Discussion
Friedreich ataxia is the most common cerebellar ataxias in the world and mostly reported in populations with Caucasian ancestry. Only few sub-Saharan African families with Friedreich ataxia are reported in the literature and none of them had black African ancestry (Smith et al., 2016). To our knowledge, mutation in FXN has not been previously identified in West Africa.
The present study is the first clinical and genetic description of FRDA in a Malian patient of Tuareg origin, an ethnic group residing between Mali and Algeria. Although cases have been reported in Algeria and other Maghrebin countries, it is not clear if these included patients with Tuareg origin.
The patient presented here had classical clinical features of FRDA with hand tremor and slurred speech as presenting symptoms and longer GAA repeats as compared to the average.
It is well known that there is an inverse correlation between the size of the allele and the age at onset and the severity of the disease. The age of onset (11 years) in this study is close to the average (15 years), however, the progression of the disease was faster than reported. In fact, the lapsed time between the first symptom and wheelchair use by the patient was five years while the average time reported in the literature is 10 years. In addition, skeletal deformities appeared earlier than seen in other populations.
Although, two thirds of patients with FRDA present hypertrophic cardiomyopathy, we did not find any cardiologic features during our investigations. This might suggest the high variability in the clinical presentation or due to the youngest age of the patient as symptoms related to cardiomyopathy usually occur in the later stage of the disease (Dutka et al., 1999). A regular follow-up could detect early cardiologic involvement.
Despite the fact that diabetes mellitus occurs in up to 30% individuals affected by Friedreich ataxia, the fasting blood sugar was normal in the patient we present here.
The neuroimaging is often normal in the early stages of FRDA, but in advanced stages atrophy of the cervical spinal cord and cerebellum may be observed. However, the patient’s brain MRI showed moderate cerebellar atrophy after only three years of disease progression.
Beside the relative longer length of GAA repeats in both alleles than reported elsewhere, these differences in the disease course could be stochastic or due to the lower quality of care compared to more developed countries or other genetic modifiers.
Nevertheless, large cohorts of patients with different ethnic and geographical backgrounds may be needed for genotype-phenotype correlation studies which could shed light into these hypotheses.
In conclusion, we report the first genetically-confirmed FRDA case in a West African family, expanding the genetic epidemiology of this disease. As genetic testing becomes available to African populations, future studies may uncover other FRDA cases and improve our understanding in the phenotypic variability and the role of the FXN gene in the function of the nervous systems. In addition, whole genome sequencing of cohorts in diverse populations may identify other disease-modifying variants that could be used as therapeutic targets.