[Management of mucopolysaccharidosis type VI in adults]. / SMJERNICE ZA LIJECENJE MUKOPOLISAHARIDOZE (MPS) VI U ODRASLIH BOLESNIKA.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome, MPS VI) is a progressive multisystemic lysosomal storage disease. Physical symptoms generally include growth retardation, and bone dysplasia. Enzyme replacement therapy is the treatment of choice and is done with recombinant version of enzyme N-acetylgalactosamine 4-sulfatase (galsulfase) which is administered intravenously. The enzyme replacement therapy should be applied once a week as a life-long treatment. Division of metabolic diseases, Department of internal medicine, University Hospital Center Zagreb continues with the treatment of MPS VI patients after they turn 18 years of life and are not treated any more by the pediatricians. The aim of this document is to provide the guidelines for diagnosis and management of adult patients with MPS VI which consists not only of regular galsulfase adiministration, but also of regular follow up and treatment of numerous comorbidities. These guidelines were produced by experts from the Division of metabolic diseases, Department of internal medicine, University Hospital Center Zagreb which is the Referral center for rare and metabolic diseases of the Ministry of Health, Republic of Croatia. The guidelines are result of collaboration with pediatricians, radiologists and biochemists without whose experience and advices appropriate treatment of these patients would not be possible. The guidelines were endorsed by the Croatian society for rare diseases, Croatian Medical Association.

[POMPE DISEASE - GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF ADULT PATIENTS]. / POMPEOVA BOLEST - SMJERNICE ZA DIJAGNOZU I LIJECENJE ODRASLIH BOLESNIKA.

These guidelines provide a short summary of recommendations on Pompe disease, how to diagnose this disease, management of adult patients with this disease, follow-up of the patients and recommendations on therapy and genetic testing. Early diagnosis and management of patients with Pompe disease requires a multidisciplinary approach of several different experts. These guidelines were produced by the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb which is a Referral expert center for rare and metabolic diseases of the Ministry of Health of the Republic of Croatia. They were endorsed by the Croatian Society for Rare Diseases, Croatian Medical Association.These are the first guidelines published in Croatia on diagnosis, treatment and follow-up of Pompe disease.

ABCG2 gene polymorphisms as risk factors for atorvastatin adverse reactions: a case-control study.

AIM: To explore the association between dose-related adverse drug reactions (ADRs) of atorvastatin and polymorphisms of ABCG2, taking into account the influence of CYP3A4 and SLCO1B1 genes. MATERIALS & METHODS: Sixty patients who experienced atorvastatin dose-related ADRs and 90 matched patients without ADRs were enrolled in the study. Genotyping for ABCG2 421C > A, CYP3A4*22, SLCO1B1 388A > G, SLCO1B1 521T > C variants was performed by real-time PCR. RESULTS: Patients with ABCG2 421CA or AA genotypes had 2.9 times greater odds of developing atorvastatin dose-dependent ADRs (OR: 2.91; 95% CI: 1.22-6.95; p = 0.016) than those with ABCG2 421CC genotype. After adjustments for clinical and genetic risk factors, ABCG2 remained a statistically significant predictor of adverse drug reactions (OR: 2.75; 95% CI: 1.1-6.87; p = 0.03;). Also, carriers of SLCO1B1 521 TC or CC genotypes had 2.3 greater odds (OR: 1.03-4.98; 95% CI: 1.03-4.98; p = 0.043) of experiencing ADRs caused by atorvastatin in comparison with carriers of SLCO1B1 521 TT genotype. CONCLUSION: Our study demonstrated an association between atorvastatin-induced ADRs and genetic variants in the ABCG2 gene.

[Gaucher disease--guidelines for diagnosis and management of adult patients]. / Gaucherova bolest--smjernice za dijagnozu i lijecenje odraslih bolesnika.

Gaucher disease is an autosomal recessive disorder, characterized by decreased levels of the lysosomal enzyme glucocerebrosidase. This deficiency results in a decreased breakdown of this glycosphingolipid glucocerebroside, which accumulates in the lysosomes of the monocyte-macrophage system. It is the most common form of sphingolipidosis. Clinically, the principle signs of Gaucher's disease are hepatosplenomegaly, bone involvement, hematological changes and CNS involvement. The diagnosis of Gaucher disease has to be confirmed by the measurement of the activity of the enzyme glucocerebrosidase in leukocytes or fibroblasts and genetic testing. An effective therapy for Gaucher disease has now been available for more than 10 years. It consists of life-long intravenous replacement of the deficient enzyme--glucocerebrosidase. If enzyme replacement therapy is started early enough, it leads to significant improvement in patient's general condition and quality of life. The aim of this document is to provide to the Croatian medical audience the guidelines for diagnosis and management of adult patients with Gaucher disease. These guidelines are produced by specialists who have long lasting experience with patients with rare metabolic diseases working in the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb which is the Referral Center for Rare and Metabolic diseases of the Ministry of Health, Republic of Croatia. They were endorsed by the Croatian Society for Rare Diseases, Croatian Medical Association. These are the first guidelines published in Croatia on diagnosis, treatment and follow-up of Gaucher disease.

