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.

Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8.

BACKGROUND: Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disorder characterized by cortical tremors and seizures. Six types of BAFME, all caused by pentanucleotide repeat expansions in different genes, have been reported. However, several other BAFME cases remain with no molecular diagnosis. OBJECTIVES: We aim to characterize clinical features and identify the mutation causing BAFME in a large Malian family with 10 affected members. METHODS: Long-read whole genome sequencing, repeat-primed polymerase chain reaction and RNA studies were performed. RESULTS: We identified TTTTA repeat expansions and TTTCA repeat insertions in intron 4 of the RAI1 gene that co-segregated with disease status in this family. TTTCA repeats were absent in 200 Malian controls. In the affected individuals, we found a read with only nine TTTCA repeat units and somatic instability. The RAI1 repeat expansions cause the only BAFME type in which the disease-causing repeats are in a gene associated with a monogenic disorder in the haploinsufficiency state (ie, Smith-Magenis syndrome [SMS]). Nevertheless, none of the Malian patients exhibited symptoms related to SMS. Moreover, leukocyte RNA levels of RAI1 in six Malian BAFME patients were no different from controls. CONCLUSIONS: These findings establish a new type of BAFME, BAFME8, in an African family and suggest that haploinsufficiency is unlikely to be the main pathomechanism of BAFME. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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.

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.

Hereditary spastic paraplegia type 35 in a family from Mali.

Variants in FA2H have been associated with a wide range of phenotypes including hereditary spastic paraplegia type 35 (SPG35); however, genetically confirmed cases have not been reported in Africa. We report here the first African family with a variant in the FA2H gene causing SPG35. Four affected siblings with consanguineous parents presented with walking difficulty at age 2-3 and progressive limb weakness. They became wheelchair-bound 2 years after disease onset. Neurological examination confirmed lower greater than upper limb weakness and atrophy, brisk reflexes throughout, and spasticity with scissor legs. The patients also had choking, urinary urgency, and mental retardation. A brain MRI showed thin corpus callosum and periventricular leucodystrophy. Testing of 58 SPG genes showed a homozygous variant in FA2H at the exon 5 donor site c.786+1G>A, which has previously been shown to cause skipping of exons 5 and 6 of the gene transcript. This variant segregated with the disease in the family. This variant has been reported previously with a similar phenotype and slow progression in a population with different background. Here, we confirm its pathogenicity and expand its genetic epidemiology. Studying diverse populations may help to increase understanding of the disease mechanism and ultimately lead to therapeutic targets.

Does the survival motor neuron copy number variation play a role in the onset and severity of sporadic amyotrophic lateral sclerosis in Malians?

INTRODUCTION: Spinal muscular atrophy (SMA) and sporadic amyotrophic lateral sclerosis (SALS) are both motor neuron disorders. SMA results from the deletion of the survival motor neuron (SMN) 1 gene. High or low SMN1 copy number and the absence of SMN2 have been reported as risk factors for the development or severity of SALS. OBJECTIVE: To investigate the role of SMN gene copy number in the onset and severity of SALS in Malians. MATERIAL AND METHODS: We determined the SMN1 and SMN2 copy number in genomic DNA samples from 391 Malian adult volunteers, 120 Yoruba from Nigeria, 120 Luyha from Kenya and 74 U.S. Caucasians using a Taqman quantitative PCR assay. We evaluated the SALS risk based on the estimated SMA protein level using the Veldink formula (SMN1 copy number + 0.2 ∗ SMN2 copy number). We also characterized the disease natural history in 15 ALS patients at the teaching hospital of Point G, Bamako, Mali. RESULTS: We found that 131 of 391 (33.5%) had an estimated SMN protein expression of ≤ 2.2; 60 out of 391 (15.3%) had an estimated SMN protein expression < 2 and would be at risk of ALS and the disease onset was as early as 16 years old. All 15 patients were male and some were physically handicapped within 1-2 years in the disease course. CONCLUSION: Because of the short survival time of our patients, family histories and sample DNA for testing were not done. However, our results show that sporadic ALS is of earlier onset and shorter survival time as compared to patients elsewhere. We plan to establish a network of neurologists and researchers for early screening of ALS.

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.