Can Genetic counseling and Preimplantation Genetic Diagnosis prevent fatal infantile-onset Pompe disease?

INTRODUCTION Pompe disease (Glycogen Storage Disease Type II) is a rare, inherited, autosomal recessive disorder due to acid alpha-glucosidase (GAA) deficiency and consequent intralysosomal accumulation of glycogen in many tissues. The most severe form, classic infantile-onset Pompe disease (IOPD) is diagnosed in early infancy during the assessment of a cardiomegaly, hypotonia or both respiratory infection and failure. Without Alglucosidase-alfa enzyme replacement therapy (ERT), these patients die before two years of age. Regarding reproductive options and potential risks to offspring, it is appropriate to offer genetic counseling to adults who are carriers for Pompe disease to help them make informed medical and personal decisions. CASE PRESENTATION A 4-month-old infant was admitted to hospital because of feeding difficulties and deterioration of general status. Patient presented early with hypertrophic cardiomyopathy, hypotonia, generalized muscle weakness, failure to thrive and respiratory distress. Complete deficiency of GAA enzyme activity caused by biallelic pathogenic homozygous GAA gene mutation (c.2269C>T) proved the IOPD diagnosis with no cross reactive immunologic material (CRIM-negative status). Alglucosidase-alfa ERT and immunomodulation were introduced at age of 4 months. However, heart and skeletal muscles were severly affected and the disease progressed rapidly as might be expected with these findings. Unfortunately, the child died at the age of one year. CONCLUSION In terms of the inheritance, genetic risk, rapid progression and implications of this severe form of Pompe disease it is reasonable to try with prenatal testing and preimplantation genetic diagnosis in expert Center if both parents are fully informed and consent

Innovative Genome Joint Analysis for identification of novel deep-intronic de novo pathogenic variants in KMT2A gene - WiedemannSteiner Syndrom

Heterozygous mutations in KMT2A gene are known to cause Wiedemann-Steiner Syndrome (WDSTS), a rare, autosomal dominant disease characterized by facial dysmorphism, intellectual disability, hypertrichosis cubiti, and psychomotor developmental delay. Whole genome sequencing (WGS) is a promising method to both identify pathogenic gene variants and facilitate personalized medical management

Whole Genome Joint Analysis for identification of rare non-coding causative variants - case report of a child with mitochondrial disease

Pediatric genetic conditions are caused by a spectrum of genomic alterations, including non-coding variants, which often fail to be identified using low throughput methods. Whole genome sequencing (WGS) can detect the full spectrum of genome alterations simultaneously, comprehensively, and unbiasedly

Innovative Whole Genome Joint Analysis – case report of early diagnosis and preventive approach to HFE Hemochromatosis

Whole Genome Joint Analysis is an innovative method to elucidate the full spectrum of genome complexities and alterations in the family members, comprehensively and unbiasedly. Once identified in the preclinical phase of the disease, causative variants can anticipate a personalized preventive approach and medical treatment

Inborn metabolic disorders in differential diagnosis of cyclic vomiting syndrome in children

Cyclic vomiting syndrome is a rare chronic disorder of unknown cause characterized by recurrent periods of frequent vomiting. The episodes are often triggered by infection and stress.Some metabolic disorders appear to hide under this clinical presentation. CASE PRESENTATION The patient is a 10-year-old girl with episodic vomiting since early childhood, born prematurely at 33 weeks and soon diagnosed with esophageal atresia with tracheoesophageal fistula which was operated the second day. Since the age of 3 she was frequently hospitalised due to episodic vomiting and poor weight gain. She underwent the Nissen fundoplication procedure at the age of 9. At the age of 10 she suffered from pneumonia accompanied by repeated vomiting episodes. Endoscopy, laboratory and radiology findings were unremarkable. Numerous infective episodes with vomiting and poor weight gain raise suspicion for metabolic etiology. The metabolic workup included several tests, all of which were negative. However, metabolic tests may not have been performed during the vomiting attack itself when they are most informative. We suggest performing metabolic tests during attacks when they are most valuable, including orotic acid in urine and allopurinol loading test to exclude urea cycle disorders. If these tests would also be negative, with persistent symptoms, we suggest OTC gene analysis. CONCLUSION The inborn errors of metabolism should be considered in the broad spectrum of differential diagnosis of recurrent vomiting in children, especially if accompanied with developmental delay, poor growth, and triggers such as infection

