Novel Variant in Muscular Dystrophy: Identification by Whole Genome Sequencing and Quad Analysis.

Background: The phenotypic spectrum of muscle disease ranges widely from elevated creatine kinase (CK) levels in the serum of asymptomatic individuals to progressive muscular dystrophy. Due to overlapping clinical features among muscular dystrophies, the diagnosis of muscle disease is established by molecular genetic tests. Early diagnosis is crucial for the clinical management of symptoms and to mitigate cardiac and musculoskeletal complications.

Novel :c.2736delC Variant in Smith-Magenis Syndrome: Identification by Whole Genome Sequencing and Joint Analysis.

Smith-Magenis syndrome is a complex neurobehavioral genetic disorder with a broad phenotypic spectrum. While the etiology of SMS is commonly attributed to one-copy interstitial deletion in the 17p11.2 region (90-95% of cases), variants identified by sequence analysis in have also been reported in 5-10% of cases.

Whole genome joint analysis reveals ATM:C.1564_1565del variant segregating with Ataxia-Telangiectasia and breast cancer.

ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma. Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family.

Diagnosis of Two Unrelated Syndromes of Prader-Willi and Calpainopathy: Insight from Trio Whole Genome Analysis and Isodisomy Mapping.

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS).

Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected.

Novel de Novo Nonsense Variants in AGO3 and KHSRP: Insights into Global Developmental Delay and Autism Spectrum Disorders through Whole Genome Analysis.

BACKGROUND Neurodevelopmental disorders (NDD) are umbrella disorders that encompass global developmental delay (GDD), intellectual disability, autism spectrum disorders, motor developmental disorders, and sleep disorders. Both GDD and autism spectrum disorder are common and yet clinically and genetically heterogeneous disorders. Despite their high prevalence and the advent of sequencing detection methods, the genomic etiology of GDD and autism spectrum disorder in most patients is largely unknown.

Fragility spinal fractures among cirrhotic liver transplant candidates in Croatia.

Introduction: Existing data on fragility spinal fractures prevalence in liver transplant candidates are scarce and inconsistent. This may be due to other comorbidities, besides hepatic osteodystrophy (HO), that contribute to bone loss and fragility fracture prevalence in chronic liver disease (CLD).

Objectives: The aim of this study was to investigate the prevalence of spinal thoracic and lumbar fragility fractures among cirrhotic, non-chronic kidney disease (CKD), non-diabetic liver transplant candidates and to explore their relationship with clinical characteristics, laboratory markers and dual-energy x-ray absorptiometry (DXA) results.

First Reported Case of Gabriele-de Vries Syndrome with Spinal Dysraphism.

Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease caused by de novo pathogenic variants in the ( gene. Individuals with this syndrome present with multiple congenital anomalies, as well as a delay in development and intellectual disability. Herein, we report the case of a newborn male patient with a novel de novo pathogenic variant in the Guanine Nucleotide-Binding Protein, Alpha Stimulating () gene, which was identified by whole-exome sequencing.

The Therapeutic Hypothermia in Treatment of Hyperammonemic Encephalopathy due to Urea Cycle Disorders and Organic Acidemias.

Background: Hyperammonemic encephalopathy in newborns with urea cycle disorders and certain organic acidurias can cause severe brain injury, coma and death. Standard therapy includes protein restriction, nitrogen-scavenging drugs, prevention of catabolism and hemodialysis. Neuroprotective hypothermia as part of the treatment has been reported only 3 times.

ORAI1 mutations abolishing store-operated Ca entry cause anhidrotic ectodermal dysplasia with immunodeficiency.

Background: Store-operated Ca entry (SOCE) through Ca release-activated Ca channels is an essential signaling pathway in many cell types. Ca release-activated Ca channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms.

Store-Operated Ca Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism.

Ca signals were reported to control lipid homeostasis, but the Ca channels and pathways involved are largely unknown. Store-operated Ca entry (SOCE) is a ubiquitous Ca influx pathway regulated by stromal interaction molecule 1 (STIM1), STIM2, and the Ca channel ORAI1. We show that SOCE-deficient mice accumulate pathological amounts of lipid droplets in the liver, heart, and skeletal muscle.

Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function.

Eccrine sweat glands are essential for sweating and thermoregulation in humans. Loss-of-function mutations in the Ca2+ release-activated Ca2+ (CRAC) channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE), and patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures. Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development.

Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature.

