Research Articles (Neurology)

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Brain tumours in the Western Cape Province of South Africa : a plea for a dedicated brain tumour registry in Africa
(Wits University Press, 2024-07-08) Basson, Dion; Schutte, Clara-Maria; Van Coller, Riaan; Gould, Trevor
BACKGROUND: Epidemiological data on brain tumours provides valuable insight into risk factors, treatment modalities and prognoses of these tumours. Despite abundant epidemiological data from brain tumour registries in high-income countries, a critical data gap persists in low- and middle-income countries. AIM: The aim of this study was to report on the epidemiology of brain tumours in South Africa's Western Cape province. METHODS: This retrospective study collected data from the National Health Laboratory Services database housed in the public healthcare sector in the Western Cape Province of South Africa. All pathology reports over 2 years (January 2018 to December 2019) that included the term “brain” or equivalent terms were analyzed to compile the epidemiological dataset. RESULTS: The dataset yielded 505 patients with brain tumours, with a mean age at diagnosis of 44 years (range: 0–82 years). A noteworthy subset (16%) of primary tumours occurred in individuals under 20 years of age. The top three primary tumour diagnoses in the study were gliomas, glioneuronal and neuronal tumours, meningiomas and pituitary tumours. Secondary brain tumours (18%) constituted a significant proportion of brain tumours, with lung and breast being the most common primary sites. Comparison with registries and audits from both high- and low-income countries revealed South Africa's unique landscape; ependymal tumours exhibited a substantial proportion, while nerve sheath tumours displayed a reduced proportion. CONCLUSION: This study offers a unique perspective on brain tumour epidemiology in South Africa's Western Cape Province. It reports on unique trends and emphasizes the feasibility and necessity of establishing a dedicated brain tumour registry.
Elevated factor VIII level in cerebral venous thrombosis : a case-control study
(Wits University Press, 2024-07-08) Bhagwan, Bhavin; Pillay, Manesh; Schutte, Clara-Maria; Masenge, Andries; Kakaza, Mandisa
BACKGROUND: Cerebral venous thrombosis (CVT) is an uncommon disorder accounting for approximately 1% of strokes worldwide There is a paucity of data regarding the association between an elevated factor VIII level and cerebral venous thrombosis (CVT). METHODS: From June 2015 to January 2022, patients with confirmed CVT on neuroimaging were identified at two public hospitals in South Africa. Their clinical presentation, radiological characteristics of thrombosis, and risk factors for CVT were analysed. Age-, sex-, and HIV status-matched controls were recruited. Factor VIII levels were analysed in patients with CVT and in controls. RESULTS: The study included 26 patients with CVT and 52 controls. The mean age was 40.3 and 41.4 years for the patients and controls, respectively. In the study group, 73% were females. An elevated factor VIII level (>150 IU/dL) was the most common risk factor, identified in 61.5% (16/26) of patients with CVT. The mean factor VIII level was significantly higher in patients with CVT compared to controls (200.1 vs 156.9, p = 0.017). An elevated factor VIII level (>200 IU/dL) increased the risk of CVT four-fold (age- and sex-adjusted OR: 4.437, 95% CI: 1.435–13.723, p = 0.009). CONCLUSION: An elevated factor VIII level is a common risk factor for CVT; hence, investigation thereof should be included in the aetiological work-up. This study suggests that a higher cut-off value for factor VIII level increases the strength of the association with CVT.
Non-motor fluctuations in Parkinson's disease : underdiagnosed yet important
(Korean Movement Disorder Society, 2025-01) Boura, Iro; Poplawska-Domaszewicz, Karolina; Spanaki, Cleanthe; Chen, Rosabel; Urso, Daniele; Van Coller, Riaan; Storch, Alexander; Chaudhuri, Kallol Ray
Non-motor fluctuations (NMFs) in Parkinson’s disease (PD) significantly affect patients’ well-being. Despite being identified over two decades ago, NMFs remain largely underrecognized, undertreated, and poorly understood. While they are often temporally associated with motor fluctuations (MFs) and can share common risk factors and pathophysiologic mechanisms, NMFs and MFs are currently considered distinct entities. The prevalence and severity of NMFs, often categorized into neuropsychiatric, sensory, and autonomic subtypes, vary significantly across studies due to the heterogeneous PD populations screened and the diverse evaluation tools applied. The consistent negative impact of NMFs on PD patients’ quality of life underscores the importance of further investigations via focused and controlled studies, validated assessment instruments and novel digital technologies. High-quality research is essential to illuminate the complex pathophysiology and clinical nuances of NMFs, ultimately enhancing clinicians’ diagnostic and treatment options in routine clinical practice.
