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

Abstract

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.

The conundrum of iron in multiple sclerosis – time for an individualised approach

“…Insights gained from studies performed in a genetically homogeneous South African population paved the way to a better understanding of the close relationship between iron absorption and immune function in MS (Kotze et al 2001; 2003; 2006). The statistically significant association observed between MS and a functional promoter polymorphism in the SLC11A1 gene, supports the notion that iron trapping in macrophages upon infection may be detrimental in a subgroup of MS patients that are iron deficient (Kotze et al 2003; van Rensburg et al 2006).…”

“…The statistically significant association observed between MS and a functional promoter polymorphism in the SLC11A1 gene, supports the notion that iron trapping in macrophages upon infection may be detrimental in a subgroup of MS patients that are iron deficient (Kotze et al 2003; van Rensburg et al 2006). The HFE gene may be in linkage disequilibrium with an MS susceptibility allele in the HLA complex on chromosome 6 (Rubio et al 2004; Kotze et al 2006). Lack of clinical manifestation of hereditary hemochromatosis (HH) without any signs of organ damage in two South African sisters with MS found to be homozygous for the C282Y mutation in the HFE gene, further substantiates the role of iron dysregulation in the aetiology of MS (Kotze et al 2006).…”

“…The HFE gene may be in linkage disequilibrium with an MS susceptibility allele in the HLA complex on chromosome 6 (Rubio et al 2004; Kotze et al 2006). Lack of clinical manifestation of hereditary hemochromatosis (HH) without any signs of organ damage in two South African sisters with MS found to be homozygous for the C282Y mutation in the HFE gene, further substantiates the role of iron dysregulation in the aetiology of MS (Kotze et al 2006). Notably, iron deficiency anaemia was reported in one of these patients during her child-bearing years.…”

Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis

“…Iron imbalance is strongly suspected in MS pathogenesis, even though there is no evidence that systemic iron overload occurs more frequently in MS patients than in general population [36,37]. …”

Application of advanced molecular technology in the diagnosis and management of genetic disorders in South Africa

“…Table 2 shows the evaluation of twelve SNPs in four unrelated individuals. These include the index case (sample 4) of a family with three medical conditions previously analysed at the clinical, pathology and genetic level: [18] multiple sclerosis, hereditary haemochromatosis, and porphyria that may be triggered by iron dysregulation or drugs affecting CYP2D6 activity. Inadequate coverage (<20x) of the most common variant CYP2D6*4 was evident in this patient (poor metaboliser), as well as samples 2 (intermediate metaboliser) and 3 (extensive metaboliser).…”