International Paediatric Mitochondrial Disease Scale

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Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions

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. Methods: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6–16 years) from five different expert centres from four different continents were evaluated in this study. Results: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23–0.99). Conclusion: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials

Enhanced Lifetime Of Excitons In Nonepitaxial Au/cds Core/shell Nanocrystals

The ability of metal nanoparticles to capture light through plasmon excitations offers an opportunity for enhancing the optical absorption of plasmon-coupled semiconductor materials via energy transfer. This process, however, requires that the semiconductor component is electrically insulated to prevent a backward charge flow into metal and interfacial states, which causes a premature dissociation of excitons. Here we demonstrate that such an energy exchange can be achieved on the nanoscale by using nonepitaxial Au/CdS core/shell nanocomposites. These materials are fabricated via a multistep cation exchange reaction, which decouples metal and semiconductor phases leading to fewer interfacial defects. Ultrafast transient absorption measurements confirm that the lifetime of excitons in the CdS shell (tau approximate to 300 ps) is much longer than lifetimes of excitons in conventional, reduction-grown Au/CdS heteronanostructures. As a result, the energy of metal nanoparticles can be efficiently utilized by the semiconductor component without undergoing significant nonradiative energy losses, an important property for catalytic or photovoltaic applications. The reduced rate of exciton dissociation in the CdS domain of Au/CdS nanocomposites was attributed to the nonepitaxial nature of Au/CdS interfaces associated with low defect density and a high potential barrier of the interstitial phase

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes

There is more to it than just congenital heart defects – The phenotypic spectrum of TAB2-related syndrome.

Background: Congenital heart defects (CHD) are the most common birth defect and disease-causing variant in TAB2 have found to be associated with isolated CHD. Recently, it became evident that pathogenic, mostly loss-of-function variants in TAB2 can also cause syndromic CHD that includes connective tissue anomalies. The number of published cases is limited posing a challenge for counseling affected patients and their relatives. Methods: Cases in whom whole exome sequencing was executed at our institute between January 2015 and June 2021 were screened for disease-causing variants in TAB2. Additionally, a PubMed-based review of the literature was performed in December 2021 in order to give an updated clinical overview of the TAB2-associated phenotypic spectrum, including our cases. Results: We identified three cases with syndromic CHD caused by different heterozygous loss-of-function variants in TAB2. In one of these cases, the variant was inherited by a healthy father. A comparison with published cases highlights that most patients were affected by structural and/or arrhythmic heart disease (about 90%) while about two third of all cases had syndromic comorbidity especially connective tissue defects and dysmorphic abnormalities. Conclusion: Our findings indicate a variable expressivity as well as reduced penetrance of TAB2-associated CHD. Disease-causing variants in TAB2 should be considered in cases with isolated CHD but also in syndromic CHD with connective tissue abnormalities. However, prediction of the patients’ clinical outcome solely based on the variant in TAB2 is still extremely challenging