Succinate in dystrophic white matter: A proton magnetic resonance spectroscopy finding characteristic for complex II deficiency

A deficiency of succinate dehydrogenase is a rare cause of mitochondrial encephalomyopathy. Three patients, 2 sisters and I boy from an unrelated family, presented with symptoms and magnetic resonance imaging signs of leukoencephalopathy. Localized proton magnetic resonance spectroscopy indicated a prominent singlet at 2.40ppm in cerebral and cerebellar white matter not present in gray matter or basal ganglia. The signal was also elevated in cerebrospinal fluid and could be identified as originating from the two equivalent methylene groups of succinate. Subsequently, an isolated deficiency of complex II (succinate:ubiquinone oxidoreductase) was demonstrated in 2 patients in muscle and fibroblasts. One of the sisters died at the age of 18 months. Postmortem examination showed the neuropathological characteristics of Leigh syndrome. Her younger sister, now 12 months old, is also severely affected; the boy, now 6 years old, follows a Milder, fluctuating clinical course. Magnetic resonance spectroscopy provides a characteristic pattern in succinate dehydrogenase deficiency

Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility

Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis

The effectiveness of technology-supported personalised learning in low- and middle-income countries: A meta-analysis

AbstractDigital technology offers the potential to address educational challenges in resource‐poor settings. This meta‐analysis examines the impact of students' use of technology that personalises and adapts to learning level in low‐ and middle‐income countries. Following a systematic search for research between 2007 and 2020, 16 randomised controlled trials were identified in five countries. Studies involved 53,029 learners aged 6–15 years. Coding examined learning domain (mathematics and literacy); personalisation level and delivery; technology use; and intervention duration and intensity. Overall, technology‐supported personalised learning was found to have a statistically significant—if moderate—positive effect size of 0.18 on learning (p = 0.001). Meta‐regression reveals how more personalised approaches which adapt or adjust to learners' level led to significantly greater impact (an effect size of 0.35) than those only linking to learners' interests or providing personalised feedback, support, and/or assessment. Avenues for future research include investigating cost implications, optimum programme length, and teachers' role in making personalised learning with technology effective. Practitioner notesWhat is already known about this topic? Promoting personalised learning is an established aim of educators. Using technology to support personalised learning in low‐ and middle‐income countries (LMICs) could play an important role in ensuring more inclusive and equitable access to education, particularly in the aftermath of COVID‐19. There is currently no rigorous overview of evidence on the effectiveness of using technology to enable personalised learning in LMICs. What this paper adds? The meta‐analysis is the first to evaluate the effectiveness of technology‐supported personalised learning in improving learning outcomes for school‐aged children in LMICs. Technology‐supported personalised learning has a statistically significant, positive effect on learning outcomes. Interventions are similarly effective for mathematics and literacy and whether or not teachers also have an active role in the personalisation. Personalised approaches that adapt or adjust to the learner led to significantly greater impact, although whether these warrant the additional investment likely necessary for implementation at scale needs to be investigated. Personalised technology implementation of moderate duration and intensity had similar positive effects to that of stronger duration and intensity, although further research is needed to confirm this. Implications for practice and/or policy: The inclusion of more adaptive personalisation features in technology‐assisted learning environments can lead to greater learning gains. Personalised technology approaches featuring moderate personalisation may also yield learning rewards. While it is not known whether personalised technology can be scaled in a cost‐effective and contextually appropriate way, there are indications that this is possible. The appropriateness of teachers integrating personalised approaches in their practice should be explored given ‘supplementary’ uses of personalised technology (ie, additional sessions involving technology outside of regular instruction) are common. </jats:sec

Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention

Pitfalls in the diagnosis of congenital hyperinsulinism: a case report and review of the literature

Background: Congenital hyperinsulinism is the most common cause for recurrent hypoglycaemia in neonates and infants. Uncontrolled hypoglycaemia leads to seizures and long-term cerebral damage. Often, the diagnosis is delayed because of nonspecific symptoms and confusing laboratory results. Patient: We report a patient with hyperinsulinism who was initially wrongly diagnosed as having idiopathic cerebral convulsions and treated accordingly. Conclusions: Diagnosis of congenital hyperinsulinism is based on a strong suspicion and a thorough family history. Normal random blood glucose or random insulin levels are not helpful in excluding this disease