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the GLUD1 gene that encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). We report here on monozygotic twin girls presented with fasting- and protein-induced hypoglycemia and mild persistent hyperammonemia.

Respiratory chain deficiency in nonmitochondrial disease.

Objective: In this study, we report 5 patients with heterogeneous phenotypes and biochemical evidence of respiratory chain (RC) deficiency; however, the molecular diagnosis is not mitochondrial disease.

Methods: The reported patients were identified from a cohort of 60 patients in whom RC enzyme deficiency suggested mitochondrial disease and underwent whole-exome sequencing.

Results: Five patients had disease-causing variants in nonmitochondrial disease genes ORAI1, CAPN3, COLQ, EXOSC8, and ANO10, which would have been missed on targeted next-generation panels or on MitoExome analysis.

[Lysosomal acid lipase deficiency in children: our experience and a novel possibility of enzyme replacement therapy].

Lysosomal acid lipase deficiency is an autosomal recessive disorder with two distinct clinical phenotypes. Wolman disease is rapidly progressive with onset in early infancy. Complete enzyme deficiency results in massive accumulation of cholesterol esters and triglycerides in intestines, liver, spleen and other monocyte-macrophage system cells causing malabsorption, hepatosplenomegaly, liver failure and death in early infancy.

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome.

Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia-mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals.

Plasma biomarker identification in S-adenosylhomocysteine hydrolase deficiency.

S-Adenosylhomocysteine hydrolase (AHCY) deficiency is a rare congenital disorder in methionine metabolism clinically characterized by white matter atrophy, delayed myelination, slowly progressive myopathy, retarded psychomotor development and mildly active chronic hepatitis. In the present study, we utilized a comparative proteomics strategy based on 2-DE/MALDI-MS and LC/ESI-MS to analyze plasma proteins from three AHCY-deficient patients prior to and after receiving dietary treatment designed to alleviate disease symptoms. Obtained results revealed candidate biomarkers for the detection of myopathy specifically associated with AHCY deficiency, such as carbonic anhydrase 3, creatine kinase, and thrombospondin 4.

Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3.

S-adenosylhomocysteine hydrolase (AdoHcyase) catalyzes the hydrolysis of AdoHcy to adenosine and homocysteine. Increased levels of AdoHcy may play a role in the development of cardiovascular diseases and numerous other conditions associated with hyperhomocysteinemia. Several polymorphic isoforms named SAHH-1 to 4 may be resolved by horizontal starch gel electrophoresis from red blood cells.

A single mutation at Tyr143 of human S-adenosylhomocysteine hydrolase renders the enzyme thermosensitive and affects the oxidation state of bound cofactor nicotinamide-adenine dinucleotide.

Recently, we have described the first human case of AdoHcyase (S-adenosylhomocysteine hydrolase) deficiency. Two point mutations in the AdoHcyase gene, the missense mutation p.Y143C (AdoHcyase in which Tyr143 is replaced by cysteine) and the truncation mutation p.

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.

We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin.

Small supernumerary marker chromosome derived from proximal p-arm of chromosome 2: identification by fluorescent in situ hybridization.

Conventional cytogenetics detected an interstitial deletion of proximal region of p-arm of chromosome 2 in a 6-month-old boy with a phenotype slightly resembling Down's syndrome. The deletion was inherited from the father, whose karyotype revealed a small ring-shaped marker chromosome, in addition to interstitial deletion. Fluorescence in situ hybridization identified the marker, which consisted of the proximal region of the p-arm of chromosome 2, including a part of its centromere.

Use of psychoactive substances among Zagreb University medical students: follow-up study.

Aim: To estimate the exposure of Zagreb University medical students to psychoactive substances in 2000 and compare it with data collected in 1989.

Methods: Students were surveyed in 2000 (n=775) and 1989 (n=986) by means of a self-reporting questionnaire. The 2000 survey also included 136 non-medical students.

Ethics in medicine: students' opinions on disclosure of true diagnosis.

Aim: To determine students opinions about diagnosis disclosure to the patient and other interested parties.

Methods: During 2000/2001 academic year, an anonymous survey was conducted among the first-year (200 questionnaires) and sixth-year medical students (200 questionnaires) at the Zagreb University School of Medicine. Students were asked what they would say about the diagnosis to the patient, patients family, friend, employer, colleague from work, health insurance agent, another physician, or medical student, if the diagnosis was inoperable lung carcinoma in a 20- and 66-year-old patient vs bacterial pneumonia in patients of the same age.