[Fabry disease--guidelines for diagnosis and management of adult patients]. / Fabryjeva bolest- smjernice za dijagnozu i lijecenje odraslih bolesnika.

Early diagnosis and management of patients with Fabry disease (FD) requires a multidisciplinary approach of several different experts. The aim of this document is to provide health care professionals with guidelines for management of adult patients with Fabry disease. These guidelines were produced by the staff of the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb, which is the Referral Expert Center for Rare and Metabolic Diseases of the Ministry of Health, Republic of Croatia. The first guidelines ever published in Croatia concerning a rare metabolic disease are presented. This document provides a short summary on Fabry disease, how to diagnose Fabry disease, management of patients with this disease, follow-up of the patients, and gives recommendations on therapy and genetic testing.

Mitochondrial myopathy associated with a novel 5522G>A mutation in the mitochondrial tRNA(Trp) gene.

We report a novel pathogenic mutation of the mitochondrial transfer RNA (tRNA) gene for tryptophan in a patient with isolated myopathy and persistently elevated creatine kinase. Muscle studies revealed ragged red fibres and decreased activity of respiratory chain complex I and cytochrome c oxidase (COX). Sequencing of the 22 mitochondrial tRNA genes revealed a mutation m.5522G>A, which alters a conserved base pairing in the D-stem of the tRNA for tryptophan. The mutation was heteroplasmic with a mutational load between 88 and 99% in COX-negative fibres. This case contributes to the genetic heterogeneity of mitochondrial diseases caused by mutations in mitochondrial tRNA genes.

[Is hypertriglyceridaemia a risk factor for coronary heart disease?]. / Je li hipertrigliceridemija cimbenik rizika od koronarne bolesti srca?

Although it is still not clear whether elevated serum triglycerides are directly atherogenic or not, the results of many studies indicate that they are undoubtedly an important risk factor/biomarker for coronary heart disease (CHD). Therefore, targeting hypertriglyceridaemia should be beneficial for subjects at high risk for CHD. Elevated triglycerides are often accompanied with low HDL cholesterol, particularly in high risk patients with diabetes type 2 and/or metabolic syndrome. Such a disturbance is called atherogenic dyslipidaemia and has an increasing prevalence. The treatment of hypertriglyceridaemia has to be focused primarily on intensive lifestyle changes (weight reduction in obesity, reduction of alcohol consumption as well as reduction of added sugars, fructose and trans-fatty acids, regular aerobic physical activity) by which reduction of up to 50% in triglycerides can be achieved. Subjects with high CHD risk who cannot lower hypertriglyceridaemia by lifestyle measures should be treated with pharmacological therapy. The available medications include fibrates, niacin and prescription omega-3 polyunsaturated fatty acids. If LDL cholesterol is elevated too, combination therapy is needed. Based upon recent studies in such patients a combination of a statin with fenofibrate and/or omega-3 fatty acids can be recommended.

Spontaneous perforation of the small intestine, a novel manifestation of classical homocystinuria in an adult with new cystathionine beta-synthetase gene mutations.

The clinical picture of classical homocystinuria is diverse. This is the first report of an adult homocystinuric patient with non-traumatic spontaneous small bowel perforation. A 47-year old man presented with abdominal rebound tenderness, hypotension and tachycardia, anemia, and elevated markers of inflammation. Other routine laboratory tests were normal. Abdominal x-ray showed no free air. An emergency laparotomy revealed jejunal perforation in the left upper quadrant. Histologic specimen showed full-thickness nonspecific inflammation of the intestinal wall with granulocytic infiltration, hemorrhage and necrosis. Tuberculosis, actinomycosis and typhus were histologically and clinically excluded. After excluding all known possible causes of perforation, we presumed a causative relationship between homocystinuria and small bowel perforation. It could be hypothesized that connective tissue weakness in homocystinuria is a result of homocysteine interference with recombinant human fibrillin-1 fragments or cross-linking of collagen through permanent degradation of disulfide bridges and lysine amino acid residues in proteins. DNA analysis showed three detectable mutations in the cystathionine beta-synthetase gene, 1278T:c.833T>C, and two new mutations, V372G:c.1133T > G, and D520G:c.1558A > G in the aternatively spliced exon 15.

