Atypical Presentations of Huntington Disease-like 2 in South African Individuals.

BACKGROUND: Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. OBJECTIVE: To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. METHODS: Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. RESULTS: Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). CONCLUSION: This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability.

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Efficacy of deep brain stimulation of the anterior-medial globus pallidus internus in tic and non-tic related symptomatology in refractory Tourette syndrome.

Introduction: Although refractory Tourette Syndrome (TS) is rare, it poses great challenges in clinical practice. Co-morbid psychiatric symptoms often occur, negatively impacting quality of life. Deep brain stimulation (DBS) targeting different brain structures seems effective for tics, but specific literature regarding response of psychiatric symptoms is more limited.This study aimed to assess the outcome of tics and non-tic related symptomatology in refractory TS treated with antero-medial globus pallidus interna (amGPi) DBS. Methods: We included all patients with refractory TS (January 2013-August 2020) from the Brain Nerve Centre and Steve Biko Academic Hospital, Pretoria, South Africa, treated with bilateral amGPi DBS; retrospective baseline, early (up to 3 months) post-DBS follow-up assessment data, as well as prospective data from the latest follow-up (mean 37.4 months) were collected using standardised scoring tools and scales. Results: Five patients were identified. Tics decreased by 63,9% (p = 0,002); quality of life improved by 39,8% (p = 0,015); self-injurious behaviour ceased; obsessive-compulsive symptoms resolved in all but one. The number of different chronic medications used more than halved. Transient stimulation-related adverse events occurred in four patients. Conclusion: This study contributes to the data of the efficacy of amGPi-targeted DBS in refractory TS, showing improvement in quality of life and both tic- and non-tic-related symptomatology..

Movement of prion-like α-synuclein along the gut-brain axis in Parkinson's disease: A potential target of curcumin treatment.

A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid ß-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved nutrient-based therapeutic interventions and preventative strategies for this debilitating and currently incurable disorder.

Screening of the glucocerebrosidase (GBA) gene in South Africans of African ancestry with Parkinson's disease.

Sequence variants in glucocerebrosidase (GBA) are a major genetic risk factor for Parkinson's disease (PD), and display ethnic-dependent frequencies, for example, variants such as p.N370S and 84insGG are common in Ashkenazi Jewish patients. Notably, there are limited studies on black patients from the African continent; hence, we conducted a study on 30 South African black PD patients. All 11 exons of GBA were screened using a nested PCR approach to avoid pseudogene contamination. We identified previously described Gaucher's disease-associated variants, p.R120W in one patient [age at onset (AAO) of 35 years], and p.R131L in another patient (AAO 30 years) and in her affected sibling (AAO 45 years). In addition, we found 3 previously identified [p.K(-27)R, p.T36del, and p.Q497*] and 2 novel (p.F216L and p.G478R) variants. Screening of ethnic-matched controls for the novel variants revealed that the allele frequency of p.F216L was 9.9%, whereas p.G478R was not found in the controls. Studies such as these are important and necessary to reveal the genetic architecture underlying PD in the understudied patients of African ancestry.

Frequency of the LRRK2 G2019S mutation in South African patients with Parkinson's disease.

G2019S in LRRK2 is the most common mutation associated with Parkinson's disease (PD). Highest frequencies are in North African Arabic (30-41%) and Ashkenazi Jewish (6-30%) populations, mostly due to founder effects. Here, we investigated the frequency of G2019S in 647 unrelated South African PD patients from different ancestral origins. It was found in only 1.2% (8/647) of patients. Notably, none of the 91 individuals of African ancestry had G2019S. It was present in 1.9% (3/154) and 1% (5/493) of early- and late-onset cases, respectively. The frequency of G2019S exhibits ethnic-specific differences and warrants further study in sub-Saharan African populations.

Longitudinal neuropsychological outcomes in treatment-resistant depression following bed nucleus of the stria terminalis-area deep brain stimulation: a case review.

Studies have demonstrated the effectiveness of deep brain stimulation (DBS) as a treatment modality for psychiatric conditions. We present a case reviewing the longitudinal neuropsychological performance outcomes following bed nucleus of the stria terminalis-area (BNST) DBS in a patient with treatment-resistant depression (TRD). The cognitive safety of DBS is well documented for various targets, however cognitive outcomes of BNST-area DBS have not been extensively reported for patients with TRD. Neuropsychological assessment was conducted pre- and post-DBS. Twelve months following DBS, augmented general cognitive performance was observed with significant changes in specific domains.

