Determining the neurocognitive profile of children with tuberous sclerosis complex within the Western Cape region of South Africa.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder associated with a wide spectrum of cognitive impairments that can often result in impaired academic, social and adaptive functioning. However, studies investigating TSC have found it difficult to determine whether TSC is associated with a distinct cognitive phenotype and more specifically which aspects of functioning are impaired. Furthermore, children with TSC living in low-income and middle-income countries, like South Africa, experience additional burdens due to low socio-economic status, high mortality rates and poor access to health care and education. Hence, the clinical population of South Africa may vary considerably from those populations from high-income countries discussed in the literature. METHODS: A comprehensive neuropsychological battery composed of internationally recognised measures examining attention, working memory, language comprehension, learning and memory, areas of executive function and general intellectual functioning was administered to 17 children clinically diagnosed with TSC. RESULTS: The exploration of descriptive data indicated generalised cognitive difficulties in most cognitive domains, aside from memory. With only two participants performing in the average to above-average ranges, the rest of the sample showed poor verbal comprehension, perceptual reasoning, working memory, processing speed, disinhibition, and problems with spatial planning, problem solving, frustration tolerance, set shifting and maintaining a set of rules. Furthermore, correlational findings indicated several associations between socio-demographic and cognitive variables. CONCLUSIONS: Importantly, this is the first study to comprehensively examine multiple domains of neurocognitive functioning in a low-resource setting sample of children with TSC. Current study findings showed that children with TSC have generalised impairments across several cognitive domains, rather than domain-specific impairments. Therefore, although examining individual aspects of cognition, such as those found in previous literature, is important, this approach is limiting. With a comprehensive assessment, including understanding the associations between domains, appropriate and directed support can be provided to ensure all aspects of development are addressed and considered.

Medical management of children with epilepsy.

Epilepsy is a common neurological condition presenting to the pediatrician. There are many seizure mimics and the differential diagnosis of paroxysmal events is wide which may make a definitive diagnosis challenging. Epilepsy is a heterogeneous condition with marked variability in presentation, underlying etiologies, associated comorbidities and outcomes. The reorganization of epilepsies in 2010 reflects an increasing understanding of the neuropathological and etiological mechanisms as a result of rapid technological advances in neuroimaging techniques and molecular genetics in particular. An increasing number of treatment options are available although high quality evidence, applicable to children, is lacking. Choices should be tailored to the individual patient applying knowledge of adverse drug effects, including the potential for seizure exacerbation in certain syndromes. Neurobehavioral and psychiatric comorbidities occur in up to 80% of children and frequently remain unrecognized. Screening for these conditions should form part of holistic management, along with awareness of the psychosocial and educational needs of the child from the time of initial diagnosis. The management of individual children with epilepsy therefore presents a myriad challenges. Early referral to a specialist with expertise in the management of pediatric epilepsy should be sought whenever there is diagnostic uncertainty or a poor response to therapy.

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

The utility of mobile telephone-recorded videos as adjuncts to the diagnosis of seizures and paroxysmal events in children with suspected epileptic seizures.

BACKGROUND: Epilepsy is often diagnosed through clinical description, but inter-observer interpretations can be diverse and misleading. OBJECTIVE: To assess the utility of smartphone videos in the diagnosis of paediatric epilepsy. METHODS: The literature was reviewed for evidence to support the use of smartphone videos, inclusive of advantages, ethical practice and potential disadvantages. An existing adult-based quality of video (QOV) scoring tool was adapted for use in children. A pilot study used convenience sampling of videos from 25 patients, which were reviewed to assess the viability of the adapted QOV tool against the subsequent diagnosis for the patients with videos. The referral mechanism of the videos was reviewed for the source and consent processes followed. RESULTS: A total of 14 studies were identified. Methodologies varied; only three focused on videos of children, and QOV was formally scored in three. Studies found that smartphone videos of good quality assisted the differentiation of epilepsy from non-epileptic events, especially with accompanying history and with more experienced clinicians. The ethics and risks of circulation of smartphone videos were briefly considered in a minority of the reports. The pilot study found that the adapted QOV tool correlated with videos of moderate and high quality and subsequent diagnostic closure. CONCLUSIONS: Data relating to the role of smartphone video of events in children is lacking, especially from low- and middle-income settings. Guidelines for caregivers to acquire good-quality videos are not part of routine practice. The ethical implications of transfer of sensitive material have not been adequately addressed for this group. Prospective multicentre studies are needed to formally assess the viability of the adapted QOV tool for paediatric videos.

