Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

Objective: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.

Methods: Whole exome sequencing of the probands was performed to identify pathogenic variants.

Functional Evidence of as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations.

CCDC186 protein is involved in the maturation of dense-core vesicles (DCVs) in the trans-Golgi network in neurons and endocrine cells. Mutations in genes involved in DCV regulation, other than , have been described in patients with neurodevelopmental disorders. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in , had previously been described.

Leigh syndrome is the main clinical characteristic of PTCD3 deficiency.

Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome.

Bioenergetic and Autophagic Characterization of Skin Fibroblasts from Patients.

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis.

Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions.

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson's Disease.

The association between Parkinson's disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD.

Pediatric Gaucher disease with intermediate type 2-3 phenotype associated with parkinsonian features and levodopa responsiveness.

Introduction: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid β-glucosidase encoded by the GBA gene. In patients with GD, childhood onset parkinsonian features have been rarely described.

Methods: Twin siblings with GD are described, including clinical follow-up and treatment response.

External quality assessment in the absence of proficiency testing: A split-sample testing program experience.

In the field of laboratory medicine, proficiency testing is a vehicle used to improve the reliability of reported results. When proficiency tests are unavailable for a given analyte, an alternative approach is required to ensure adherence to the International Organization for Standardization (ISO) 15189:2012 standard. In this study, we report the results of a split-sample testing program performed as an alternative to a formal PT.

Implementation of second-tier tests in newborn screening for the detection of vitamin B related acquired and genetic disorders: results on 258,637 newborns.

Background: Alteration of vitamin B metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B deficiency have been detected by clinical symptoms and only few of them trough NBS programs.

Leigh syndrome associated with TRMU gene mutations.

tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease.

Biallelic mutations in NDUFA8 cause complex I deficiency in two siblings with favorable clinical evolution.

Isolated complex I (CI) deficiency is the most common cause of oxidative phosphorylation (OXPHOS) dysfunction. Whole-exome sequencing identified biallelic mutations in NDUFA8 (c.[293G > T]; [293G > T], encoding for an accessory subunit of CI, in two siblings with a favorable clinical evolution.

Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia.

Pathogenic mutations in NDUFAF4 have been reported in very few cases. Here we present new data to further delineate the phenotypic spectrum of NDUFAF4 deficiency. We describe two siblings presenting with facial dysmorphia and lactic acidosis in the neonatal period.

Leigh Syndrome in a Pedigree Harboring the m.1555A>G Mutation in the Mitochondrial 12S rRNA.

Background: Leigh syndrome (LS) is a serious genetic disease that can be caused by mutations in dozens of different genes.

Methods: Clinical study of a deafness pedigree in which some members developed LS. Cellular, biochemical and molecular genetic analyses of patients' tissues and cybrid cell lines were performed.

Datasets describing the introduction of the high-sensitive troponin in the emergency department.

Chest pain is a common clinical condition in the emergency department. A high sensitive (hs) troponin test assay may help to identify patients with acute coronary syndrome earlier compared to conventional tests but also entails the risk of a high proportion of positive test results in patients without cardiac disease. We assessed the impact of the introduction of the hs-troponin test in clinical practice in an emergency department.

An incidental finding in newborn screening leading to the diagnosis of a patient with mutations.

Short-chain enoyl-CoA hydratase (ECHS1) is a mitochondrial beta-oxidation enzyme involved in the metabolism of acyl-CoA fatty acid esters, as well as in valine metabolism. ECHS1 deficiency has multiple manifestations, including Leigh syndrome early at birth or in childhood with poor prognosis, to cutis laxa, exercise-induced dystonia and congenital lactic acidosis. Here we describe the case of a newborn with mutations in ECHS1 that caught our attention after the incidental finding of 3-hydroxy-butyryl\3-hydroxy-isobutyryl\malonylcarnitine (C4OH\C3DC) and tiglylcarnitine (C5:1) on blood spot in the newborn screening (NBS) program.

Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology.

3-Methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole-exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3-MGA-uria.

Non-cardiac chest pain patients in the emergency department: Do physicians have a plan how to diagnose and treat them? A retrospective study.

Background: Non-cardiac chest pain is common and there is no formal recommendation on what diagnostic tests to use to identify underlying diseases after an acute coronary syndrome has been ruled out.

Objective: To evaluate the diagnostic tests, treatment recommendations and initiated treatments in patients presenting with non-cardiac chest pain to the emergency department (ED).

Methods: Single-center, retrospective medical chart review of patients presenting to the ED.

Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease.

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients ( = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes.

Haematopoietic stem cell transplantation for mucopolysaccharidosis type VII: A case report.

Mucopolysaccharidosis type VII (MPS VII) is an inherited disease characterized by the cellular accumulation of undegraded GAGs due to the deficiency of the lysosomal enzyme β-glucuronidase. We describe a case of a 2-year-old female affected by a moderate form of MPS VII and submitted twice to HSCT with the aim of stabilizing skeletal problems and preventing neurocognitive alterations. The child underwent a second transplantation due to the rejection of the graft after a reduced-intensity conditioning in the first transplant.

A statistical algorithm showing coenzyme Q and citrate synthase as biomarkers for mitochondrial respiratory chain enzyme activities.

Laboratory data interpretation for the assessment of complex biological systems remains a great challenge, as occurs in mitochondrial function research studies. The classical biochemical data interpretation of patients versus reference values may be insufficient, and in fact the current classifications of mitochondrial patients are still done on basis of probability criteria. We have developed and applied a mathematic agglomerative algorithm to search for correlations among the different biochemical variables of the mitochondrial respiratory chain in order to identify populations displaying correlation coefficients >0.