A novel variant in the GNE gene in a Malian patient presenting with distal myopathy.

Background: GNE myopathy (GM) is a rare autosomal recessive disorder caused by variants in the GNE gene and characterized by progressive distal muscle weakness and atrophy. We report a novel variant in theGNE gene causing GM in a consanguineous Malian family. Case presentation: A 19-year-old male patient from a consanguineous family of Bambara ethnicity was seen for progressive walking difficulty and frequent falls. Neurological examination found distalmuscle weakness and atrophy and reduced tendon reflexes in four limbs. Electroneuromyography (ENMG) showed an axonal neuropathy pattern with reduced distal motor amplitudes. Charcot-Marie-Tooth (CMT) gene panel testing (Medical Neurogenetics LLC, Atlanta, GA) was negative. However, whole exome sequencing (WES) revealed a novel biallelic variant in GNE (c.1838G>A:p.Gly613Glu), segregating with the phenotype in the family. This variant is predicted to be pathogenic by several in silicoprediction tools including CADD= 29. Moreover, protein folding model showed major structural disruptions in the mutant protein. Conclusion: This study reports a novel variant in the GNE gene causing GM, the first molecularly diagnosed in sub-Saharan Africa (SSA). It highlights the diagnosis challenges in this region and broadens the genetic spectrum of this rare disease.

Hereditary spastic paraplegia in Mali: epidemiological and clinical features.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases divided into pure and complex forms, with spasticity in lower limbs only, or associated with other neurologic and non-neurologic manifestations, respectively. Although widely reported in other populations, very little data exist in sub-Saharan Africa. METHODS: Patients with neurodegenerative features were evaluated over a 19-month period at the Department of Neurology, Teaching Hospital of Point "G", Bamako, Mali. The diagnosis of HSP was considered based on family history and the absence of other known non-genetic causes. Genetic analysis including candidate gene and whole exome sequencing was performed and variant pathogenicity was tested using prediction tools and ACMG guidelines. RESULTS: Of the 170 families with hereditary neurological disorders enrolled, 16 had features consistent with HSP, a frequency of 9%. The average age of onset was 14.7 years with 46% starting before age 6. The male/female ratio was 2.6:1. Complex forms were seen in 75% of cases, and pure forms in 25%. Pyramidal findings were present in all patients. Associated features included mental retardation, peripheral neuropathy, epilepsy, oculomotor impairment and urinary urgency. Most patients were treated with a muscle relaxant and physical therapy, and restorative surgery was done in one. Genetic testing identified novel variants in three families (19%). CONCLUSION: This study confirms the clinical variability of HSPs and adds African data to the current literature.

GJB1 variants in Charcot-Marie-Tooth disease X-linked type 1 in Mali.

X-linked Charcot-Marie-Tooth type 1 (CMTX1) disease is one of the most common subtypes of inherited neuropathies and is caused by mutations in the GJB1 gene. To date, more than 400 mutations have been reported in GJB1 worldwide but none in sub-Saharan Africa (SSA). We aimed to clinically characterize patients with CMTX1 and identify the genetic defects. All patients were examined thoroughly, and Nerve Conduction Studies (NCS) were done. EEG and pure tone audiometry (PTA) were also done in select individuals having additional symptoms. DNA was extracted for CMT gene panel testing (50 genes + mtDNA and PMP22 duplication), and putative variants were screened in available relatives. The predominant starting symptom was tingling, and the chief complaint was gait difficulty. Neurological examination found a distal muscle weakness and atrophy, and sensory loss, skeletal deformities, decreased or absent reflexes and steppage gait. The inheritance pattern was consistent with dominant X-linked. NCS showed no response in most of the tested nerves in lower limbs, and normal or reduced amplitudes in upper limbs. A severe sensorineural hearing impairment and a focal epileptic seizure were observed in one patient each. A high intra and inter-familial clinical variability was observed. Genetic testing found three pathogenic missense variants in GJB1, one in each of the families (Val91Met, Arg15Trp, and Phe235Cys). This is the first report of genetically confirmed cases of CMTX1 in SSA, and confirms its clinical and genetic heterogeneity.