RYR1 mutations are a common cause of congenital myopathies with central nuclei.

OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

Medical cannabis: What practitioners need to know.

The South African (SA) Constitutional Court recently decriminalised the private cultivation, possession and use of cannabis by adults. Cannabis contains varying amounts of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), depending on various cultivation factors. No commercial plant-derived cannabis products are currently registered by the SA Health Products Regulatory Authority (SAHPRA) for medical use. Such products are therefore unregulated, but are freely available in SA, and may be of inadequate quality and unverified composition, and not guaranteed to be safe or effective. SAHPRA has to date approved only one synthetic medical cannabis product, dronabinol. Evidence supporting benefit from medical cannabis exists for two drug-resistant childhood forms of epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. Adjuvant therapy with medical cannabis can reduce seizure frequency for Lennox-Gastaut syndrome and Dravet syndrome by 18.8% and 22.8%, respectively, and may be beneficial for other rare forms of epilepsy. There is moderate evidence for chemotherapy-induced nausea and vomiting with the synthetic cannabinoids. Multiple sclerosis-associated spasticity showed a small clinical improvement in self-reported spasticity when a purified form of THC/CBD was added to existing therapy. Currently, low-level or no convincing evidence exists for the use of medical cannabis for chronic pain, sleep and weight disorders, and neuropsychiatric disorders. Cannabis is associated with a greater risk of adverse effects than active and placebo controls, and may be involved in clinically significant drug-drug interactions. The evolving regulatory and legal landscape on the use of medical cannabis will guide prescription and recreational use in the coming years.

A retrospective description of primary immuno-deficiency diseases at Red Cross War Memorial Children's Hospital, Cape Town, South Africa, 1975 - 2017.

BACKGROUND: The primary immunodeficiency diseases (PIDs) constitute a diverse and ever-expanding group of inborn errors affecting a wide range of immune functions. They are not well documented in sub-Saharan Africa. OBJECTIVES: To describe the spectrum of PIDs at a tertiary paediatric hospital. METHODS: A retrospective descriptive study of PIDs diagnosed at Red Cross War Memorial Children's Hospital, Cape Town, South Africa (SA), between 1975 and 2017 was undertaken. RESULTS: We identified 252 children with PIDs, spanning eight of the nine categories listed in the 2017 classification of the International Union of Immunological Societies. Predominantly antibody deficiencies, combined immunodeficiencies with associated syndromic features, and immunodeficiencies affecting cellular and humoral immunity accounted for most children with PIDs (n=199, 79.0%). The mean age (standard deviation) at diagnosis was 46 (50) months, and the male/female ratio was 1.5:1. There was a history of parental consanguinity in 3 cases (1.2%). Recurrent infection was the most prevalent presenting phenotype, manifesting in 177 patients (70.2%). Genetic or chromosomal confirmation was obtained in 42/252 cases (16.7%). Common interventions used to prevent infection were antimicrobial prophylaxis and immunoglobulin replacement therapy, administered to 95 (37.7%) and 93 (36.9%) of the patients, respectively. Six of 7 children who underwent haematopoietic stem cell transplantation (HSCT) had successful outcomes. The 7th patient died 2 months after HSCT from overwhelming infection. Although we could not account for the children lost to follow-up during the study period, 53 deaths were confirmed (21.0%). CONCLUSIONS: Several challenges exist in the recognition and treatment of children with PIDs in our setting. These include limited access to genetic diagnostics and HSCT. Suboptimal treatment options contribute to the overall mortality of PIDs in SA.

