Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene.

Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period.

Clinical practice.

Basal ganglia and thalamus (BGT) hypoxic-ischaemic brain injury is currently the most contentious issue in cerebral palsy (CP) litigation in South Africa (SA), and merits a consensus response based on the current available international literature. BGT pattern injury is strongly associated with a preceding perinatal sentinel event (PSE), which has a sudden onset and is typically unforeseen and unpreventable. Antepartum pathologies may result in fetal priming, leading to vulnerability to BGT injury by relatively mild hypoxic insults.

Cerebral palsy and its medicolegal implications in low- resource settings - the need to establish causality and revise criteria to implicate intrapartum hypoxia: A narrative review.

The objective of this study was to establish scientific causality and to devise criteria to implicate intrapartum hypoxia in cerebral palsy (CP) in low-resource settings, where there is potential for an increase in damaging medicolegal claims against obstetric caregivers, as is currently the situation in South Africa. For the purposes of this narrative review, an extensive literature search was performed, including any research articles, randomised controlled trials, observational studies, case reports or expert or consensus statements pertaining to CP in low-resource settings, medicolegal implications, causality, and criteria implicating intrapartum hypoxia. In terms of causation, there are differences between high-income countries (HICs) and low-resource settings.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis.

A case for genomic medicine in South African paediatric patients with neuromuscular disease.

Paediatric neuromuscular diseases are under-recognised and under-diagnosed in Africa, especially those of genetic origin. This may be attributable to various factors, inclusive of socioeconomic barriers, high burden of communicable and non-communicable diseases, resource constraints, lack of expertise in specialised fields and paucity of genetic testing facilities and biobanks in the African population, making access to and interpretation of results more challenging. As new treatments become available that are effective for specific sub-phenotypes, it is even more important to confirm a genetic diagnosis for affected children to be eligible for drug trials and potential treatments.

Right of Reply.

To the Editor: The article by Bhorat et al. [1] in the SAMJ, entitled 'Cerebral palsy and criteria implicating intrapartum hypoxia in neonatal encephalopathy - an obstetric perspective for the South African setting', starts off by raising concerns about 'steep rises in insurance premiums, placing service delivery under serious threat'. It does not acknowledge any service delivery issues that already exist in the public sector obstetric services in South Africa (SA).

Medullary neuroschistosomiasis in a pediatric patient: a case report.

A pediatric patient with neurological deficit was examined using magnetic resonance imaging (MRI]. The images revealed abnormal signal intensity and enhancement of the spinal cord, indicating myelopathy. Identifying the cause of the myelopathy required a differential diagnosis.

Cerebral Palsy and Criteria Implicating Intrapartum Hypoxia in Neonatal Encephalopathy - An Obstetric Perspective for the South African Setting.

The science surrounding cerebral palsy indicates  that it is a complex medical condition with multiple contributing variables and factors, and causal pathways are often extremely difficult to delineate. The pathophysiological processes are often juxtaposed on antenatal factors, genetics, toxins, fetal priming, failure of neuroscientific autoregulatory mechanisms, abnormal biochemistry and abnormal metabolic pathways. Placing this primed compromised compensated brain through the stresses of an intrapartum process could be the final straw in the pathway  to brain injury and later CP.

Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), or glutaric aciduria type II (GAII), is a group of clinically heterogeneous disorders caused by mutations in electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) - the two enzymes responsible for the re-oxidation of enzyme-bound flavin adenine dinucleotide (FADH) via electron transfer to the respiratory chain at the level of coenzyme Q10. Over the past decade, an increasing body of evidence has further coupled mutations in FAD metabolism (including intercellular riboflavin transport, FAD biosynthesis and FAD transport) to MADD-like phenotypes. In this review we provide a detailed description of the overarching and specific metabolic pathways involved in MADD.

Panel-Based Nuclear and Mitochondrial Next-Generation Sequencing Outcomes of an Ethnically Diverse Pediatric Patient Cohort with Mitochondrial Disease.

Mitochondrial disease (MD) is a group of rare inherited disorders with clinical heterogeneous phenotypes. Recent advances in next-generation sequencing (NGS) allow for rapid genetic diagnostics in patients who experience MD, resulting in significant strides in determining its etiology. This, however, has not been the case in many patient populations.

The dilemma of diagnosing coenzyme Q deficiency in muscle.

Background: Coenzyme Q (CoQ) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD).

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency.

Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G>A (p.

International Paediatric Mitochondrial Disease Scale.

Objective: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study.

Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease?

The decision of the UK House of Commons in 2015 to endorse the use of pioneering in vitro fertilisation techniques to protect future generations from the risk of mitochondrial DNA (mtDNA) disease has sparked worldwide controversy and debate. The availability of such technologies could benefit women at risk of transmitting deleterious mutations. MtDNA disease certainly occurs in South Africa (SA) in all population groups.

3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients.

Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator.

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease.

Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients.

An overview of a cohort of South African patients with mitochondrial disorders.

Mitochondrial disorders are frequently encountered inherited diseases characterized by unexplained multisystem involvement with a chronic, intermittent, or progressive nature. The objective of this paper is to describe the profile of patients with mitochondrial disorders in South Africa. Patients with possible mitochondrial disorders were accessed over 10 years.

Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia.

A young, adult, African male patient presented with progressive proximal muscle weakness, external ophthalmoplegia and ptosis, as well as cardiac conduction abnormalities resembling Kearns-Sayre syndrome (KSS). Magnetic resonance imaging (MRI) of the brain revealed normal basal ganglia but bilateral well-circumscribed lesions in the cerebellar peduncles. Enzyme deficiencies in oxidative phosphorylation (OXPHOS) complexes I, IV and V was measured in muscle tissue.

Combined tarsal and carpal tunnel syndrome in mucolipidosis type III. A case study and review.

Mucolipidosis type III (MLIII) (MIM# 252600) is an uncommon autosomal recessive disorder that results from uridine 5'-diphosphate-N-acetylglucosamine: lysosomal hydrolase N-acetyl-1-phosphotransferase or UDP-GlcNAc 1-phosphotransferase deficiency. Clinical manifestations include developmental delay, short stature and other structural abnormalities. Less common clinical features, such as carpal tunnel syndrome, claw hand deformities, trigger fingers, and claw toes have previously been reported, but no specific association with tarsal tunnel syndrome has been reported in the literature.