AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) comprises a large group of neurogenetic disorders characterized by progressive lower extremity spasticity. Neurological evaluation and genetic testing were completed in a Malian family with early-onset HSP. Three children with unaffected consanguineous parents presented with symptoms consistent with childhood-onset complicated HSP. Neurological evaluation found lower limb weakness, spasticity, dysarthria, seizures, and intellectual disability. Brain MRI showed corpus callosum thinning with cortical and spinal cord atrophy, and an EEG detected slow background in the index patient. Whole exome sequencing identified a homozygous missense variant in the adaptor protein (AP) complex 2 alpha-2 subunit (AP2A2) gene. Western blot analysis showed reduced levels of AP2A2 in patient-iPSC derived neuronal cells. Endocytosis of transferrin receptor (TfR) was decreased in patient-derived neurons. In addition, we observed increased axon initial segment length in patient-derived neurons. Xenopus tropicalis tadpoles with ap2a2 knockout showed cerebral edema and progressive seizures. Immunoprecipitation of the mutant human AP-2-appendage alpha-C construct showed defective binding to accessory proteins. We report AP2A2 as a novel genetic entity associated with HSP and provide functional data in patient-derived neuron cells and a frog model. These findings expand our understanding of the mechanism of HSP and improve the genetic diagnosis of this condition.

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.

A rare case of thyrotoxic periodic paralysis revealing Graves' disease in a young Malian.

Sporadic thyrotoxic periodic paralysis (TPP) is a rare muscle disorder that manifests with abrupt muscle weakness and hypokalemia associated with hyperthyroidism. It is mostly reported in the Asian population, and rare in Caucasians. Only few cases have been reported in people with black ancestry. Here, we report a rare case of thyrotoxic periodic paralysis revealing Graves' disease in a young Malian. A 17-year-old man was admitted in the Neurology clinic with rapid proximal tetraplegia that started after strenuous physical activities at the school. Clinical examination confirmed the proximal weakness. In addition, he had bilateral ptosis, exophthalmia, and horizontal ophthalmoplegia. Laboratory testing showed normal serum potassium and creatinine, low calcium and TSH levels. However, CK, FT4, thyroid stimulating hormone antibody, and acetylcholine receptor antibody levels were high. In addition, electrocardiogram was normal while thyroid Doppler-ultrasound showed heterogeneous, hypoechogenic, hypertrophic, and hyper vascularized gland. Patient had completely recovered his limb weakness within the following hours with symptomatic treatment. The clinical findings were consistent with Graves' disease, and he was put on Neomercazole. He did not present another episode of paralysis after 4-years of follow up. This is a first case of thyrotoxic periodic paralysis reported in Mali and one of the rare cases in sub-Saharan Africa. Despite its scarcity, all patients with acute weakness consecutive to effort, whether recurring or not, should be screened for TPP.

A novel de novo variant in the RUNX2 gene causes cleidocranial dysplasia in a Malian girl.

Key Clinical Message: Cleidocranial dysplasia (CCD) is a rare genetic skeletal disorder with only few cases reported in Africa, mostly based on clinical and radiological findings. We report the first case in Mali, caused by a novel de novo variant in the RUNX2 gene. Abstract: Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia characterized by an aplastic/hypoplastic clavicles, patent sutures and fontanels, dental abnormalities and a variety of other skeletal changes. We report a novel de novo variant in the RUNX2 gene causing a severe phenotype of CCD in a Malian girl.

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.

Novel variant in CADM3 causes Charcot-Marie-Tooth disease.

CADM3 has been recently reported causing a rare axonal Charcot-Marie-Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with autosomal dominant and sporadic patterns, respectively. Eight patients and their relatives were enroled from both families. The mean age at diagnosis was 33.9 years, and walking difficulty was commonly the first symptom. Neurological examination showed distal muscle weakness and atrophy, sensory loss and foot and hand deformities. A high clinical variability was noted, but as seen in CADM3-associated neuropathy, symptoms were more pronounced in the arms in some patients. Nerve conduction studies showed no response in most of the examined nerves, and an axonal type of neuropathy, where recorded. Whole exome sequencing revealed a novel missense variant (c.1102G>T; Gly368Cys) in CADM3, segregating with the disease. Functional analyses showed a significant decrease in CADM3-Gly368Cys protein levels in the membrane and major structural changes in its predicted secondary structure. Therefore, we extend the genotype spectrum of CADM3, underlining the need for genetic studies in underrepresented populations like in Africa.

An unusual case of Dyke-Davidoff-Masson syndrome revealed by status epilepticus in a Malian patient.

The Duke-Davidoff-Masson syndrome (DDMS) is a rare neurological condition with unknown prevalence, globally. To date, <100 cases have been reported worldwide. We report the case of an 18-year-old patient admitted for status epilepticus seizure, and who presented a right hemiparesis, body asymmetry, joints ankylosis, and mental retardation. Brain CT-scan revealed left hemisphere atrophy, skull bone thickening, and hyperpneumatization of the frontal sinuses; all consistent with DDMS. Seizures improved remarkably on Levetiracetam and Valproate. This is the first report of an unusual DDMS in Mali, and the diagnosis delay highlights the challenges for the management of these diseases in resource-limited settings.

A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family.

BACKGROUND: Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent. METHODS: After a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis. RESULTS: Eight individuals from a large non-consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post-lingual and mixed type of HI, one individual had conductive HI while three had normal hearing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A > G; p.Asp429Gly) segregating with BO syndrome in the family. CONCLUSION: This is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub-Saharan African population, expanding the genetic spectrum of the condition.