Clinical and Genetic Aspects of Huntington's Disease in the Malian Population.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by mutation in the HTT gene and characterized by involuntary movements as well as cognitive and behavioral impairment. Since its first description 150 years ago, studies have been reported worldwide. However, genetically confirmed cases have been scarce in Africa. OBJECTIVE: To describe the clinical and genetic aspects of HD in the Malian population. METHODS: Patients with HD phenotype and their relatives were enrolled after obtaining consent. Symptoms were assessed using the Total Motor Scale (TMS) of the United Huntington's Disease Rating Scale (UHDRS) and the Mini-Mental State Examination (MMSE). Brain imaging and blood tests were performed to exclude other causes. DNA was extracted for HTT sequencing. RESULTS: Eighteen patients (13 families) with a HD phenotype were evaluated. A familial history of the disease was found in 84.6% with 55.5% of maternal transmission. The average length of the HTT CAG repeat was 43.6±11.5 (39-56) CAGs. The mean age at onset was 43.1±9.7years. Choreic movements were the predominant symptoms (100% of the cases) with an average TMS of 49.4±30.8, followed by cognitive impairment (average MMSE score: 23.0±12.0) and psychiatric symptoms with 22.2% and 44.4%, respectively. CONCLUSION: This is one of the largest HD cohorts reported in Africa. Increasing access to genetic testing could uncover many other HD cases and disease-modifying genetic variants. Future haplotype and psychosocial studies may inform the origin of the Malian mutation and the impact of the disease on patients and their relatives.

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.

[A rare case of Horton's disease without inflammatory syndrome in the Department of Neurology of the Teaching Hospital of Point G, Bamako, Mali]. / Un cas rare de maladie de Horton sans syndrome inflammatoire dans le Service de Neurologie du CHU du Point G, Bamako, Mali.

Horton's disease is the most common inflammatory disease of the vessels after the age of 50 years. We report here the caseof a 64-year-old male, who presented a chronic frontal headache resistant to usual analgesics. Physical examination found pain on bitemporal pressure, a slight induration of temporal arteries and a bilateral decreased temporal pulse. Biological inflammatory testing was normal. However, Doppler ultrasound revealed bilateral intimal infiltration of the temporal artery, supporting the diagnosis of Horton's disease. Put on corticoids, headaches were completely resolved.

La maladie de Horton (MH) est la plus fréquente des maladies inflammatoires des vaisseaux après l'âge de 50 ans.Nous rapportons le cas d'un patient de 64 ans, ayant présenté une céphalée frontale, d'aggravation progressive etrebelle aux antalgiques usuels. L'examen physique a retrouvé une douleur à la pression bitemporale, une légère induration et une diminution des pouls temporaux de façon bilatérale. Le bilan biologique inflammatoire est revenu normal. Par contre, l'échographie doppler a mis en évidence une infiltration intimale bilatérale de l'artère temporale en faveur de la MH. Mis sous corticothérapie, le patient a rapporté une disparition des céphalées.

Neuropsychiatric and socio-cultural aspects in a Malian family with spinocerebellar ataxia.

INTRODUCTION: Spino-cerebellar ataxia or SCA are dominant neurological diseases caused by mutations in several genes. According to social and cultural contexts, especially in populations with low education level, the advent of such diseases might generate other kinds of suffering beside those caused by the physical impairment and disability. The aim of this work was to determine the impact of this disease in patients and their relatives. METHODS: It was a qualitative approach carried out through semi-directive clinical interviews, neuropsychiatric observations and the administration of the Hamilton depression scale. RESULTS: The study included a polygamous family in which mothers had 10 and 12 maternities. Neurological manifestations concerned four children of the same siblings and the father in a subtle form. The mother of these children was designated as responsible for the transmission of the disease and presented a reaction depression. Irritability, anxiety and depression reactions were observed in two patients and an unaffected brother. The advent of the disease was associated to the hatching of a latent familial conflict related to the father's status that has been established only after four years. CONCLUSION: In a social and cultural setting of polygamy, the advent of dominant ataxia with anticipation might revive latent familial conflicts and have psychological and social repercussions on the affected individuals and their relatives.

INTRODUCTION: Les ataxies spinocérébelleuses dominantes ou SCA sont des maladies neurologiques causées par des mutations dans plusieurs gènes. En fonction des contextes socioculturels, surtout dans des populations à faible niveau éducatif, de telles pathologies sont susceptible d'engendrer d'autres types de souffrances en dehors de celles dues à l'atteinte physique et au handicap. Le présent travail a pour objectif de déterminer l'impact du vécu de cette maladie chez les patients ainsi que chez leurs parents. MÉTHODES: Il s'est agi d'une approche qualitative réalisée à travers des entretiens cliniques semi-directifs, des observations neuropsychiatriques et l'administration de l'échelle de dépression d'Hamilton. RÉSULTATS: L'étude a concerné une famille polygame dans laquelle les mères avaient eu 10 et 12 maternités. Les manifestations neurologiques ont concerné quatre enfants d'une même fratrie utérine et, de façon fruste, le père. La mère de ces enfants était désignée comme responsable de la transmission de la maladie et avait présenté une dépression réactionnelle. Des réactions d'irritabilité, d'anxiété et de dépression ont été observées chez deux patients et un frère non atteint. L'apparition de la maladie était associée à l'éclosion d'un conflit familial latent lié au statut du père qui n'a été établi que quatre années plus tard. CONCLUSION: Dans un contexte socioculturel de polygamie, le déclenchement d'une ataxie dominante avec notion d'anticipation est susceptible de raviver des conflits intrafamiliaux latents et de se répercuter sur la sphère psychologique et sociale des personnes affectées et de leur entourage.

