A putative founder effect for Parkinson’s disease in South African Afrikaners

There is evidence for a founder effect for Parkinson’s disease in South African Afrikaners. This finding is of importance for two reasons. Firstly, given that established genetic causes of PD have not been identified in the Afrikaner population, it appears likely that this population carries unique mutations that remain to be identified by genome-wide screening. Secondly, in the event that effective treatments are developed, particularly for presymptomatic patients, the Afrikaner population may be considered to be at risk and requiring careful assessment with accurate biomarkers

A putative founder effect for Parkinson's disease in South African Afrikaners

Neurodegenerative diseases are important causes of disability and death, with prominent examples including Alzheimer’s disease, Parkinson’s disease (PD) and motor neuron disease. Although familial clustering of these illnesses was well known before the advent of modern molecular genetics, meaningful strides in identifying the origin of neurodegenerative diseases have really only begun to be made in the past two decades. All these disorders are characterised by a small percentage of affected patients whose disease is clearly the result of Mendelian inherited genetic illness, either recessive or dominant. In particular, dominant disease is exemplified in the case of Alzheimer’s disease by presenilin 2 mutations that arose in German immigrants from the Volga river region in the 17th century,[1] and in PD by mutations in the LRRK2 protein that are linked to a founder effect dating back to the 2nd century, probably in Ashkenazi Jews.http://www.samj.org.zaam201

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

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 PNKDhttp://www.karger.com/Journal/Home/224132hb201

TOR1A mutation-related isolated childhood-onset generalised dystonia in South Africa

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.http://www.samj.org.zadm2022Neurolog

Comparison of HTLV-associated myelopathy (HAM) in HIV-positive and HIV-negative patients at a tertiary South African hospital

BACKGROUND. HTLV-1 associated myelopathy (HAM), or tropical spastic paraparesis, is caused by a retrovirus, the human T-cell lymphotropic virus (HTLV). Although patients with HAM and HIV infection have been described, to our knowledge no direct comparison has been made between patients who are HIV positive and suffering from HAM (HHAM) v. those who are HIV negative and suffering from HAM. AIM. We aimed to compare clinical and radiological findings in HIV-positive and -negative patients with HAM. METHODS. Adult patients who presented to the Neurology Unit at the Steve Biko Academic Hospital from May 2005 to June 2012 with a progressive myelopathy and HTLV seropositivity were retrospectively identified and their clinical and radiological data were collected and reviewed. RESULTS. 21 patients with HAM were identified, of whom 9 were HIV-positive and 11 HIV-negative. One patient, whose HIV status had not been established, was not included in the study. Although the trend did not reach statistical significance, co-infected patients tended to present at an earlier age (HHAM 6/9 (66%) <40 years old; HAM 2/11 (18%) <40 years old) and presented to hospital earlier (HHAM 6/9 (66%) 3 years symptomatic). Cord atrophy occurred in 7/8 dually infected patients and 8/10 HIV-negative patients. CONCLUSION. Although the study is limited by the small number of patients, co-infected patients tended to have a younger age of onset and to present to hospital sooner, and thoracic cord atrophy was very common.http://www.samj.org.zaam201

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.http://www.samj.org.zaam201

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

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.http://www.samj.org.zaam2016Chemical PathologyInternal MedicineNeurolog

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.https://www.sciencedirect.com/journal/clinical-parkinsonism-and-related-disordershj2023NeurologyPsycholog