Seizures in Children with HIV infection in South Africa: A retrospective case control study.

PURPOSE: Data relating to the role that Human immunodeficiency virus (HIV) contributes towards seizures in HIV-infected children is limited. The management of seizures in this group is complex due to potential interactions between antiseizure medication and antiretroviral therapies. This study explores the seizure semiology and course of a population of affected children based on questions raised from a previous epidemiological study. METHODS: A retrospective case-control study of all patients presenting to an HIV neurology clinic between 2008-2015 was conducted. A multinomial logistic regression model was used to identify risk factors for seizure occurrence in HIV-infected children, as well as factors associated with seizure control. RESULTS: Of 227 HIV-infected children (median 82 months, interquartile range 41-109), 52 (23%) reported a past or present history of seizures. Prior bacterial meningitis (p = 0.03, OR 12.5, 95% CI 1.2-136.1), cerebrovascular accident (CVA, p = 0. 005, OR 8.1, 95% CI 1.9-34.9) and or tuberculous meningitis (TBM, p = 0.0004) was associated with an increased risk of seizures in HIV-infected children. Generalised tonic-clonic seizures were the predominant seizure type (64%) with the majority caused by an infectious aetiology (62%). Thirty-two (62%) of these patients had epilepsy in-line with the latest diagnostic criteria. HIV-infected children with epilepsy who were treated with efavirenz were more likely to have poor seizure control (OR 23.1 95% CI 3.4-159.6, p = 0.0001). CONCLUSIONS: This study provides new data highlighting the complex clinical presentation and management challenges of HIV-infected children with seizures.

Lake sediment fecal and biomass burning biomarkers provide direct evidence for prehistoric human-lit fires in New Zealand.

Deforestation associated with the initial settlement of New Zealand is a dramatic example of how humans can alter landscapes through fire. However, evidence linking early human presence and land-cover change is inferential in most continental sites. We employed a multi-proxy approach to reconstruct anthropogenic land use in New Zealand's South Island over the last millennium using fecal and plant sterols as indicators of human activity and monosaccharide anhydrides, polycyclic aromatic hydrocarbons, charcoal and pollen as tracers of fire and vegetation change in lake-sediment cores. Our data provide a direct record of local human presence in Lake Kirkpatrick and Lake Diamond watersheds at the time of deforestation and a new and stronger case of human agency linked with forest clearance. The first detection of human presence matches charcoal and biomarker evidence for initial burning at c. AD 1350. Sterols decreased shortly after to values suggesting the sporadic presence of people and then rose to unprecedented levels after the European settlement. Our results confirm that initial human arrival in New Zealand was associated with brief and intense burning activities. Testing our approach in a context of well-established fire history provides a new tool for understanding cause-effect relationships in more complex continental reconstructions.

The African Hospitalist Fellowship.

The African Paediatric Fellowship Programme is rolling out a training course for newly qualified paediatricians to equip them with the leadership skills to function in complex general paediatric settings. The care of children in Africa carries its own unique demands, from the layering effects of multiple conditions through to establishing and sustaining services under severe resource constraints. This novel training concept aims to strengthen confidence and knowledge in areas that are not priorities during standard general paediatric training. The skills gained are considered of great relevance in assisting general paediatricians to achieve their full potential in their careers.

Tuberous sclerosis complex in the Western Cape, South Africa: The clinical presentation features.

