Friedreich ataxia in a family from Mali, West Africa/Friedreich ataxia in a Malian family.

Friedreich ataxia is the most common inherited ataxia in the world, but yet to be reported in black African. We report the first genetically confirmed case in a West African family. Studying genetic diseases in populations with diverse backgrounds may give new insights into their pathophysiology for future therapeutic targets.

INTRODUCTION

Friedreich ataxia is an autosomal recessive cerebellar ataxia due to a progressive degeneration of corticospinal and spinocerebellar tracts and posterior columns of spinal cord. It is the most common inherited ataxia in the world with a prevalence of 1/50 000 people. However, most cases were described in populations with Caucasian ancestry.

Clinically, the disease is characterized by progressive gait and limb ataxia, dysarthria, loss of vibration and proprioceptive sense, and pyramidal involvement with upgoing toes. Cardiomyopathy, diabetes, scoliosis, and pes cavus are common associated systemic symptoms. MRI shows spinal cord atrophy. The disease is caused by a triplet (GAA) expansion within the first intron of the frataxin (FXN) gene located on chromosome 9q13. Normal alleles have only a small number of GAA trinucleotide repeats (usually 8‐33), whereas abnormal expanded alleles contain more than 90 repeats. Despite the high consanguinity rate in some West African ethnic groups, no genetically confirmed case has been reported in that region. Here, we report the first genetically confirmed West African family with Friedreich ataxia caused by mutations in the FXN gene.

MATERIAL AND METHODS

Patient was seen under a research protocol approved by the institutional ethical committee of Faculté de Médecine et d’Odonto‐stomatologie (FMOS), Mali. The patient was examined by a multidisciplinary team including neurologist, ophthalmologist, cardiologist, and ENT specialist after giving an informed consent. Brain MRI, nerve conduction study, and blood chemistries including vitamins B12 and E, blood glucose, and blood cell counts were performed to consolidate our diagnosis and to exclude other ataxia causes. DNA was extracted from peripheral blood in the patient for genetic testing. Genetic testing was done by Athena Diagnostics in Marlborough, Massachusetts, USA.

Direct testing for the repeat expansion mutation in the FXN gene was performed by PCR amplification of the repeat region followed by high‐resolution electrophoresis to determine the number of tandem repeats in each allele. Southern blot analysis was used, as necessary, to confirm homozygosity of normal alleles and to verify the number of repeats in highly expanded alleles. Southern blot analysis is performed using BsiHKA restriction digestion of genomic DNA and hybridization with a gene‐specific probe. This methodology is greater than 99% accurate for the detection of repeat expansion mutations.

RESULTS

A 17‐year‐old boy from a consanguineous Tuareg family (Figure 1A) was seen for walking difficulty. His past medical history was consistent with normal pregnancy and delivery, and no developmental delay. He is the second child of a sibship of seven, and presented symptoms at age 11 starting with hand tremor and slurred speech. Then, parents noticed progressive walking difficulty followed by frequent falls few months later, and skeletal deformities were noticed around age 14. These symptoms worsened gradually leading the patient to being wheelchair‐bound at age 16.

FIGURE 1

Clinical features of the Friedreich ataxia patient showing. A, Pedigree of the family showing first cousins marriage (asterisks indicating those seen in clinic and the black arrow indicates the proband), B and C, image of pes cavus and lumbar kyphosis, respectively, and D, brain MRI of the patient with Friedreich ataxia showing cerebellar atrophy (red arrow)

Clinical examination found dysarthria with very few words, spasticity with brisk and diffuse reflexes, hypertonia with scissor legs, loss of vibration and joint sense, and bilateral extensor plantar responses. In addition, he had scoliosis, lumbar kyphosis, and pes cavus (Figure 1B and C). Cardiologic, ophthalmologic, and ENT examination revealed no abnormalities. Brain MRI showed cerebellar atrophy (Figure 1D) while nerve conduction study revealed axonal sensory polyneuropathy. Blood chemistries including blood glucose and cell counts were normal, but platelet and vitamin B12 levels were high. These features are consistent with Friedreich ataxia, and the testing of the FXN gene associated with this disease identified GAA expansions in the first intron of the gene in both alleles. The first allele had 999 GAA expansion while the second had 766. This haplotype was not previously reported. Clinical and laboratory findings are summarized in Table 1.

TABLE 1

Clinical and laboratory findings in the patient with Friedreich ataxia

Features	Findings
Current age (years)	17
Age at onset (years)	11
Initial symptom	Hand tremor
Presenting symptom	Walking difficulty
Gait ataxia	Present
Dysarthria	Present
Spasticity	Present
Hypoacusis	Present
Cardiomyopathy	Absent
Retinitis pigmentosa	Absent
Diabetes	Absent
Skeletal deformities	Scoliosis, pes cavus, and lumbar kyphosis
Brain MRI	Cerebellar atrophy
Spinal cord MRI	Not done
Nerve conduction study	Sensory axonal polyneuropathy
Audiometry	Normal
Tympanometry	Normal
Vitamin E	Normal
Vitamin B12	846 pmol/l; normal range (145‐569)
Platelets	549 Giga/l; normal range (166‐395)
Genetic result	999 and 766 GAA repeat expansions

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. 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 whether 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 5 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. 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.

CONFLICT OF INTEREST

None declared.

AUTHOR CONTRIBUTIONS

CAKC, COG, GL: conception and design of the study, data interpretation, drafting of the manuscript, final approval of the version to be submitted, submission of the manuscript, and agreed to be accountable for all aspects of the work. LC, HOB, OS, AS, AT, S Diarra, SHD, TC, S Diallo, AY, ABM, MK, SFT, KHF: data interpretation, critical revising of the manuscript, final approval of the version to be submitted, and agreed to be accountable for all aspects of the work.

ETHICS STATEMENT

This study is approved by the institutional ethical committee of Faculté de Médecine et d’Odonto‐stomatologie (FMOS), Mali. The guardian and the patient signed the informed consent and assent forms, respectively.