Atypical presentations of Huntington disease-like 2 in South African individuals
(Wiley, 2024-07) Narotam-Jeena, Heena; Guttman, Mark; Van Hillegondsberg, Ludo; Van Coller, Riaan; Krause, Amanda; Carr, Jonathan
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.
Short-term changes in hypsarrhythmia assessed by spectral analysis : group and individual assessments
(Sage, 2024) Farinha, Jessica M.; Bartel, Peter R.; Becker, Piet J.; Hazelhurst, Lynton T.
Please read abstract in the article.
Addressing the gap for racially diverse research involvement : the King's model for minority ethnic research participant recruitment
(Elsevier, 2023-12) Chaudhuri, K.Ray; Podlewska, A.; Lau, Yue Hui; Gonde, C.; McIntosh, A.; Qamar, M.A.; O’Donoghue, S.; Larcombe, K.; Adeeko, M.; Gupta, A.; Bajwah, S.; Lafond, S.; Awogbemila, O.; Van Coller, Riaan; Murtagh, A.M.; Ocloo, J.E.
OBJECTIVES : Ethnic minorities (EM) are still underrepresented in research recruitment. Despite wide literature outlining the barriers, enablers and recommendations for driving inclusion and diversity in research, there is still little evidence for successful diversity in research participation, which has a direct impact on the quality of care provided to ethnically diverse individuals. A new, comprehensive approach to recruitment strategies is therefore necessary. STUDY DESIGN : service improvement initiative. METHODS : In the light of the Covid-19 pandemic and the key public health need to address the disparity in care provided to non-white populations, we used a novel, comprehensive approach (The King’s Model) comprising of local and community actions to promote inclusive research recruitment. We then compared rates of diverse recruitment in studies where the novel approach, was applied to studies which had been closed to recruitment at the time of analysis and where ethnicity data was available. RESULTS : Our results demonstrate that following the introduction of the King’s Model for diverse recruitment, commercial interventional study diverse recruitment increased from 6.4% to 16.1%, and for non-commercial studies, from 30.2% to 41.0% and 59.2% in the selected studies. CONCLUSIONS : King’s Model is potentially a useful tool in enhancing non-Caucasian recruitment to clinical research. Enriched by additional recommendations based on our experiences during the Covid-19 research recruitment drive, we propose the King’s Model is used to support ethnically diverse research recruitment. Further evidence is needed to replicate our findings, although this preliminary evidence provides granular details necessary to address the key unmet need of validating clinical research outcomes in non-white populations.
Lentiform fork sign on magnetic resonance imaging after methamphetamine and alcohol misuse
(American Medical Association, 2023-04) Hiesgen, Juliane; Badenhorst, Jacques; juliane.hiesgen@up.ac.za
A 37-year-old man presented to the emergency department with a 3-day history of acute blindness. He had delayed the consultation because of the belief that the symptoms were transient adverse reactions from an overuse of alcohol and drugs.
PTPA variants and impaired PP2A activity in early-onset Parkinsonism with intellectual disability
(Oxford University Press, 2023-04) Fevga, Christina; Tesson, Christelle; Mascaro, Ana Carreras; Courtin, Thomas; Van Coller, Riaan; Sakka, Salma; Ferraro, Federico; Farhat, Nouha; Bardien, Soraya; Damak, Mariem; Carr, Jonathan; Ferrien, Melanie; Boumeester, Valerie; Hundscheid, Jasmijn; Grillenzoni, Nicola; Kessissoglou, Irini A.; Kuipers, Demy J.S.; Quadri, Marialuisa; French and Mediterranean Parkinson disease Genetics Study Group, International Parkinsonism Genetics Network; Corvol, Jean-Christophe; Mhiri, Chokri; Hassan, Bassem A.; Lesage, Suzanne; Mandemakers, Wim; Brice, Alexis; Bonifati, Vincenzo
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 alphasynuclein, 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.
