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GNE-myopathy (GNE-M) is a rare autosomal recessive disorder caused by variants in the GNE gene. We report a novel variant in GNE causing GNE-M in a Malian family. A 19-year-old male patient from consanguineous marriage was seen for progressive walking difficulty. Neurological examination found predominant distal muscle weakness and atrophy, decreased tendon reflexes, predominating in lower limbs. Electroneuromyography showed an axonal neuropathy pattern. However, whole exome sequencing (WES) revealed a novel biallelic variant in GNE c.1838G > A:p.Gly613Glu, segregating with the phenotype within the family. This study highlights its diagnosis challenges in sub-Saharan Africa and broadens the genetic spectrum of this rare disease.
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Structural variants are responsible for a large part of genomic variation between individuals and play a role in both common and rare diseases. Databases cataloguing structural variants notably do not represent the full spectrum of global diversity, particularly missing information from most African populations. To address this representation gap, we analysed 1,091 high-coverage African genomes, 545 of which are public data sets, and 546 which have been analysed for structural variants for the first time. Variants were called using five different tools and datasets merged and jointly called using SURVIVOR. We identified 67,795 structural variants throughout the genome, with 10,421 genes having at least one variant. Using a conservative overlap in merged data, 6,414 of the structural variants (9.5%) are novel compared to the Database of Genomic Variants. This study contributes to knowledge of the landscape of structural variant diversity in Africa and presents a reliable dataset for potential applications in population genetics and health-related research.
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BACKGROUND: Our recent studies have shown headache disorders to be very common in the central and western sub-Saharan countries of Benin and Cameroon. Here we report headache in nearby Mali, a strife-torn country that differs topographically, culturally, politically and economically. The purposes were to estimate headache-attributed burden and need for headache care. METHODS: We used cluster-random sampling in seven of Mali's eleven regions to obtain a nationally representative sample. During unannounced household visits by trained interviewers, one randomly selected adult member (18-65 years) from each household was interviewed using the structured HARDSHIP questionnaire, with enquiries into headache in the last year and, additionally, headache yesterday (HY). Headache on ≥ 15 days/month (H15+) was diagnosed as probable medication-overuse headache (pMOH) when associated with acute medication use on ≥ 15 days/month, and as "other H15+" when not. Episodic headache (on < 15 days/month) was recorded as such and not further diagnosed. Burden was assessed as impaired participation (days lost from paid and household work, and from leisure activity). Need for headache care was defined by criteria for expectation of benefit. RESULTS: Data collection coincided with the SARS-CoV-2 pandemic. The participating proportion was nonetheless extremely high (99.4%). The observed 1-year prevalence of any headache was 90.9%. Age- and gender-adjusted estimates were 86.3% for episodic headache, 1.4% for pMOH and 3.1% for other H15+. HY was reported by 16.8% with a mean duration of 8.7 h. Overall mean headache frequency was 3.5 days/month. Participants with pMOH lost more days from paid (8.8 days/3 months) and household work (10.3 days/3 months) than those with other H15+ (3.1 and 2.8 days/3 months) or episodic headache (1.2 and 0.9 days/3 months). At population level, 3.6-5.8% of all time was spent with headache, which led to a 3.6% decrease in all activity (impaired participation). Almost a quarter (23.4%) of Mali's adult population need headache care. CONCLUSION: Headache is very common in Mali, as in its near neighbours, Benin and Cameroon, and associated with substantial losses of health and productivity. Need for headache care is high - a challenge for a low-income country - but lost productivity probably translates into lost gross domestic product.
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Costo de Enfermedad , Cefalea , Evaluación de Necesidades , Humanos , Adulto , Malí/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Adulto Joven , Adolescente , Cefalea/epidemiología , Anciano , PrevalenciaRESUMEN
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.
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Complejo 2 de Proteína Adaptadora , Endocitosis , Paraplejía Espástica Hereditaria , Animales , Niño , Preescolar , Femenino , Humanos , Masculino , Complejo 2 de Proteína Adaptadora/genética , Endocitosis/genética , Endocitosis/fisiología , Mutación/genética , Mutación Missense , Neuronas/metabolismo , Neuronas/patología , Linaje , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , XenopusRESUMEN
Background: Huntington's disease like 2 (HDL2) has been reported exclusively in patients with African ancestry, mostly originating from South Africa. Case report: We report three patients in Mali including a proband and his two children who have been examined by neurologists and psychiatrists after giving consent. They were aged between 28 and 56 years old. Psychiatric symptoms were predominant in the two younger patients while the father presented mainly with motor symptoms. Genetic testing identified a heterozygous 40 CTG repeat expansion in the Junctophilin-3 (JPH3) gene in all three patients. Discussion: This study supports the hypothesis that HDL2 may be widely spread across Africa. Highlights: We report here the first case of HDL2 in West Africa, suggesting that HDL2 is widely spread across African continent, and increasing access to genetic testing could uncover other cases.
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Enfermedad de Huntington , Niño , Humanos , Adulto , Persona de Mediana Edad , Malí , Enfermedad de Huntington/genética , Familia , Pruebas Genéticas , HeterocigotoRESUMEN
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.
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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.