Importance of Diagnostic Imaging Technology in asymptomatic patients and therapeutic imaging approach: Child with ruptured brain AVM

Brain arteriovenous malformation is a type of high flow vascular malformation shunt in which blood flows from a feeding artery to a draining vein forming a connection called nidus (shunting arterioles/venous loops). They may not become clinically evident for several years. Other possible clinical presentations include headaches, seizures, and hemorrhage, which can be a vital complication

HYPOKALEMIC METABOLIC ALKALOSIS – A REPORT OF SIX CASES

U ovom radu prikazano je 6 bolesnika s hipokaliemijskom metaboličkom alkalozom kod kojih je postavljena dijagnoza Bartterova ili Gitelmanova sindroma. Oba su sindroma posljedica mutacija gena za prijenosnike uključene u reapsorpciju natrija, klorida i kalija u epitelnim stanicama debelog uzlaznog kraka Henleove petlje i distalnih zavijenih kanalića. Tipično se ovi sindromi, uz hipokaliemiju i metaboličku alkalozu, očituju hiperreninemičnim hiperaldosteronizmom bez hipertenzije te poliurijom i mišićnom slabošću. Ostale kliničke manifestacije bolesti su varijabilne i ovise o fenotipskoj ekspresiji mutiranih gena. Točna dijagnoza ovih dvaju sindroma moguća je samo na osnovi skupih i rutinski najčešće nedostupnih genetičkih analiza. Rutinske laboratorijske pretrage, vezane ponajprije uz nalaze elektrolita u serumu i urinu, mogu pomoći u prepoznavanju obaju sindroma, njihovu međusobnom razlikovanju i pravodobnom početku liječenja. Najvažniji razlikovni nalazi između Bartterova i Gitelmanova sindroma jesu koncentracija magnezija u serumu i kalciurija. Za Bartterov sindrom tipična je hiperkalciurija, dok su za Gitelmanov sindrom tipične hipokalciurija i hipomagneziemija. Pravodobno prepoznavanje i liječenje bolesnika s Bartterovim i Gitelmanovim sindromom važno je jer elektrolitska neravnoteža, karakteristična za ove sindrome, dovodi do povećanog morbiditeta i mortaliteta.In this article six patients with hypokalemic metabolic alkalosis, classified as Bartter or Gitelman syndrome are presented. Both syndromes result from different gene mutation inducing impaired function of the transporters involved in sodium, chloride and potassium reapsorption in thick ascending limb of the loop of Henle and distal convoluted tubules. These syndromes typically present with hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism without hypertension, polyuria and muscle weakness. Other clinical characteristics may vary considerably, depending on the gene expression. Correct diagnosis is only possible using expensive and not-routinely available genetic testing. Routine laboratory tests, especially those considering serum and urine electrolytes, can help in recognizing these syndromes and therefore in timely beginning of treatment. The most important distinctive laboratory findings are serum magnesium concentration and urine calcium excretion. In Bartter syndrome typically there is hypercalciuria with or without hypomagnesemia, while in Gitelman syndrome typical findings are hypocalciuria and hypomagnesemia. Recognizing and treating these patients is important due to possible increased morbidity and mortality induced by severe electrolyte imbalance

A path towards a cultured skin fi broblast biobank of patients with inherited errors of metabolism in Croatia