Current profile of Charcot-Marie-Tooth disease in Africa: A systematic review.

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features. METHODS: We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria. RESULTS: A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT-associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations. INTERPRETATION: This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.

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.

Hearing loss and brain disorders: A review of multiple pathologies.

Several causative factors are associated with hearing loss (HL) and brain disorders. However, there are many unidentified disease modifiers in these conditions. Our study summarised the most common brain disorders associated with HL and highlighted mechanisms of pathologies. We searched the literature for published articles on HL and brain disorders. Alzheimer's disease/dementia, Parkinson's disease, cognitive impairment, autism spectrum disorder, ataxia, epilepsy, stroke, and hypoxic-ischaemic encephalopathy majorly co-interact with HL. The estimated incidence rate was 113 per 10,000 person-years. Genetic, epigenetic, early life/neonatal stress, hypoxia, inflammation, nitric oxide infiltration, endoplasmic reticulum stress, and excess glutamate were the distinguished modifiers identified. Various mechanisms like adhesion molecules, transport proteins, hair cell apoptosis, and neurodegeneration have been implicated in these conditions and are serving as potential targets for therapies. To improve the quality of life of patients, these understandings will improve clinical diagnoses and management of HL and brain disorders.

Hearing Impairment in South Africa and the Lessons Learned for Planetary Health Genomics: A Systematic Review.

Hearing impairment (HI) is a silent planetary health crisis that requires attention worldwide. The prevalence of HI in South Africa is estimated as 5.5 in 100 live births, which is about 5 times higher than the prevalence in high-income countries. This also offers opportunity to drive progressive science, technology and innovation policy, and health systems. We present here a systematic analysis and review on the prevalence, etiologies, clinical patterns, and genetics/genomics of HI in South Africa. We searched PubMed, Scopus, African Journals Online, AFROLIB, and African Index Medicus to identify the pertinent studies on HI in South Africa, published from inception to April 30, 2021, and the data were summarized narratively. We screened 944 records, of which 27 studies were included in the review. The age at diagnosis is ∼3 years of age and the most common factor associated with acquired HI was middle ear infections. There were numerous reports on medication toxicity, with kanamycin-induced ototoxicity requiring specific attention when considering the high burden of tuberculosis in South Africa. The Waardenburg Syndrome is the most common reported syndromic HI. The Usher Syndrome is the only syndrome with genetic investigations, whereby a founder mutation was identified among black South Africans (MYO7A-c.6377delC). GJB2 and GJB6 genes are not major contributors to nonsyndromic HI among Black South Africans. Furthermore, emerging data using targeted panel sequencing have shown a low resolution rate in Black South Africans in known HI genes. Importantly, mutations in known nonsyndromic HI genes are infrequent in South Africa. Therefore, whole-exome sequencing appears as the most effective way forward to identify variants associated with HI in South Africa. Taken together, this article contributes to the emerging field of planetary health genomics with a focus on HI and offers new insights and lessons learned for future roadmaps on genomics/multiomics and clinical studies of HI around the world.

Etiologies of Childhood Hearing Impairment in Schools for the Deaf in Mali.

Objectives: To identify the etiologies of hearing impairment (HI) in schools for students who are deaf and to use a systematic review to summarize reports on the etiologies and clinical and genetic features of HI in Mali. Methods: We included individuals with HI that started before the age of 15 years old. Patients were carefully evaluated under standard practices, and pure-tone audiometry was performed where possible. We then searched for articles published on HI in the Malian population from the databases' inception to March 30, 2020. Results: A total of 117 individuals from two schools for the deaf were included, and a male predominance (sex ratio 1.3; 65/52) was noted. HI was pre-lingual in 82.2% (n = 117), and the median age at diagnosis was 12 years old. The etiologies were environmental in 59.4% (70/117), with meningitis being the leading cause (40%, 20/70), followed by cases with genetic suspicion (29.3%, 21/117). In 11.3% (8/117) of patients, no etiology was identified. Among cases with genetic suspicion, three were syndromic, including two cases of Waardenburg syndrome, while 15 individuals had non-syndromic HI. An autosomal recessive inheritance pattern was observed in 83.3% of families (15/18), and consanguinity was reported in 55.5% (10/18) of putative genetic cases. Conclusion: This study concludes that environmental factors are the leading causes of HI in Mali. However, genetic causes should be investigated, particularly in the context of a population with a high consanguinity rate.

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.

The Hearing Impairment Ontology: A Tool for Unifying Hearing Impairment Knowledge to Enhance Collaborative Research.

Hearing impairment (HI) is a common sensory disorder that is defined as the partial or complete inability to detect sound in one or both ears. This diverse pathology is associated with a myriad of phenotypic expressions and can be non-syndromic or syndromic. HI can be caused by various genetic, environmental, and/or unknown factors. Some ontologies capture some HI forms, phenotypes, and syndromes, but there is no comprehensive knowledge portal which includes aspects specific to the HI disease state. This hampers inter-study comparability, integration, and interoperability within and across disciplines. This work describes the HI Ontology (HIO) that was developed based on the Sickle Cell Disease Ontology (SCDO) model. This is a collaboratively developed resource built around the 'Hearing Impairment' concept by a group of experts in different aspects of HI and ontologies. HIO is the first comprehensive, standardized, hierarchical, and logical representation of existing HI knowledge. HIO allows researchers and clinicians alike to readily access standardized HI-related knowledge in a single location and promotes collaborations and HI information sharing, including epidemiological, socio-environmental, biomedical, genetic, and phenotypic information. Furthermore, this ontology illustrates the adaptability of the SCDO framework for use in developing a disease-specific ontology.

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.