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous condition, which affects multiple organ systems. This study aimed to determine the presenting features of children with TSC in Cape Town, South Africa. A cross-sectional study was conducted at a TSC clinic, and clinical features at presentation were prospectively collected. Thirty-nine children (23 boys; median age 10 (range 1 - 26) years; median diagnosis age 16 (0 - 153) months) were recruited. Twenty-one (54%) children presented with focal seizures. Seven (18%) children had epileptic spasms. Skin manifestations led to a diagnosis in 13 (33%) and neuroimaging in 22 (56%) children. Antenatal screening detected cardiac rhabdomyomas in 3 children. One child had a positive family history. In the paediatric service, TSC diagnosis usually followed neuroimaging, whereas at the neurology service skin manifestations indicated TSC. In conclusion, most children with TSC presented as emergency cases with seizures. Health practitioner awareness of the common TSC clinical signs was lacking, with the diagnosis often delayed.

Duchenne muscular dystrophy in the Western Cape, South Africa: Where do we come from and where are we going?

Duchenne muscular dystrophy (DMD) is one of the most common and severe of the inherited dystrophies, with an incidence of 1 in 3 500 live, male births worldwide. Becker muscular dystrophy (BMD) has a lower incidence of 1:14 000 - 18 000 boys and a milder progression and longer life expectancy. Over the last two decades, better understanding of the underlying disease aetiology as well as major advances in medical technology have brought about significantly improved genetic diagnosis and clinical care for B/DMD patients. Exciting developments in the field of gene-based therapies have once again put B/DMD in the limelight, with renewed focus on the importance of comprehensive genetic testing protocols. We present a historical overview of the medical and molecular service for B/DMD offered over the last three decades in South Africa, specifically in the Western Cape, from a clinical as well as a laboratory perspective.

Acute sensory neuropathy in an adolescent girl following BCG vaccination.

A 13-year-old girl developed a sensory neuropathy following bacille Calmette-Guérin (BCG) vaccination, consistent with acute inflammatory demyelinating polyradiculoneuropathy or acute sensory axonal neuropathy.

Infantile-onset paroxysmal dystonia: a diagnostic dilemma.

A 4-year-old boy presented with a history of paroxysmal dystonic posturing since birth. Episodes were triggered by stress, fatigue, and cold. Sleep, for as short as 1 minute, resulted in complete resolution of dystonia. He was developmentally normal, with no focal neurologic deficits. Cerebrospinal fluid, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were borderline low. On ictal spectroscopy, there was reduced blood flow to the right temporal region, caudate nuclei, and thalami. The typical infantile form of dystonia is benign, resolving by 2 years of age in an otherwise normal child. Our patient remains symptomatic at 4 years of age.

Migrating partial seizures in infancy: two new cases.

Two infants presented at 3 weeks and 3 months of age with intractable partial seizures. Extensive investigations failed to identify an underlying cause. There was no response to antiepileptic drug therapy and no developmental progress following the onset of the seizures. In both infants there was a distinctive pattern of seizures that arose independently from multiple regions of both hemispheres. Interictal electroencephalograms revealed multifocal epileptiform activity. The infants died aged 9 and 12 months. One underwent postmortem examination, which was normal with no hippocampal sclerosis. These infants fulfill the diagnostic criteria of the syndrome of migrating partial seizures in infancy described by Coppola and colleagues in 1995.

Positron emission tomography in imaging spinal cord tumors.

The ability of positron emission tomography (PET) to detect spinal cord tumors was studied prospectively in 14 patients presenting over a 5-year period. Abnormal uptake by [18F]-fluorodeoxyglucose (FDG) or 11C-methionine was detected in all except one. These data were assessed in relation to magnetic resonance imaging (MRI) findings with regard to tumor type and extent preoperatively, findings at operation, and subsequent clinical course. The group consisted of six astrocytomas, five ependymomas, one mixed ependymoma and astrocytoma, one schwannoma, and one ganglioglioma, all confirmed histologically. This is the largest study comparing spinal PET to MRI. Accurate preoperative correlation between PET and MRI was found in all eight patients scanned at first presentation. The PET uptake was in keeping with the low-grade histology of the tumors. Postoperatively, PET and MRI findings were in agreement in nine patients. In eight of these the findings were in keeping with the subsequent clinical course. In three patients, however, the PET findings were at variance with the clinical course and MRI findings. In one, persistent FDG uptake after radiotherapy was seen where there was subsequent tumor resolution. In two patients with low-grade astrocytomas, scanned with FDG and 11C-methionine, respectively, tracer was not taken up by residual tumor. In this small group of patients, PET did not provide additional useful information. This could be because all tumors studied were low grade and the limited spatial resolution of PET does not lend itself to imaging small spinal cord tumors. The prospective study of larger numbers of patients with a wider range of tumor types is required, but this might be difficult to achieve given the rarity of spinal cord tumors.

Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort.

BACKGROUND: Duchenne/Becker muscular dystrophy (D/BMD) is an X-linked recessive muscle disorder affecting 1/3 500 live male births worldwide. Up to 70% of all D/BMD cases are caused by exonic deletions or duplications routinely identified in diagnostic laboratories worldwide.The remaining patients harbour other sequence alterations for which testing availability is limited owing to the expense of interrogating the large DMD gene. Genetic screening for D/BMD in South Africa currently includes multiple ligase-dependent probe amplification (MLPA) for exonic deletions and duplications and linkage analysis. No genetic testing for small mutations in the DMD gene is offered, leaving a third of D/BMD families without genetic closure. The advent of potential mutation-specific therapies for DMD necessitates comprehensive testing protocols. OBJECTIVE: To investigate the effectiveness and affordability of high-resolution melting curve analysis (hrMCA) for detection of small/point mutations in the DMD gene, for possible inclusion into the local public health-funded diagnostic service. METHODS: DNA from 24 patients who had previously tested deletion-negative with multiplex polymerase chain reaction (mPCR) was analysed by MLPA and hrMCA. RESULTS: MLPA revealed eight previously undetected exonic rearrangements: five deletions and three duplications. HrMCA of the remaining samples revealed three nonsense, four frameshifts, one splice-site, one missense and one single-base substitution in the Dp427promoter/exon1 of the DMD gene. In addition, 41 polymorphisms and three changes of uncertain significance were detected. CONCLUSION: These findings identify hrMCA as an affordable and effective mutation scanning tool for incorporation into the local diagnostic setting, allowing for better genetic counselling of more DMD families and selection of potential candidates for future therapies.

Neuropsychiatric movement disorders following streptococcal infection.

The aim of this study was to describe post-streptococcal movement disorders that form part of the acute rheumatic fever complex. The clinical records of patients diagnosed with Sydenham's chorea were analyzed retrospectively to investigate epidemiology, the significance of socioeconomic deprivation, clinical manifestations, treatments, outcomes, long-term morbidity, and disease evolution. Forty-two patients (21 males, 21 females) were diagnosed with Sydenham's chorea. The median presentation age was 9 years 8 months (range 3y 5mo to 13y 2mo). Nineteen patients were of indigenous African ancestry; 23 were of mixed ancestry. All patients lived in poverty and had poor access to medical care. Twelve of the total group had disabling symptoms for longer than 2 years; six of these patients developed paediatric autoimmune neuropsychiatric disorder associated with Streptococcus (Paediatric autoimmune neuropsychiatric disorder associated with Streptococcus [PANDAS]), five Tourette syndrome (TS), and one learning difficulties. Poor outcome was significantly more prevalent in patients of mixed ancestry, in those with a positive family history, previous behavioural problems, or a failure to complete 10 days of penicillin and 'bed-rest'/hospitalization. Sydenham's chorea is one manifestation of post-streptococcal neuropsychiatric movement disorders. This study demonstrates that patients can present with one diagnosis and evolve other neuropsychiatric conditions such as TS and PANDAS. In the South African context, it is important to delineate neuropsychiatric movement disorders associated with streptococcal infections. The potential genetic susceptibility should be explored.