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Every year on February 28, the global community comes together to observe Rare Disease Day, a day dedicated to raising awareness and understanding for the millions of individuals who live with rare disorders. While individual rare diseases may seem uncommon, their collective impact is significant, affecting the lives of countless families and communities worldwide. This day serves as a crucial platform to amplify the voices of those affected, advocate for increased research and support, and inspire hope for a future where rare diseases can be prevented, diagnosed earlier, and effectively treated.
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Enfermedades Raras , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Enfermedades Raras/terapiaRESUMEN
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.
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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.
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Epilepsias Mioclónicas , Adulto , Humanos , Epilepsias Mioclónicas/genética , Intrones , Repeticiones de Microsatélite , ARN , Convulsiones/genéticaRESUMEN
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.
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Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated. Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study. Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research. Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.
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Enfermedades no Diagnosticadas , Recién Nacido , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Salud Global , Atención a la Salud , Gastos en SaludRESUMEN
Introduction: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden. Methods: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved. Results: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries. Discussion: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.
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Enfermedades no Diagnosticadas , Humanos , Enfermedades Raras/diagnóstico , Encuestas y CuestionariosAsunto(s)
Población Negra , Genómica , África , Genómica/tendencias , Genética Médica , Humanos , Población Negra/genéticaRESUMEN
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.
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Epilepsia , Paraplejía Espástica Hereditaria , Humanos , Masculino , Femenino , Adolescente , Niño , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/epidemiología , Paraplejía Espástica Hereditaria/genética , Malí/epidemiología , Extremidad Inferior , Epilepsia/complicaciones , Mutación , LinajeRESUMEN
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.
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The African Society of Human Genetics (AfSHG) was formed to provide a forum for human genetics and genomics scientists in Africa to interact, network, and collaborate. This is critical to facilitate development of solutions to the public health burden of many rare and common diseases across the continent. AfSHG fully supports the Black Lives Matter movement, which is dedicated to fighting racism and ensuring that society values the lives and humanity of Black people. The AfSHG would like to add its "voice" to the public outcry against racism sparked by George Floyd's death and to declare its commitment to ensuring that injustice and systematic racism, as well as abuse and exploitation of Africans and their biological material, are no longer tolerated. This is particularly relevant now as African genomic variation is poised to make significant contributions across several disciplines including ancestry, personalized medicine, and novel drug discovery. "Black Lives Matter and Black Research Matters" is AfSHG's call for the global community to support halting, and reversing, the perpetuation of exploitation of African people through neocolonial malpractices in genomic research. We also propose five key ways to curb racism in science, so that we can move forward together, with a common humanity, collectively embracing scientific endeavors.
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Racismo , África , Genómica , Genética Humana , Humanos , Racismo/prevención & controlRESUMEN
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.
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Pérdida Auditiva , Péptidos y Proteínas de Señalización Intracelular , Proteínas Nucleares , Proteínas Tirosina Fosfatasas , Adolescente , Adulto , Síndrome Branquio Oto Renal , Niño , Pérdida Auditiva/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Persona de Mediana Edad , Proteínas Nucleares/genética , Linaje , Proteínas Tirosina Fosfatasas/genética , Adulto JovenRESUMEN
The rich and diverse genomics of African populations is significantly underrepresented in reference and in disease-associated databases. This renders interpreting the Next Generation Sequencing (NGS) data and reaching a diagnostic more difficult in Africa and for the African diaspora. It increases chances for false positives with variants being misclassified as pathogenic due to their novelty or rarity. We can increase African genomic data by (1) making consent for sharing aggregate frequency data an essential component of research toolkit; (2) encouraging investigators with African data to share available data through public resources such as gnomAD, AVGD, ClinVar, DECIPHER and to use MatchMaker Exchange; (3) educating African research participants on the meaning and value of sharing aggregate frequency data; and (4) increasing funding to scale-up the production of African genomic data that will be more representative of the geographical and ethno-linguistic variation on the continent. The RDWG of H3Africa is hereby calling to action because this underrepresentation accentuates the health disparities. Applying the NGS to shorten the diagnostic odyssey or to guide therapeutic options for rare diseases will fully work for Africans only when public repositories include sufficient data from African subjects.
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Enfermedades no Diagnosticadas , África , Población Negra/genética , Genómica , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genéticaRESUMEN
To embrace the prospects of accurately diagnosing thousands of monogenic conditions, predicting disease risks for complex traits or diseases, tailoring treatment to individuals' pharmacogenetic profiles, and potentially curing some diseases, research into African genomic variation is a scientific imperative. African genomes harbor millions of uncaptured variants accumulated over 300,000 years of modern humans' evolutionary history, with successive waves of admixture, migration, and natural selection combining with extensive ecological diversity to create a broad and exceptional genomic complexity. Harnessing African genomic complexity, therefore, will require sustained commitment and equitable collaboration from the scientific community and funding agencies. African governments must support academic public research and industrial partnerships that build the necessary genetic medicine workforce, utilize the emerging genomic big data to develop expertise in computer science and bioinformatics, and evolve national and globalgovernance frameworks that recognize the ethical implications of data-driven genomic research and empower its application in African social, cultural, economic, and religious contexts.