Guest editorial : Autoimmune encephalitis
(South African Medical Association, 2023-03) Hiesgen, Juliane; Schutte, Clara-Maria
Since the identification of anti-N-methyl-D-aspartate (NMDA) receptor antibodies about 15 years ago, many patients with rapidly progressing psychiatric symptoms, abnormal movements, seizures or unexplained coma, have been diagnosed with autoimmune encephalitis (AE). The symptom onset is often unspecific and might mimic psychiatric disease, but the later course is frequently characterized by severe disease, often requiring intensive care. Clinical and immunological criteria are helpful in identifying the patients, but no biomarkers exist to guide the clinician in therapy or predict outcome. While persons of all ages can be affected by AE, some types of AE affect more children and young adults and are more prevalent in women. This review will focus on encephalitides associated with neuronal cell-surface or synaptic antibodies, which can result in characteristic syndromes, and are often recognizable on clinical grounds. AE subtypes associated with antibodies against extracellular epitopes can occur with or without tumours. Because the antibodies bind and alter the function of the antigen, the effects are often reversible if immunotherapy is initiated, and the prognosis is favourable in most instances. The first part of this series will introduce the topic, provide an overview of current neuronal surface antibodies and how they present, describe the most common subtype, anti-NMDA receptor encephalitis, and discuss the difficulties in recognizing patients with underlying AE amongst patients with new onset psychiatric disorders.
Autoimmune encephalitis : epidemiology, pathophysiology and clinical spectrum (Part 1)
(South African Medical Association, 2023-03) Hiesgen, Juliane; Schutte, Clara-Maria
Since the identification of anti-N-methyl-D-aspartate (NMDA) receptor antibodies about 15 years ago, many patients with rapidly progressing psychiatric symptoms, abnormal movements, seizures or unexplained coma have been diagnosed with autoimmune encephalitis (AE). The symptom onset is often unspecific, and might mimic psychiatric disease, but the later course is frequently characterised by severe disease, often requiring intensive care. Clinical and immunological criteria are helpful in identifying the patients, but no biomarkers exist to guide the clinician in therapy or predict outcome. While persons of all ages can be affected by AE, some types of AE affect more children and young adults and are more prevalent in women. This review focuses on encephalitides associated with neuronal cell-surface or synaptic antibodies, which can result in characteristic syndromes, and are often recognisable on clinical grounds. AE subtypes associated with antibodies against extracellular epitopes can occur with or without tumours. Because the antibodies bind and alter the function of the antigen, the effects are often reversible if immunotherapy is initiated, and the prognosis is favourable in most instances. The first part of this series introduces the topic, provides an overview of currently known neuronal surface antibodies and how they present, describes the most common subtype anti-NMDA receptor encephalitis, and discusses the difficulties in recognising patients with underlying AE among patients with new-onset psychiatric disorders.
Autoimmune encephalitis : epidemiology, pathophysiology and clinical spectrum (Part 2)
(South African Medical Association, 2023-04) Hiesgen, J.; Schutte, Clara-Maria; juliane.hiesgen@up.ac.za
Autoimmune encephalitis (AE) represents a growing number of severe autoimmune-inflammatory diseases affecting both the white and grey matter of the brain. In part 1 of this series, we focused on the epidemiology, pathophysiology and clinical presentation of this condition, with two illustrative cases. In this part, we introduce the clinical criteria for AE, particularly for the diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, which were developed to facilitate immune treatment in suspected cases before antibody results are available. We subsequently discuss the work-up, differential diagnosis and treatment options for patients with this disease.
Late-onset efavirenz toxicity : a descriptive study from Pretoria, South Africa
(AOSIS, 2023-01-19) Munsami, Lyneshree; Schutte, Clara-Maria; De Villiers, Maryke; Hiesgen, Juliane
BACKGROUND : The neuropsychiatric side effects of efavirenz occur mainly early during treatment and are usually mild. A lesser-known and serious complication is late-onset efavirenz toxicity causing ataxia and encephalopathy. Data regarding this condition are limited. OBJECTIVES : We describe the clinical picture of late-onset efavirenz toxicity, investigate co-morbidities and report outcomes. METHOD : This descriptive study of all patients with late-onset efavirenz toxicity was conducted over three years at Kalafong Provincial Tertiary Hospital, Pretoria, South Africa. RESULTS : Forty consecutive patients were identified. Mean age was 42.1 years, three patients (7.5%) were male and the mean efavirenz level was 49.0 μg/mL (standard deviation [s.d.]: 24.8). Cerebellar ataxia (82.5%) and encephalopathy (47.5%) were the most common presenting features (40.0% had both); four patients presented with psychosis. Presence of encephalopathy and/or cerebellar ataxia was associated with higher efavirenz levels compared with psychosis (52.1 μg/mL, s.d.: 24.1 vs 25.0 μg/mL, s.d.: 17.1). In most patients, symptoms resolved, but four patients (10.0%) died, and one patient remained ataxic. CONCLUSION : Late-onset efavirenz toxicity typically presented with ataxia and encephalopathy, but psychosis can be the presenting feature. The outcome after withdrawal was good, but the mortality of 10.0% is concerning. Recent changes in guidelines favour dolutegravir, but many patients remain on efavirenz, and awareness of the condition is vital. WHAT THIS STUDY ADDS : This large, single-centre study contributes to the limited data of HIV-positive patients with late-onset efavirenz toxicity and emphasises its ongoing relevance in clinical practice.
