Analysis of viral and genetic factors in South African patients with multiple sclerosis.

A significant association was previously demonstrated between multiple sclerosis (MS) and the functional 5'-(GT)n polymorphism in the promoter region of the SLC11A1 gene, which has been implicated in both autoimmune and infectious disease susceptibility. In the present study the role of viral infection was investigated in South African MS patients in relation to specific SLC11A1 genotypes. Serum and peripheral blood mononuclear cells (PBMC) of 49 MS patients, 33 close relatives and 39 unrelated controls previously genotyped for SLC11A1 were screened for the presence of MS-associated retrovirus (MSRV) and two herpes virus (HHV-6 and EBV) sequences. Expression of the pol gene of MSRV was detected in the serum RNA of 34/49 (69%) MS patients whilst absent in the serum of 39 unrelated healthy control individuals (p < 0.001) but was also present in 23/33 (70%) of the unaffected close relatives of the patients. HHV-6 and EBV sequences were detected in both MS patients and control individuals. The viral sequences were not confined to a specific SLC11A1 genotype. Infection with these viruses is excluded as the primary cause for MS in the South African population since no significant differences were detected between MS patients and their unaffected close family members.

Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis.

Caucasian South African patients with multiple sclerosis (MS) were screened for the most common hereditary haemochromatosis (HH) mutations, H63D and C282Y, in order to determine the impact of iron overload on clinical outcome of MS. DNA screening for mutations H63D and C282Y in 118 apparently unrelated MS patients did not reveal significant differences in allele frequencies in comparison with a control group from the same population. Of 17 MS patients heterozygous for C282Y, 3 had below normal and none had above normal transferrin saturation levels. One of the index MS patients, and subsequently also her sister who also has MS, tested positive for two copies of mutation C282Y. Determination of iron status revealed high serum ferritin and transferrin saturation levels in both patients. However, the index patient, being unaware of her C282Y status, had received treatment for iron deficiency in the past and her MS symptoms were less severe than those of her sister who has been wheelchair bound for the past 12 years and who did not take iron supplements. Lack of clinical manifestation of HH without any signs of organ damage in the C282Y homozygous MS patients is in accordance with a role of iron dysregulation in the aetiology of MS.

Overrepresentation of the founder PPOX gene mutation R59W in a South African patient with severe clinical manifestation of porphyria.

A patient, who presented with abdominal pain and severe photosensitivity that resulted in scarring and mutilation of the fingers, nose and ears, was referred for biochemical assessment of porphyria and DNA screening. Although these clinical manifestations were suggestive of both acute porphyria and congenital erythropoietic porphyria, the biochemical profile was consistent with variegate porphyria (VP). Analysis of the protoporphyrinogen oxidase (PPOX) gene underlying VP resulted in the identification of the founder mutation R59W in a heterozygous state in this patient. Despite extensive mutation analysis, no other potential disease-causing genetic alterations could be detected in the PPOX gene or the uroporphyrinogen III synthase gene. Slight overrepresentation of the mutant PPOX allele was however, observed repeatedly in DNA of the proband compared to other R59W heterozygotes, including his mother who also tested positive for mutation R59W using restriction enzyme analysis and direct DNA sequencing. Confirmation of this phenomenon by real-time polymerase chain reaction analysis and microsatellite analysis, using highly informative markers flanking the PPOX gene, raised the possibility of partial homozygosity for VP in this patient. This study represents the first report of overrepresentation of mutation R59W in a patient with a severe form of VP. A homozygote for the R59W mutation has never been detected, and the severe clinical manifestation observed in our patient is consistent with the hypothesis that such a genotype will not be compatible with life.