Sensory neuropathy and metabolic risk factors in human immune deficiency virus infected South Africans receiving protease inhibitors

BackgroundProtease inhibitors (PI)s have been associated with distal sensory polyneuropathy (DSP) and metabolic complications in high-income countries. No data exist in Africans where second-line antiretroviral therapy (ART) often include PIs.MethodWe performed a cross-sectional study to assess the DSP frequency and metabolic risk factors in community-based South Africans taking ritonavir-boosted lopinavir as PI. Examination findings categorized subjects as having DSP (≥1 neuropathic sign) or symptomatic DSP [DSP with symptom(s)]. Fasting-state glucose and lipid profiles were assessed. We compared the ritonavir/lopinavir-group to a nested group on first-line ART [dideoxy-nucleoside reverse transcriptase inhibitors (d-drugs)] selected from a dataset collected at the same time and matched for d-drug exposure.ResultsThe ritonavir/lopinavir-group (n=86) consisted predominantly of women (84%) with a median age of 36years (IQR 32–41). The median current CD4+ count was 489cells/μL (IQR 291–665). The median exposure time to ritonavir/lopinavir was 18months (IQR 10–26) and to d-drugs, 24months (IQR 16–38). DSP was present in 78% and symptomatic DSP in 48%; symptoms were most frequently of moderate intensity. Only age independently associated with DSP and symptomatic DSP (p=0.08 and p=0.04, respectively). None of the metabolic syndrome components showed associations with DSP or symptomatic DSP despite a trend towards hypertriglyceridemia overall. The ritonavir/lopinavir-group had less DSP compared to the d-drug only group (p=0.002) but the frequency of symptomatic DSP was similar (p=0.49).ConclusionRitonavir-boosted lopinavir did not add additional risk to developing DSP in this community-based African cohort after a median of 18months on second-line ART.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-015-0073-8) contains supplementary material, which is available to authorized users

The complexity of HIV vasculopathy

We present a case and discuss stroke related to human immunodeficiency virus (HIV) infection and the difficulties of reaching a firm diagnosis of the cause of the aneurysmal vasculopathy. In the absence of a clear aetiology we suggest looking for varicella zoster virus (VZV) replication in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) and treating with intravenous acyclovir, aiming for HIV control with appropriate antiretroviral therapy and providing suitable antiplatelet agents. If there is a high index of suspicion of VZV, therapy with acyclovir may be prudent even if the CSF PCR is negative (as may occur after the first 2 weeks of reactivation of infection). Determination of a VZV plasma:CSF IgG ratio is not readily available and would only provide surrogate support for a previous VZV infection in the central nervous system compartment

Using Whole Genome Sequencing in an African Subphenotype of Myasthenia Gravis to Generate a Pathogenetic Hypothesis

Myasthenia gravis (MG) is a rare, treatable antibody-mediated disease which is characterized by muscle weakness. The pathogenic antibodies are most frequently directed at the acetylcholine receptors (AChRs) at the skeletal muscle endplate. An ophthalmoplegic subphenotype of MG (OP-MG), which is characterized by treatment resistant weakness of the extraocular muscles (EOMs), occurs in a proportion of myasthenics with juvenile symptom onset and African genetic ancestry. Since the pathogenetic mechanism(s) underlying OP-MG is unknown, the aim of this study was to use a hypothesis-generating genome-wide analysis to identify candidate OP-MG susceptibility genes and pathways. Whole genome sequencing (WGS) was performed on 25 AChR-antibody positive myasthenic individuals of African genetic ancestry sampled from the phenotypic extremes: 15 with OP-MG and 10 individuals with control MG (EOM treatment-responsive). Variants were called according to the Genome Analysis Toolkit (GATK) best practice guidelines using the hg38 reference genome. In addition to single variant association analysis, variants were mapped to genes (±200 kb) using VEGAS2 to calculate gene-based test statistics and HLA allele group assignment was inferred through “best-match” alignment of reads against the IMGT/HLA database. While there were no single variant associations that reached genome-wide significance in this exploratory sample, several genes with significant gene-based test statistics and known to be expressed in skeletal muscle had biological functions which converge on muscle atrophy signaling and myosin II function. The closely linked HLA-DPA1 and HLA-DPB1 genes were associated with OP-MG subjects (gene-based p < 0.05) and the frequency of a functional A > G SNP (rs9277534) in the HLA-DPB1 3′UTR, which increases HLA-DPB1 expression, differed between the two groups (G-allele 0.30 in OP-MG vs. 0.60 in control MG; p = 0.04). Furthermore, we show that rs9277534 is an HLA-DBP1 expression quantitative trait locus in patient-derived myocytes (p < 1 × 10−3). The application of a SNP to gene to pathway approach to this exploratory WGS dataset of African myasthenic individuals, and comparing dichotomous subphenotypes, resulted in the identification of candidate genes and pathways that may contribute to OP-MG susceptibility. Overall, the hypotheses generated by this work remain to be verified by interrogating candidate gene and pathway expression in patient-derived extraocular muscle

