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.
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.
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.
Radiological features of cleidocranial dysplasia. (A) The orthopantomogram at age 8 showing germ retention and polyodontia with supernumerary teeth; (B) Chest X‐rays showing a total absence of the clavicles and (C) Pelvic x‐rays showing a left coxa Vara lesion; Brain CT‐scan showing (D) a dilatation of the occipital horns of the lateral ventricles at the time of diagnosis and (E) 3 years later; 3D reconstruction of the CT‐scan of the skull in (F) anterior view showing patent anterior fontanel, the absence of the upper part of the frontal and the parietal bones, (G) posterior view showing the absence of the parietal bone with preservation of the occipital bone, and (H, I) progression of the cranial bone development after 3 years of evolution with a notable reduction of the bone defect.
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.
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.
Most cases of Branchio‐otic syndrome (BO) have been reported in populations of European ancestry. Using Whole Exome, and Sanger Sequencing, we identified a monoallelic pathogenic variant in EYA1 c.1286A>G; p.(Asp429Gly) segregating with Branchio‐otic syndrome (BO)syndrome, in eight individuals from a large non‐consanguineous Malian family, with autosomal dominant inheritance. It is the first time the identified variant has been reported in Africa, expanding the genetic spectrum of the disease.
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.
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.
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.
•Hereditary spastic paraplegia type 11 is a rare complex neurodegenerative disease.•A novel homozygote deletion variant in the spatacsin gene in a Malian patient.•Although SPG11 is not reported in ...sub-Saharan Africa, it may not be uncommon.•While infectious and traumatic causes of spinal injury are most common in sub-Saharan Africa, genetic causes should also be investigated.
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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