are indicated. Although ty-pos OCA in Southern Africa is likely to be a homogeneous disorder, genetic heterogeneity cannot be excluded as differences due to the presence/absence of ephelides within families have been observed. To date 57% of the genome has been excluded from linkage with ty-pos OCA.

Red or rufous albinism in southern Africa.

Red or rufous albinism is a rare type of oculocutaneous albinism described, but not as yet fully investigated, in Africa and New Guinea. Twelve rufous albino subjects from 10 families participated in this preliminary study. The prevalence of rufous albinism was found to be approximately one in 8,580 among school children in the negroid population. The combination of the unusual red skin colour, ginger to reddish hair colour, low susceptibility to sun damage, and minimal visual problems, in affected individuals, suggested that they form a group which is distinct from the brown and other types of albinism. The mode of inheritance was found to be recessive. Tyrosinase assays showed that rufous albinos are tyrosinase positive and on electron microscopy studies normal melanosomes and melanocytes were observed in hair bulbs and skin. Visual evoked potential testing did not show the gross decussation abnormalities of the optic pathway detected in other types of albinism. Rufous albinism might be at one end of the spectrum of types of oculocutaneous albinism and, because affected people have such mild symptoms, their inclusion in this group might be debatable.

Autosomal recessive polycystic kidney disease. Evidence for high frequency of the gene in the Afrikaans-speaking population.

Polycystic kidney disease was investigated in 28 families in which at least one member attended the paediatric nephrology clinic at a Johannesburg or Pretoria hospital. Twenty-five (89.3%) of the families had autosomal recessive polycystic kidney disease (ARPKD), and of these a significantly larger number than would have been expected (92%) were Afrikaans-speaking. There was a consanguineous marriage in the ancestry of 2 patients but 6 of the families (26%) had ancestors with one surname in common and 7 of the families (28%) had their origin in the western Transvaal. A point prevalence for ARPKD of 1:26,000 was estimated for the Afrikaans population (based on the age cohort 0 - 19 years) and the carrier rate for the gene was 1:83; on the basis of the live-birth rate for ARPKD of 1:11,000 the carrier rate is 1:53. These findings suggest that ARPKD may be unusually frequent in the Afrikaans-speaking population. A founder effect is probably responsible.

A decade of mid-trimester amniocentesis in Johannesburg. Prenatal diagnosis, problems and counselling.

Selected data from 4,554 cases of amniocentesis performed in Johannesburg over a decade are presented. The demand for the service increased fivefold over the 10 years. The indications were: chromosome defects (83%), neural tube defects (11%), other disorders (4%) and parental anxiety (2%). A correct prenatal diagnosis was made in 99.9% of cases and sexing was correct in 99.6% of cases. Abnormalities were detected in 3.2% of pregnancies. The rate of 'spontaneous' abortion within 1 week after amniocentesis was 0.7%, and the total 16-28-week fetal loss rate is not much increased over the risk for such an event in any second-trimester pregnancy. The procedure has become a safe and a successful one in expert hands.

Albinism and skin cancer in Southern Africa.

The presence of skin cancer was investigated in 111 albinos belonging to the black (Negro) population of Johannesburg, South Africa. The overall rate was 23.4%, the risk increasing with age. Identifiable risk factors included: environmental exposure to ultraviolet radiation; inability to produce ephelides ('freckles'); and possibly ethnicity. The head was the site most commonly affected, and squamous was far more common than basal cell carcinoma. No melanomas were detected. Recommendations are made regarding prevention of skin cancer in the at-risk group.

The tyrosinase-positive oculocutaneous albinism locus is not linked to the beta-globin locus in man.

Twenty informative families have been studied. and linkage between the tyrosinase-positive oculocutaneous albinism locus and the beta-globin locus has been excluded with a maximum lod score of -9.85 at 0 = 0.05. In lower mammals there is linkage between the p locus (considered to be equivalent to the human tyrosinase-positive oculocutaneous albinism) and the beta-globin locus.

The response of black mothers to the birth of an albino infant.

The nature of the response of 37 black mothers to their albino infants, in comparison with matched controls, was investigated longitudinally by means of interviews and observations. Mothers were found initially to be depressed and unhappy, uncomfortable with close contact with their infants, and reluctant to hold and breast-feed them. When observed in interaction with the infants, the mothers showed fewer behaviors in comparison with the controls. Three months later the mothers appeared to be interacting normally with their infants, but they expressed feelings of unhappiness that persisted until the infants reached 9 months of age. The birth of an albino infant seems to cause a delay in maternal attachment and a sadness similar to that described in connection with the birth of an infant with other congenital disorders.