A review of the genetic spectrum of hereditary spastic paraplegias, inherited neuropathies and spinal muscular atrophies in Africans

Background Genetic investigations of inherited neuromuscular disorders in Africans, have been neglected. We aimed to summarise the published data and comment on the genetic evidence related to inherited neuropathies (Charcot-Marie-Tooth disease (CMT)), hereditary spastic paraplegias (HSP) and spinal muscular atrophy (SMA) in Africans. Methods PubMed was searched for relevant articles and manual checking of references and review publications were performed for African-ancestry participants with relevant phenotypes and identified genetic variants. For each case report we extracted phenotype information, inheritance pattern, variant segregation and variant frequency in population controls (including up to date frequencies from the gnomAD database). Results For HSP, 23 reports were found spanning the years 2000–2019 of which 19 related to North Africans, with high consanguinity, and six included sub-Saharan Africans. For CMT, 19 reports spanning years 2002–2021, of which 16 related to North Africans and 3 to sub-Saharan Africans. Most genetic variants had not been previously reported. There were 12 reports spanning years 1999–2020 related to SMN1-SMA caused by homozygous exon 7 ± 8 deletion. Interestingly, the population frequency of heterozygous SMN1-exon 7 deletion mutations appeared 2 × lower in Africans compared to Europeans, in addition to differences in the architecture of the SMN2 locus which may impact SMN1-SMA prognosis. Conclusions Overall, genetic data on inherited neuromuscular diseases in sub-Saharan Africa, are sparse. If African patients with rare neuromuscular diseases are to benefit from the expansion in genomics capabilities and therapeutic advancements, then it is critical to document the mutational spectrum of inherited neuromuscular disease in Africa. Highlights Review of genetic variants reported in hereditary spastic paraplegia in Africans Review of genetic variants reported in genetic neuropathies in Africans Review of genetic underpinnings of spinal muscular atrophies in Africans Assessment of pathogenic evidence for candidate variant

Exome sequencing identifies novel dysferlin mutation in a family with paucisymptomatic heterozygous carriers

BACKGROUND: We investigated a South African family of admixed ancestry in which the first generation (G1) developed insidious progressive distal to proximal weakness in their twenties, while their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. Our aim was to identify deleterious mutations that segregate with the affected individuals in this family. METHODS: Exome sequencing was performed on five cases, which included three affected G1 siblings and two pauci-symptomatic G2 offspring. As controls we included an unaffected G1 sibling and a spouse of one of the G1 affected individuals. Homozygous or potentially compound heterozygous variants that were predicted to be functional and segregated with the affected G1 siblings, were further evaluated. Additionally, we considered variants in all genes segregating exclusively with the affected (G1) and pauci-symptomatic (G2) individuals to address the possibility of a pseudo-autosomal dominant inheritance pattern in this family. RESULTS: All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF (dysferlin) mutation, with their asymptomatic sibling and both pauci-symptomatic G2 offspring carrying only a single mutant allele. Sanger sequencing confirmed segregation of the variant. No additional potentially contributing variant was found in the DYSF or any other relevant gene in the pauci-symptomatic carriers. CONCLUSION: Our finding of a truncating dysferlin mutation confirmed dysferlinopathy in this family and we propose that the single mutant allele is the primary contributor to the neuromuscular symptoms seen in the second-generation pauci-symptomatic carriers

Acute intermittent porphyria presenting as progressive muscular atrophy in a young black man

Acute intermittent porphyria, the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe a 23-year-old black South African man presenting with a progressive stuttering, lower motor neuron syndrome developing over months. He had not experienced pain or neuropsychiatric symptoms. One year after symptom onset he was bed-bound with a flaccid quadriparesis. There was marked amyotrophy, but without fasciculations. Sensation was intact apart from a hypo-aesthetic patch over the thigh. Electrophysiological investigations showed an active motor axonopathy. Urinary porphyrins, δ-aminolaevulinic acid and porphobilinogen were elevated. Mutation analysis revealed the c445C>T (R149X) mutation in the porphobilinogen deaminase gene. The patient responded dramatically to haem arginate and could walk with assistance 2 weeks later. We identified the first molecularly confirmed acute intermittent porphyria in a black South African. The clinical presentation mimicked a progressive lower motor neuron syndrome.

The characteristics of juvenile myasthenia gravis among South Africans

Objectives. To report the characteristics of juvenile-onset