Rijetke bolesti etiološki su heterogena skupina najčešće nasljednih, kroničnih i degenerativnih bolesti s pojavnošću manjom od 5 na 10 000 osoba. Poznato je više od 7000 rijetkih bolesti od kojih više od 600 ima osobitosti nasljednih metaboličkih poremećaja. Zbog velike kliničke heterogenosti i zahtjevnih dijagnostičkih testova put do konačne dijagnoze je često dug te uključuje i obradu u ino zemnim laboratorijima. Unatoč tome, dio bolesnika ostaje bez konačne dijagnoze. U situacijama kad je bolesnik vitalno ugrožen uz mogućnost letalnog ishoda i pri sumnji na nasljednu metaboličku bolest, biopsija kože je dio standardnog postupka. Posljednjih godina sve je više dostupnih mogućnosti liječenja za širok spektar nasljednih metaboličkih bolesti. Osnovni preduvjet za njihovu djelotvornost je pravodobna dijagnoza. Kultivirani kožni fi broblasti pohranjeni u biobanke vrijedan su biološki materijal. Osim za postavljanje dijagnoze, mogu se primijeniti i za provjeru djelotvornosti novih pristupa liječenju kao što su male molekule pratitelji. Sve navedeno upućuje na značenje organiziranja biobanke fi broblasta prema međunarodno prihvaćenim standardima.Rare diseases are an etiologically heterogeneous group of hereditary, chronic and degenerative disorders with the incidence lower than 5 per 10,000 individuals. More than 7,000 rare diseases have been identifi ed so far, and more than 600 of them have the characteristics of hereditary metabolic disorders. Due to the high clinical heterogeneity and demanding diagnostic tests, the path to fi nal diagnosis is often long and may also involve tests performed in laboratories abroad. Despite this, a number of patients remain without fi nal diagnosis. In life-threatening situations for the patient and in case of suspected hereditary metabolic disease, skin biopsy is part of the routinely performed standard procedure. Recent years have seen an increasing availability of treatment options for a broad range of hereditary metabolic diseases. The basic precondition for therapy effi cacy is timely diagnosis. Cultured skin fi broblasts that are stored in biobanks are a valuable biological material. Except for making diagnosis, they may be used to verify the effi cacy of novel approaches to treatment, e.g., small chaperon molecules. All of the above indicates the signifi cance of establishing a fi broblast biobank according to the internationally accepted standards

LYSOSOMAL ACID LIPASE DEFICIENCY IN CHILDREN: OUR EXPERIENCE AND A NOVEL POSSIBILITY OF ENZYME REPLACEMENT THERAPY

Manjak lizosomske kisele lipaze autosomno je recesivno nasljedna bolest s dva klinička fenotipa. Wolmanova bolest počinje u ranoj dojenačkoj dobi i brzo je progresivna. Zbog masivnog nakupljanja kolesterolskih estera i triglicerida u crijevima, jetri, slezeni i drugim stanicama monocitno-makrofagnog reda dolazi do malapsorpcije, hepatosplenomegalije, zatajenja jetre i smrti u prvoj godini života. Bolest nakupljanja kolesterolskih estera može se očitovati od rane dječje do kasne odrasle dobi, varijabilna je tijeka i progresije. Glavna su obilježja različito izražena jetrena bolest, uključujući cirozu i zatajenje jetre, hiperkolesterolemija i rana ateroskleroza. Karakterističan je patohistološki nalaz mikrovezikularne steatoze i fibroze, a patognomoničan je ultrastrukturni nalaz kristala kolesterolskih estera. Dijagnozu potvrđuju mjerenje enzimske aktivnosti i/ili analiza gena. Liječenje je donedavno bilo suportivno i simptomatsko. Klinička istraživanja enzimskoga nadomjesnog liječenja pokazuju vrlo ohrabrujuće rezultate. Prikazujemo dojenče s Wolmanovom bolešću i dvoje djece s bolešću nakupljanja kolesterolskih estera s ciljem skretanja pozornosti na bolesti zbog manjka lizosomske kisele lipaze i što ranijeg početka optimalne skrbi.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. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression. Main features are variously expressed hepatopathy, including cirrhosis and liver failure, hypercholesterolemia and premature atherosclerosis. Characteristic is pathohistological finding of microvesicular steatosis and fibrosis and patognomonic are typical cholesterol ester crystals. Diagnosis is confirmed by enzyme assay and/or gene analysis. Until recently treatment was symptomatic. Ongoing clinical trials of enzyme replacement therapy have shown very promising results. We are presenting an infant with Wolman disease and two children with cholesterol ester storage disease with the aim to raise awareness about this disease and to start optimal care early

Manjak lizosomske kisele lipaze u djece: vlastita iskustva i nova mogućnost enzimskoga nadomjesnog liječenja [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. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression. Main features are variously expressed hepatopathy, including cirrhosis and liver failure, hypercholesterolemia and premature atherosclerosis. Characteristic is pathohistological finding of microvesicular steatosis and fibrosis and patognomonic are typical cholesterol ester crystals. Diagnosis is confirmed by enzyme assay and/or gene analysis. Until recently treatment was symptomatic. Ongoing clinical trials of enzyme replacement therapy have shown very promising results. We are presenting an infant with Wolman disease and two children with cholesterol ester storage disease with the aim to raise awareness about this disease and to start optimal care early