Familial cortical myoclonic tremor and epilepsy: Description of a new South African pedigree with 30 year follow up.

AIM: The aims of this study were to report the index case of a South African family with cortical myoclonic tremor and epilepsy, to describe the pedigree with the clinical findings and results of additional investigations, and to report the unique follow-up evaluation of affected and unaffected family members after 30 years. METHODS: The index case led to evaluation of the clinical files of patients from 1978/1979 and clinical assessment and investigation of patients from this cohort as well as newly identified family members. Patients were examined clinically; cortical myoclonic tremor severity was scored by using the Fahn-Tolosa- Marin-Tremor Rating Scale and the Myoclonus Rating Scale. Cortical origin of myoclonus was proven. Statistical analyses were done to assess the impact of cortical myoclonic tremor on quality of life. CONCLUSION: Clinical data was available for 23 patients. Increase in cortical myoclonic tremor and age showed a statistically significant correlation with worsening of the sub-score for Quality of Life (FTMTRS) and myoclonus rating scale. After 30 years eleven of fourteen patients could be followed up. Progression of cortical myoclonic tremor severity was noted but epilepsy control was adequate with all patients reporting less than two seizures per year. No clinical features of neurodegeneration were found. DISCUSSION: We describe the initial presentation and 30 year follow-up of a four generation South African family with FCMTE. The unique long term follow up of this pedigree supports previous findings that the condition does not cause additional progressive neurological deterioration and quality of life is mostly influenced by worsening of the cortical myoclonic tremor with age.

A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics.

Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients.

Severe porphyric neuropathy--importance of screening for porphyria in Guillain-Barré syndrome.

The hepatic porphyrias are a group of rare metabolic disorders, each of which is associated with a specific enzymatic alteration in the haem biosynthesis pathway. In South Africa (SA), a high incidence of variegate porphyria (VP) is seen as a result of a founder effect, but acute intermittent porphyria (AIP) is also encountered. The development of acute neurovisceral attacks is related to environmental factors, including medications, hormones and diet. A possible manifestation of a severe attack is rapidly progressing quadriparesis, which may mimic Guillain-Barré syndrome. We present four such cases, highlighting that acute porphyria should be considered in the differential diagnosis of Guillain-Barré syndrome. Three patients presented to Steve Biko Academic Hospital, Pretoria, SA, with progressive quadriparesis, and one to a private hospital with acute abdominal pain followed by rapidly progressive quadriparesis. Two patients had started antiretroviral therapy before the development of symptoms, and one had started antituberculosis therapy. All patients had marked weakness with depressed reflexes, and showed varying degrees of confusion. An initial diagnosis of Guillain-Barré syndrome led to administration of intravenous immunoglobulins in two patients. On testing for porphyria, it was found that two patients had AIP and two VP. Electrophysiological investigations revealed severe mainly motor axonal neuropathy in all. Two patients deteriorated to the point of requiring mechanical ventilation, and one of them died due to complications of critical illness. Haemin was administered to three patients, but the process of obtaining this medication was slow, which delayed the recommended early administration. The surviving patients showed minimal recovery and remained severely disabled. Porphyric neuropathy should always be considered as a differential diagnosis in a patient with an acute neuropathy, especially in SA. Absence of abdominal pain does not exclude the possibility of porphyria, and attacks may be precipitated by antiretroviral and antituberculosis medication. The outcome of our patients was not favourable; specifically, obtaining haemin was a challenge in the state hospital setting.

Successful treatment of disabling paroxysmal nonkinesigenic dyskinesia with deep brain stimulation of the globus pallidus internus.

UNLABELLED: Paroxysmal nonkinesigenic dyskinesia (PNKD) causes episodes of treatment-resistant involuntary movements. Previous case reports showed effective treatment of PNKD with deep brain stimulation (DBS). We report 2 patients in whom DBS was highly successful when other treatment modalities had failed. METHODS: Two patients aged 34 and 24 years with a longstanding history of PNKD were treated with globus pallidus internus (GPi) DBS. Motor effects were monitored and followed up postoperatively and again at 6 months after surgery. RESULTS: Both patients responded very well to GPi DBS with complete suppression of dyskinesia after surgery in 1 patient and in the second after an additional adjustment of stimulation. CONCLUSION: GPi DBS might be an effective alternative treatment modality for PNKD.