A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a very heterogeneous neurological condition with more than 90 reported genetic entities. It is the most common inherited peripheral neuropathy; however, cases are rarely reported in sub-Saharan Africa. In addition, only few families, mostly of Caucasian ancestry, have been reported to have Charcot-Marie-Tooth disease type 2D (CMT2D) mutations. To date no case of CMT2D was reported in Africa. We present here a consanguineous family with CMT phenotype in which a novel mutation in the GARS (glycyl-tRNA synthetase) gene was identified. METHODS: Patients were examined thoroughly and nerve conduction studies (NCS) were performed. DNA from the proband was used for CMT gene panel testing (including 50 genes, PMP22 duplication and mtDNA). Putative mutations were verified in all available family members to check for segregation. RESULTS: Two individuals, a male and a female, were found to be affected. Symptoms started in their teenage years with muscle weakness and atrophy in hands. Later, distal involvement of the lower limbs was noticed. Patients complained of minor sensory impairment. NCS showed no response in the upper as well as the lower limbs. Genetic testing surprisingly identified a novel heterozygous missense mutation c.794C>A (p.Ser265Tyr) in the GARS gene associated with CMT2D. This variant segregated with the disease in the family and was also seen in the mother who presented no symptoms. CONCLUSION: This is the first report of a genetically confirmed CMT2D case in Africa, expanding its genetic epidemiology. Increasing access to genetic testing may reveal more novel CMT variants or genes in the African population that could be relevant to other populations and further our understanding of their mechanism.

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss.

Hereditary spastic paraplegias (HSPs) are well-characterized disorders but rarely reported in Africa. We evaluated a Malian family in which three individuals had HSP and distal muscle atrophy and sensory loss. HSP panel testing identified a novel heterozygous missense mutation in KIF5A (c.1086G>C, p.Lys362Asn) that segregated with the disease (SPG10). Lys362 is highly conserved across species and Lys362Asn is predicted to be damaging. This study shows that HSPs are present in sub-Saharan Africa, although likely underdiagnosed. Increasing efficiency and decreasing costs of DNA sequencing will make it more feasible to diagnose HSPs in developing countries.

Non-motor signs in patients with Parkinson's disease at the University Hospital of Point "G", Mali.

INTRODUCTION: Despite significant progress in the field of scientific research on Parkinson's disease (PD), the prevalence and pathophysiology of its non-motor signs remains less understood than the classic motor signs of bradykinesia, rigidity, tremor and postural instability. Data covering this topic are rare in Africa, and almost non-existent in sub-Saharan Africa. Thus, this study aims to highlight the frequency of certain non-motor signs in PD patients followed in the Department of Neurology of the University Hospital Point "G", Bamako, Mali. METHODOLOGY: This is a retrospective and descriptive study from January 2012 to November 2013. We identified records of patients with dopamine-responsive idiopathic Parkinson's disease, and quantified associated non-motor symptoms. Data were analyzed with Epi-Info 2000 version 3.5.5. RESULT: During this period we reviewed 60 patient charts of which 68.3% were men. The average age of patients was 66.51 ranging from 25 to 94 years.Non-motor symptoms were present in 90% of cases, including sensitive disorders in 76.7%, dysautonomia in 73.3%, and psycho-behavioral disorders, including sleep disorders, in 81.7%. CONCLUSION: At the end of this study, we observed an important place for non-motor signs in the clinical manifestation of PD patients in general.

Socio-cultural adaptation and standardization of Dubois' five words testing in a population of normal subject in Mali, West Africa.

INTRODUCTION: Dubois' five words testing (5WT) is a verbal memory test that depends on many parameters. The aim of this study is to adapt Dubois' 5WT to the Malian socio-cultural conditions to (i) determine performances of normal subjects to the 5WT and (ii) provide reference scores of the 5WT. METHODS: A sample of 276 normal subjects aged ≥ 50 years (154 males and 122 females; 144 literates and 132 illiterates) were enrolled from February 2008 to January 2009. Subjects with a history of symptoms likely to modify cognitive functions and those who were found disabled under Lawton's four simplified item test were excluded. RESULTS: The learning score in illiterates was 1.51 in Dubois' 5WT and 4.90 in the modified 5WT. The mean value of the modified 5WT total score was 9.71. Majority (90.22%) of the subjects scored the maximum (10). The modified 5WT reduced with both the age (p < 0.006) and education level (p < 0.04). CONCLUSION: Our results show that Dubois' 5WT is influenced by culture and the socio-educative level in French. Its adaptation to the socio-cultural context could prove useful and efficient in countries with a low literacy rate and a diverse cultural background.