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.
•AP2A2 mutation is a novel genetic entity associated with neurodegenerative disease.•Mutation causes cell type specific defects in adaptor protein levels and function.•Patient derived cortical neurons have alteration of axonal initial segment length.•ap2a2 knockout in Xenopus tropicalis recapitulates seizures detected in patients.
We introduce here the term “River Culture” to delineate an eco-social approach to mitigate the biological and cultural diversity crisis in riverscapes. It is based on the insight that current ...environmental change endangers both, biological and cultural diversities in rivers and their basins, and those activities to improve ecosystem functions, biodiversity and capacity of the biological species to evolve will have a similarly positive effect on human cultural diversity. “River Culture” has two dimensions, including (a) the influence of the biophysical setting of rivers (specifically, their pulsating flow regimes and their biological features) on the expression of elements of human culture in general and (b) the aspect of “learning from the river” for the development of technologies and management options that are targeted to maintain and improve ecosystem functions and diversity in a more sustainable way. The River Culture approach, as given in this concept and discussion paper, is preliminarily based on five tenets: (1) Reset values and priorities in riverscape management in favor of human wellbeing and a harmonious coexistence of man and riverscape; (2) Live in the rhythm of the waters, i.e. adapt management options in accordance with the hydrological dynamics rather than fighting against them; (3) Transform traditional use of rivers into modern cultural activities and management options; (4) ‘Ecosystem bionics’: by copying survival strategies of flood-pulse adapted organisms novel forms of human use can be developed; (5) Make the catchment (river basin) the geographical base unit for all kinds of political decisions in landscape management.
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.
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.
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.
The CMT2D is a rare subtype of CMT with only few cases reported worldwide. We report here a novel mutation in the GARS gen in a Malian family, probably the first case in Africa.
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.
To describe the clinical and genetic aspects of HD in the Malian population.
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.
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.
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.
The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity ...among African individuals has been surveyed
. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
Abstract
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.
Yalcouyé et al. report that variants in CADM3 gene cause an axonal-type neuropathy. This study provides further evidence of the implication of CADM3 in the pathogenesis of Charcot–Marie–Tooth disease and raises the importance of including diverse and underrepresented populations like African in genetic studies.
Graphical Abstract
Graphical Abstract
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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