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Purpose: Despite the high number of patients with phalangeal fractures, evidence-based recommendations for the treatment of specific phalangeal fractures could not be concluded from the literature. The purpose of the present study was to assess current epidemiological data, classification of the fracture type, and mode of treatment. Methods: This study presents a retrospective review of 261 patients with 283 phalangeal fractures ≥ 18 years of age who were treated in our level I trauma centre between 2017 and 2018. The data were obtained by the analysis of the institution’s database, and radiological examinations. Results: The average age of the patients was 40.4 years (range 18–98). The ratio of male to female patients was 2.7:1. The two most typical injury mechanisms were crush injuries (33%) and falls (23%). Most phalangeal fractures occurred in the distal phalanx (P3 43%). The 4th ray (D4 29%) was most frequently affected. The P3 tuft fractures, and the middle phalanx (P2) base fractures each accounted for 25% of fracture types. A total of 74% of fractures were treated conservatively, and 26% required surgery, with Kirschner wire(s) (37%) as the preferred surgical treatment. The decision for surgical treatment correlated with the degree of angular and/or rotational deformity, intraarticular step, and sub-/luxation of specific phalangeal fractures, but not with age and gender. Conclusions: Our findings demonstrated the popularity of conservative treatment of phalangeal fractures, while surgery was only required in properly selected cases. The correct definition of precise fracture pattern in addition to topography is essential to facilitate treatment decision-making.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

Mitochondrial diseases are a heterogeneous group of disorders characterized by faulty oxidative phosphorylation. They can present with a broad range of symptoms occurring at any age. Their diverse clinical manifestation is accompanied by a vast genetic heterogeneity making molecular diagnosis challenging. To identify disease causing variants I initially investigated the coding regions using whole exome sequencing (WES). For identification of noncoding pathogenic variants I subsequently established a RNA sequencing (RNA-seq) analysis. I validated prioritized variants and novel disease-associated genes using functional complementation assays, quantitative proteomics, and metabolomics., Mitochondriopathien sind eine heterogene Gruppe von Erkrankungen die durch eine fehlerhafte oxidative Phosphorylierung charakterisiert sind. Sie können mit einer Großzahl von Symptomen in jedem Alter auftreten. Ihre diverse klinische Manifestierung geht mit einer großen genetischen Heterogenität einher was eine große Herausforderung für die molekulare Diagnose darstellt. Um krankheitsverursachenden Varianten zu identifizieren habe ich zunächst die kodierenden Bereichen mittels Whole Exome Sequencing (WES) untersucht. Zur Identifizierung von nicht-kodierenden pathogenen Varianten habe ich anschließend eine Transkriptomanalyse durchgeführt. Priorisierte Varianten und neue krankheitsassoziierte Gene habe ich mittels funktioneller Komplementationsstudien, quantitativer Proteomanalyse und Metabolomdaten validiert.

Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.

Mitochondrial diseases are a heterogeneous group of disorders characterized by faulty oxidative phosphorylation. They can present with a broad range of symptoms occurring at any age. Their diverse clinical manifestation is accompanied by a vast genetic heterogeneity making molecular diagnosis challenging. To identify disease causing variants I initially investigated the coding regions using whole exome sequencing (WES). For identification of noncoding pathogenic variants I subsequently established a RNA sequencing (RNA-seq) analysis. I validated prioritized variants and novel disease-associated genes using functional complementation assays, quantitative proteomics, and metabolomics., Mitochondriopathien sind eine heterogene Gruppe von Erkrankungen die durch eine fehlerhafte oxidative Phosphorylierung charakterisiert sind. Sie können mit einer Großzahl von Symptomen in jedem Alter auftreten. Ihre diverse klinische Manifestierung geht mit einer großen genetischen Heterogenität einher was eine große Herausforderung für die molekulare Diagnose darstellt. Um krankheitsverursachenden Varianten zu identifizieren habe ich zunächst die kodierenden Bereichen mittels Whole Exome Sequencing (WES) untersucht. Zur Identifizierung von nicht-kodierenden pathogenen Varianten habe ich anschließend eine Transkriptomanalyse durchgeführt. Priorisierte Varianten und neue krankheitsassoziierte Gene habe ich mittels funktioneller Komplementationsstudien, quantitativer Proteomanalyse und Metabolomdaten validiert.