Fiat lux : light and pedagogy for the 21st century
(Sage, 2023-04) Lech, James C.; Halma, Matthew T.J.; Obajuluwa, Adejoke O.; Baker, Malcolm Kevin; Hamblin, Michael R.
BACKGROUND : The relationship between the quality of the learning environment and student outcomes is receiving more serious attention from educational psychologists, neurologists, ophthalmologists, orthopedists, surgeons, oncologists, architects, ergonomists, nutritionists, and Michelin star chefs. There is a role for ergonomic office and school design to positively impact worker and student productivity, and one design attribute drawing attention is the indoor lit environment. In this review, we expand upon the role that light plays in education, as it has enabled millions of pupils to read at late hours, which were previously too dark. However, still unappreciated is the biological effects of artificial light on circadian rhythm and its subsequent impacts on health and learning outcomes. SUMMARY : This review describes the current state of light in the educational environment, its impact, and the effect of certain inexpensive and easy-to-implement adaptations to better support student growth, learning and development. We find that the current lighting environment for pupils is sub-optima based on biological mechanism and may be improved through cost effective interventions. These interventions can achieve greater biological harmonization and improve learner outcomes. KEY MESSASGE : This review describes the current state of light in the educational environment, its impact, and the effect of certain inexpensive and easy-to-implement adaptations to better support student growth, learning and development. We find that the current lighting environment for pupils is sub-optima based on biological mechanism and may be improved through cost effective interventions. These interventions can achieve greater biological harmonization and improve learner outcomes.
Efficacy of deep brain stimulation of the anterior-medial globus pallidus internus in tic and non-tic related symptomatology in refractory Tourette syndrome
(Elsevier, 2022) Kisten, Ravendran; Van Coller, Riaan; Cassimjee, Nafisa; Lubbe, Elsabeth (Elsa); Vaidyanathan, Janardan; Slabbert, Pieter; Enslin, Nico; Schutte, Clara-Maria
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.
Acute obstructive hydrocephalus in posterior reversible encephalopathy syndrome
(Health and Medical Publishing Group, 2023-01) Hiesgen, Juliane; Annor, T.N.
Posterior reversible encephalopathy syndrome (PRES) is an uncommon, subacute neurological disorder that presents radiologically with a pattern of bilateral parieto-occipital areas of vasogenic oedema. Conditions commonly associated with PRES include autoimmune disorders, cytotoxic drugs, metabolic abnormalities and, most frequently, hypertensive emergencies. Clinically, headache, visual disturbances, seizures and an altered level of consciousness are often reported. The outcome is favourable if the underlying cause is addressed. Posterior fossa involvement resulting in obstructive hydrocephalus is a rare presentation and may be misdiagnosed as a mass lesion or infection, leading to delayed or unnecessary treatment. We describe the clinical presentation, findings on neuroimaging and conservative management of a man with PRES resulting in severe cerebellar oedema and acute obstructive hydrocephalus. This case illustrates that awareness of atypical neuroimaging in PRES is important for the management of these patients and to avoid morbidity and mortality.
Neuro-Behcet – clinical and radiological findings in a patient of sub-Saharan African origin
(Elsevier, 2022-03) Pretorius, Johannes Jacobus; Hiesgen, Juliane; Myburgh, Michael; Suleman, Farhana Ebrahim; farhanah.suleman@up.ac.za
Behçet’s disease is a rare, systemic variable vessel vasculitis mostly seen in patients from the Middle East, Northern Africa and Central Asia. Neuro-Behçet disease (NBD) is often diagnosed in patients with known Behçet’s disease who present with neurological symptoms and radiological features of central nervous system involvement. There are very few cases with neuro-Behcet reported from Sub-Saharan Africa in the literature. We report a case of severe parenchymal neuro-Behçet with pseudo-tumoral brainstem lesions in a young male patient of South African origin.
