A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics.

Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months.

Inherited metabolic disorders in Cyprus.

Selective screening for inherited metabolic disorders (IMD) began in Cyprus in 1990. Over the last thirty-three years 7388 patients were investigated for IMD and 200 diagnoses were made (diagnostic yield 2.7%).

A novel large intragenic DPYD deletion causing dihydropyrimidine dehydrogenase deficiency: a case report.

Background: Dihydropyrimidine dehydrogenase (DPD), is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. Deleterious variants in the DPYD gene cause DPD deficiency, a rare autosomal recessive disorder. The clinical spectrum of affected individuals is wide ranging from asymptomatic to severely affected patients presenting with intellectual disability, motor retardation, developmental delay and seizures.

variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing.

Pompe disease is a rare metabolic myopathy caused by pathogenic variants affecting the activity of the lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Impaired GAA function results in the accumulation of undegraded glycogen within lysosomes in multiple tissues but predominantly affects the skeletal, smooth and cardiac muscle. The degree of residual enzymatic activity appears to roughly correlate with the age of onset and the severity of the clinical symptoms.

Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter.

The high-affinity copper transporter CTR1 is encoded by CTR1 (SLC31A1), a gene locus for which no detailed genotype-phenotype correlations have previously been reported. We describe identical twin male infants homozygous for a novel missense variant NM_001859.4:c.

Stbd1-deficient mice display insulin resistance associated with enhanced hepatic ER-mitochondria contact.

Starch binding domain-containing protein 1 (STBD1) is an endoplasmic reticulum (ER)-resident, glycogen-binding protein. In addition to glycogen, STBD1 has been shown to interact with several proteins implicated in glycogen synthesis and degradation, yet its function in glycogen metabolism remains largely unknown. In addition to the bulk of the ER, STBD1 has been reported to localize at regions of physical contact between mitochondria and the ER, known as Mitochondria-ER Contact sites (MERCs).

When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease.

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression.

Stbd1 promotes glycogen clustering during endoplasmic reticulum stress and supports survival of mouse myoblasts.

Imbalances in endoplasmic reticulum (ER) homeostasis provoke a condition known as ER stress and activate the unfolded protein response (UPR) pathway, an evolutionarily conserved cell survival mechanism. Here, we show that mouse myoblasts respond to UPR activation by stimulating glycogenesis and the formation of α-amylase-degradable, glycogen-containing ER structures. We demonstrate that the glycogen-binding protein Stbd1 is markedly upregulated through the PERK signalling branch of the UPR pathway and is required for the build-up of glycogen structures in response to ER stress activation.

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content.

The gene encodes acid ceramidase (AC), an enzyme that is implicated in the metabolism of ceramide (Cer). Mutations in the gene cause two different disorders, Farber disease (FD), a rare lysosomal storage disorder, and a rare form of spinal muscular atrophy combined with progressive myoclonic epilepsy (SMA-PME). In the absence of human in vitro neuronal disease models and to gain mechanistic insights into pathological effects of deficiency, we established and characterized a stable knockdown () SH-SY5Y cell line.

A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.

Background: Mutations in the GBA gene that encodes the lysosomal enzyme acid β-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD.

Classic galactosaemia in the Greek Cypriot population: An epidemiological and molecular study.

Classic galactosaemia is an inherited metabolic disorder of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) resulting from mutations in the GALT gene. The objectives of the present study were the determination of the carrier frequency of classic galactosaemia in the Greek Cypriot population and the molecular characterization of the disease alleles. We performed an epidemiological study involving 528 Greek Cypriots originating from all parts of Cyprus.

Biochemical Characterization of the c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia.

The gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the c.

Mouse Stbd1 is -myristoylated and affects ER-mitochondria association and mitochondrial morphology.

Starch binding domain-containing protein 1 (Stbd1) is a carbohydrate-binding protein that has been proposed to be a selective autophagy receptor for glycogen. Here, we show that mouse Stbd1 is a transmembrane endoplasmic reticulum (ER)-resident protein with the capacity to induce the formation of organized ER structures in HeLa cells. In addition to bulk ER, Stbd1 was found to localize to mitochondria-associated membranes (MAMs), which represent regions of close apposition between the ER and mitochondria.

Chitotriosidase deficiency in the Cypriot population: Identification of a novel deletion in the CHIT1 gene.

Objectives: The purpose of this study was to determine the normal range of chitotriosidase activity in the Cypriot population and the frequency of the 24bp duplication polymorphism. Furthermore, we compared the allele frequency of this polymorphism in two locations with different malaria endemicity in the past.

Design And Methods: Plasma chitotriosidase activity was measured using a fluorogenic substrate.

Novel GLA Deletion in a Cypriot Female Presenting with Cornea Verticillata.

Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the hydrolytic enzyme α-galactosidase A (α-Gal-A). It is characterized by progressive lysosomal accumulation of globotriaosylceramide (Gb3) and multisystem pathology, affecting the skin, nervous and cerebrovascular systems, kidneys, and heart. Heterozygous females typically exhibit milder symptoms and a later age of onset than males.

Minimally symptomatic mcardle disease, expanding the genotype-phenotype spectrum.

Introduction: We report the clinical, biochemical, and molecular findings in a Cypriot family with minimally symptomatic McArdle disease.

Methods: Myophosphorylase in muscle was assessed by histochemistry, quantitative spectrophotometry, and western blot analysis. Mutation identification was performed by PCR amplification of all PYGM exons, followed by bidirectional sequencing.

The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.

Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts.

Molecular analysis of Cypriot patients with Glutaric aciduria type I: identification of two novel mutations.

Objectives: The purpose of this study was to identify the mutations in the glutaryl-CoA dehydrogenase gene (GCDH) in ten Cypriot patients with Glutaric aciduria type I (GAI).

Design And Methods: Molecular analysis of the GCDH gene was performed by direct sequencing of the patients' genomic DNA. In silico tools were applied to predict the effect of the novel variants on the structure and function of the protein.

A Novel Large Deletion Encompassing the Whole of the Galactose-1-Phosphate Uridyltransferase (GALT) Gene and Extending into the Adjacent Interleukin 11 Receptor Alpha (IL11RA) Gene Causes Classic Galactosemia Associated with Additional Phenotypic Abnormalities.

Objective The characterization of a novel large deletion in the galactose-1-phosphate uridyltransferase (GALT) gene accounting for the majority of disease alleles in Cypriot patients with classic galactosemia. Methods DNA sequencing was used to identify the mutations followed by multiplex ligation-dependent probe amplification (MLPA) analysis in the cases suspected of harboring a deletion. In order to map the breakpoints of the novel deletion, a PCR walking approach was employed.

The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening.

Objectives: The purpose of this study was to identify the mutations responsible for phenylalanine hydroxylase deficiency in Cypriot patients detected through neonatal screening.

Design And Methods: Analysis of the PAH gene was performed by direct sequencing of the patients' genomic DNA, MLPA analysis and real-time PCR.

Results: Among 22 independent alleles thirteen previously described mutations were detected (detection rate 100%), all in compound heterozygosity: p.

Maple syrup urine disease in Cypriot families: identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit.

We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elalpha gene (c.

Hb Agrinio [alpha29(B10)Le-->uPro (alpha2)] in combination with --(MED I). Results in a severe form of Hb H disease.

We report two cases of compound heterozygote patients for the --(MED I) and Hb Agrinio [alpha29(B10)Le-->uPro (alpha2)] anomalies in two unrelated Greek Cypriot families. The first patient had a serious form of Hb H disease and died at the age of 21 due to complications arising during an operation. The second patient showed a severe hematological picture and has been regularly transfused since an early age.