Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools

Parkinson's disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants in CFAP65, RTF1, NRXN2, TEP1 and CCNF. The variant in NRXN2 was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. If NRXN2 is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD

Listerial brainstem encephalitis – treatable, but easily missed

CITATION: Fredericks, P., et al. 2015. Listerial brainstem encephalitis – treatable, but easily missed. South African Medical Journal, 105(1):17-20, doi:10.7196/SAMJ.8700.The original publication is available at http://www.samj.org.zaENGLISH ABSTRACT: Listerial brainstem encephalitis (LBE) is an uncommon form of listerial central nervous system infection that progresses rapidly and is invariably fatal unless detected and treated early. We report on six adult patients with LBE, of whom five were managed or co-managed by our unit during the period January - June 2012. All presented with a short prodromal illness followed by a combination of brainstem signs, including multiple cranial nerve palsies with emphasis on the lower cranial nerves, ataxia, motor and sensory long-tract signs, a depressed level of consciousness and apnoea. In two cases the diagnosis was delayed with adverse outcomes. LBE may be difficult to diagnose: clinicians may not be aware of this condition, the brainstem location may not be recognised readily, general markers of inflammation such as the erythrocyte sedimentation rate, C-reactive protein level or white cell count may be normal, and the cerebrospinal fluid is typically normal or there are only mild and nonspecific findings. Serological tests are unreliable, and diagnosis is achieved through blood cultures, magnetic resonance imaging and clinical recognition.AFRIKAANSE OPSOMMING: Geen opsomming beskikbaarhttp://www.samj.org.za/index.php/samj/article/view/8700Publisher's versio