Developing and testing a South African Brief Cognitive Score in literate and illiterate people of mixed language groups
(AOSIS, 2021-05-27) Schutte, Clara-Maria; Tsikane, Mukhethwa; Nchoe, Keorapetse; cschutte@medic.up.ac.za
BACKGROUND: The Folstein mini mental state exam (MMSE) is the most commonly administered assessment of cognitive functioning; however, its utility in illiterate individuals is limited. In South Africa, more than eight million adults are considered functionally illiterate and cognitive evaluation using standard scales is inaccurate. Other countries have developed adapted MMSE scales for their local purposes. AIM: The first aim of this study was to develop a South African Brief Cognitive Score (SA BCS) for use in minimally literate or illiterate individuals. The second aim was to test this SA BCS against the original Folstein MMSE in patients with memory problems. SETTING: The study was conducted in Tshilamba, Tshiombo, Tshifudi, Dzimauli and Pile in Venda as well as Rethabiseng and Zithobeni in Bronkhorstspruit for the illiterate study group, and Steve Biko Academic Hospital for the literate study groups. METHODS: The SA BCS was developed considering our local requirements and substituting questions needing literacy with items that did not. Both the original Folstein MMSE and the SA BCS were administered to groups of literate and illiterate normal individuals. Thereafter, the tests were repeated in groups of literate and illiterate patients with cognitive decline. RESULTS: Firstly, 33 illiterate and 31 literate subjects were assessed. The average original Folstein score was 29.29/30 for the literate subjects, and for the SA BCS 29.80. For the illiterate subjects, the average score for the original Folstein MMSE was 21.24/30 and for the SA BCS 27.45. Kruskall-Wallis equality of population rank test confirmed a significant improvement in the scores of the SA BCS in the illiterate group when compared to the original Folstein (p = 0.0001). In the second part of the study, 20 literate and 20 illiterate patients were assessed as before. In the literate group, the average original Folstein MMSE score was 20.5, while the average score for the South African BCS was 22.5. In the illiterate group, the average Folstein MMSE was 18.9; and the average score in the South African BCS was 22.8. The Kruskal-Wallis equality of population rank test showed a significant difference (p = 0.008) between the scores of the illiterate versus literate patients when the Folstein MMSE was used to assess cognition. With the SA BCS, no significant difference was found between the groups (p = 0.79). CONCLUSION: The SA BCS appears to have potential to be a more reliable scale when assessing cognition in illiterate or minimally literate subjects when compared to the original Folstein MMSE.
TOR1A mutation-related isolated childhood-onset generalised dystonia in South Africa
(Health and Medical Publishing Group, 2021-10) Van Coller, Riaan; Schutte, Clara-Maria; Lubbe, Elsabeth (Elsa); Ngele, B.; riaan.vancoller@up.ac.za
BACKGROUND : Childhood-onset generalised dystonia is commonly caused by TOR1A mutations and is known to respond well to pallidal deep-brain stimulation (DBS) surgery. The incidence and prevalence of monogenic dystonia in individuals from Africa and specifically of African ancestry are unknown, and no local cases of TOR1A mutation dystonia are found in the literature. OBJECTIVES : To describe our experience with the outcome of TOR1A mutation-positive patients with isolated generalised dystonia (IGD) of childhood onset who were treated with pallidal DBS. METHODS : All patients with TOR1A mutations from Steve Biko Academic Hospital and the Pretoria Neurology Institute in Pretoria, South Africa (SA), who underwent DBS for IGD of childhood onset were identified. We conducted a retrospective analysis of their demographics, clinical presentation and time to generalisation, genetic status and family history, and response to DBS treatment of the internal segment of the globus pallidus (GPi), utilising pre- and post-surgical scores of the United Dystonia Rating Scale (UDRS). Results. Three patients, all of black African ancestry, were identified. The median age at onset was 12 years and the median time to surgery from dystonia generalisation was 3 years. Two children presented with cervical-onset dystonia. Two patients were related, representing the only two with a positive family history. All three patients had a positive outcome after surgery, with improvement of 67 - 90% on the UDRS recorded at last follow-up. CONCLUSION : TOR1A mutations are found in SA patients of black African ancestry, with age of onset and generalisation comparable to those described in international studies. However, onset with cervical dystonia was more common than previously reported. Response to GPi DBS was excellent in all patients.
The HGR motif is the antiangiogenic determinant of vasoinhibin : implications for a therapeutic orally active oligopeptide
(Springer, 2022-02) Pablo Robles, Juan; Zamora, Magdalena; Siqueiros-Marquez, Lourdes; Adan-Castro, Elva; Ramirez-Hernandez, Gabriela; Freinet Nunez, Francisco; Lopez-Casillas, Fernando; Millar, Robert P.; Bertsch, Thomas; Martínez de la Escalera, Gonzalo; Triebel, Jakob; Clapp, Carmen
The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.
Movement of prion-like α-synuclein along the gut–brain axis in Parkinson's disease : a potential target of curcumin treatment
(Wiley, 2021-07) Chetty, Devina; Abrahams, Shameemah; Van Coller, Riaan; Carr, Jonathan; Kenyon, Colin; Bardien, Soraya
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 β-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.

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