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.
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.
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.
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.
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.
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.
A sample of 276 normal subjects aged ≥50years (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.
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).
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.
•Dubois' 5WT is influenced by culture and the socio-educative level in French.•Modified 5WT according to local socio-cultural realities improves performances.•Our modified 5WT could be used in other countries to better diagnose AD.•Future studies including patients and normal controls will elucidate our hypothesis.
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.
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.
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 94years.
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%.
At the end of this study, we observed an important place for non-motor signs in the clinical manifestation of PD patients in general.
The SCA3 is an autosomal dominant heterogeneous neurodegenerative disorder characterized with gait ataxia, dysarthria and parkinsonism. Is the most common SCA worldwide, however only few cases were ...reported in Africa.
To clinically characterize families with SCA3 and identify the underlying genetic defect.
Patients with ataxia were examined in our Neurogenetics Clinic. DNA was collected from probands for genetic analysis. Brain imaging and blood chemistries were performed to exclude common causes.
287 families with a wide range of neurodegenerative were enrolled, and 177 patients presented with autosomal dominant ataxia. The gene panel testing showed CAG repeats in the ATXN3 gene in 4 probands. The mean age of onset was 29 years ranging from 10 to 59, anticipation has been noted in all families. The mean age at diagnosis was 43 years. For the genetic testing the average of CAG was 73 repeats, the four probands had cerebellar atrophy on the brain imaging.
We found a positive correlation between age of onset and CAG repeat numbers. Studying families with high number of affected sibs will allow refine or consolidate the natural history of these diseases. The haplotype studies may establish the origin of these mutations. We identified a penetrance in the different families, a very few cases (2) of non-penetrance are known, the MJD is considered fully penetrant.
We identified three families with SCA3; confirming that this disease is not uncommon in sub-Saharan Africa. Studying families with high number of affected sibs will allow refine or consolidate the natural history of these diseases.
This study was funded by the NIH through H3Africa project. There was no conflict of interest in this study.
Le syndrome d’encéphalopathie postérieure réversible (PRES) est un syndrome neurologique aigu ou subaigu réversible. Compte tenu de l’intérêt diagnostique, thérapeutique et évolutif de ce syndrome, ...rare dans la pratique courante, nous rapportons l’observation d’un cas au Mali.
Patiente âgée de 42 ans, mariée mère deux enfants, césarisée deux fois, aux antécédents d’hyperplasie endométriale et d’hypertension artérielle de découverte récente (4 jours) sous amlodipine 10mg. Elle a été admise pour céphalée, trouble de la vision à type de cécité bilatérale en neurologie. Avant son admission en neurologie elle avait été vu aux urgences de l’hôpital pour céphalée aiguë inhabituelle accompagnée de vomissements (4 fois) avec une tension systolique à 223mmHg 4 jours avant puis un médecin interniste qui retrouvait une TA à 20/14cmHg. Elle était admise pour perte de la vision.
L’examen neurologique d’entrée retrouvait une cécité bilatérale avec une parésie à 4/5 aux 4 membres (NIHSS à 7). L’IRM réalisée en urgence mettait en évidence plus de dix lésions lacunaires en hypersignal sur T2 diffusion sur en sus- et sous-tentoriel de façon bilatérale (hémisphères cérébelleux, lobes occipitaux, temporaux, pariétale droite). La goutte épaisse trouvait 32 trophozoïtes, Sur le plan thérapeutique elle recevait une association amlodipine 10mg et valsartan 160mg, l’artesunate injectable, et du paracétamol injectable. L’évolution a été marquée par la disparition complète des signes et symptômes le 3e jour de son hospitalisation (NIHSS à 0). L’IRM de contrôle réalisée 6 semaines après était revenu strictement normal. Le diagnostic de PRES syndrome a été retenu devant l’évolution clinique favorable et la disparition des signes d’imageries à l’IRM de contrôle.
Le PRES est un syndrome clinicoradiologique associant un tableau neurologique à des images radiologiques bilatérales et symétriques localisées aux lobes pariéto-occipitaux, et dont l’évolution est classiquement réversible. Dans notre observation la régression des signes cliniques et imagériques était très rapide.
Maladie rare d’évolution favorable, l’IRM diffusion est capitale dans le diagnostic.
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.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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