Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non-human primates.

Aim: We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator.

Methods: The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses.

A Homozygous Splice Site Mutation in SLC25A42, Encoding the Mitochondrial Transporter of Coenzyme A, Causes Metabolic Crises and Epileptic Encephalopathy.

SLC25A42 is an inner mitochondrial membrane protein which has been shown to transport coenzyme A through a lipid bilayer in vitro. A homozygous missense variant in this gene has been recently reported in 13 subjects of Arab descent presenting with mitochondriopathy with variable clinical manifestations. By exome sequencing, we identified two additional individuals carrying rare variants in this gene.

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps.

Blue Diaper Syndrome and Mutations.

Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis.

SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN).

Purpose: Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype.

Methods: We aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology.

The role of the clinician in the multi-omics era: are you ready?

Since Garrod's first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment.

Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency.

Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed.

The genotypic and phenotypic spectrum of MTO1 deficiency.

Background: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10).

Material And Methods: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration.

Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes.

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia primarily characterized by the features such as disproportionate dwarfism, short ribs, short limbs, dysplastic nails, cardiovascular malformations, post-axial polydactyly (PAP) (bilateral) of hands and feet. EVC/EVC2 located in head-to-head arrangement on chromosome 4p16 are the causative genes for EvC syndrome. In the study, we present two families, A and B, with Pakistani and Republic of Kosovo origin, respectively.

Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations.

Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum.

A subset of patients with polyglucosan body myopathy was found to have underlying mutations in the RBCK1 gene. Affected patients may display diverse symptoms ranging from skeletal muscular weakness, cardiomyopathy to chronic autoinflammation and immunodeficiency. It was suggested that the exact localization of the mutation within the gene might be responsible for the specific phenotype, with N-terminal mutations causing severe immunological dysfunction and mutations in the middle or C-terminal part leading to a myopathy phenotype.

Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

Objective: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.

Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease.

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies.

Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase.

Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany.

Background: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available.

Objective: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up.

A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of .

Background: Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). mutations were recently identified as causal. encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN).

Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.

Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.

Identification of this additional patient from a distant part of the originally described pedigree (Synofzik et al. 2014) confirms pathogenicity of DNAJC3 mutations. Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration).

SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.

Objective: To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding to the increasing number of complex lipid cHSP genes.

Methods: Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.

Results: 5 of 6 affected subjects shared cHSP as a common disease phenotype.

Combined Respiratory Chain Deficiency and Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.

Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency.

Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage.

Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families.

Purpose: To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin.

Methods: Linkage in two families (A and B) was established to on chromosome 4q27, in family C to on chromosome 14q32.1, and in family D to on chromosome 12q21.