The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include collaboration in genetic studies in Mali and in a review of procedures for reporting of secondary genomic findings from exome sequencing. Through the Mali collaboration, over 120 families have been evaluated, with more than 17 different genetic diagnoses in 24 families. Our current focus is on the remaining families with phenotypes of interest, autosomal recessive inheritance & consanguinity. Exome sequencing and segregation analysis are done through NISC for candidate gene identification. We evaluated a Malian family in which three individuals had hereditary spastic paraplegia (HSP) and distal muscle atrophy and sensory loss. HSP panel testing identified a novel heterozygous missense mutation in KIF5A (c.1086G>C, p.Lys362Asn) that segregated with the disease (SPG10). Lys362 is highly conserved across species and Lys362Asn is predicted to be damaging. This study shows that HSPs are present in sub-Saharan Africa, although likely underdiagnosed. Increasing efficiency and decreasing costs of DNA sequencing will make it more feasible to diagnose HSPs in developing countries.
| Jerath, Nivedita U; Mankodi, Ami; Crawford, Thomas O et al. (2018) Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle Nerve 57:749-755 |
| Guinto, Cheick O; Diarra, Salimata; Diallo, Salimata et al. (2017) A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss. Ann Clin Transl Neurol 4:272-275 |
| Geiger, Joshua T; Schindler, Alice B; Blauwendraat, Cornelis et al. (2017) TUBB2B Mutation in an Adult Patient with Myoclonus-Dystonia. Case Rep Neurol 9:216-221 |
| Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig (2017) SCA8 should not be tested in isolation for ataxia. Neurol Genet 3:e150 |
| Landouré, Guida; Samassékou, Oumar; Traoré, Mahamadou et al. (2016) Genetics and genomic medicine in Mali: challenges and future perspectives. Mol Genet Genomic Med 4:126-34 |
| Darnell, Andrew J; Austin, Howard; Bluemke, David A et al. (2016) A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research. Am J Hum Genet 98:435-41 |
| Rinaldi, Carlo; Schmidt, Thomas; Situ, Alan J et al. (2015) Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA Neurol 72:561-70 |
| Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya et al. (2015) Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability. Hum Mutat 36:48-56 |
| Grunseich, Christopher; Schindler, Alice B; Chen, Ke-Lian et al. (2015) Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency. J Neurol 262:1066-8 |
| Grunseich, Christopher; Kats, Ilona R; Bott, Laura C et al. (2014) Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat. Neuromuscul Disord 24:978-81 |
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