[Low HDL-cholesterol--an important risk factor for cardiovascular diseases]. / Snizeni HDL-kolesterol--vazan cimbenik rizika od kardiovaskularnih bolesti.

It has been known for quite a long time that the concentration of HDL-cholesterol correlates inversely with cardiovascular disease (CVD) risk and that low HDL-cholesterol is an independent CVD risk factor. This review aims to highlight evidence on several topics concerning the role of HDL particles and the importance of HDL-cholesterol. The main antiatherogenic functions of HDL particles are presented in details--reverse cholesterol transport, but also their anti-oxidant, anti-inflammatory, anti-thrombotic and anti-apoptotic properties as well as endothelial stabilizing and repair properties. Lifestyle management of low HDL-cholesterol is explained, particularly physical activity and aerobic exercise, smoking cessation, weight reduction in the overweight individuals and composition of the diet but also moderate alcohol consumption stressing the fact that HDL particles from alcoholics are dysfunctional. This is important since it has been shown that it is not only the quantity of HDL particles, and thus HDL-cholesterol level in plasma, that matters, but their quality and impaired functionality as well. HDL from diabetic subjects also lose some of their antiatherogenic properties but a common feature of patients with diabetes type 2 is atherogenic dyslipidemia which is characterized exactly by low HDL-cholesterol and high triglycerides. Diabetic patients with such dyslipidemia are at particularly high CVD risk and the results of recent studies such as ACCORD-Lipid suggest that in them treatment of these lipid abnormalities may be beneficial. Treatment options with fibrates, particularly fenofibrate, and niacin are discussed based upon published trials, as well as combination therapy with these medicines and other lipid-lowering drugs.

Diabetic dyslipidemia or 'diabetes lipidus'?

Diabetes mellitus is one of the most important risk factors for cardiovascular diseases. The results of several studies have shown that achieving satisfactory glucoregulation results in a significant reduction in the incidence of microvascular and macrovascular complications, and cardiovascular mortality. However, the risk of the development of cardiovascular diseases is markedly increased in the presence of dyslipoproteinemia. Research has shown that hyperglycemia not only causes apoptosis of ß-cells in the islets of Langerhans (glucotoxicity) but also determines the degree of accumulation of oxidized LDLs. On the other hand, dyslipoproteinemia itself has a toxic effect on ß-cells, but only in the presence of increased blood glucose levels, thus increasing the risk of the development of cardiovascular diseases exponentially. As diabetes and the lipid metabolism disorder can be neither scrutinized nor treated separately, the authors query whether 'diabetes lipidus' would be a more appropriate term.

Clinical study on the effect of simvastatin on paraoxonase activity.

Human paraoxonase (PON1) is a serum high-density lipoprotein-associated phosphotriesterase. High-density lipoprotein (HDL) plays the role of a carrier and the site of action of this enzyme. According to a majority of authors, PON1 acts as an antioxidant, preventing low-density lipoprotein (LDL) peroxidation. However, due to the fact that in vivo serum PON1 is predominantly associated with HDL, its major physiological role might be to protect HDL, rather than LDL, from oxidation. Nevertheless, the physiological substrate of PON1 still remains to be discovered. The objective of this study was to determine changes in PON1 activity during treatment with simvastatin (CAS 79902-63-9, Lipex) in patients with type IIa and/or IIb hyperlipoproteinemia. PON1 activity was assessed in 32 patients with hyperlipoproteinemia type IIa or IIb with an LDL cholesterol concentration higher than 4.2 mmol/l. Patients received simvastatin in a daily dose of 20 mg. The lipid status and PON1 activity were assessed at baseline, as well as 3 and 6 months after the beginning of treatment. The study demonstrated a statistically significant lipid lowering effect of simvastatin on total and LDL cholesterol, and an increase in PON1 activity in patients with both types of hyperlipoproteinemia. No statistically significant correlation was observed either between changes in PON1 activity and HDL, HDL2, HDL3 and LDL cholesterol and triglyceride levels, or between their first differences in patients with both type IIa and IIb hyperlipoproteinemia. The obtained results suggest that the antioxidant properties of simvastatin might be caused by a mechanism independent of apoAI-containing lipoprotein concentration. The antioxidant properties of simvastatin, which play an important role in HDL protection from oxidation, could be the mechanism inducing the increase in PON1 activity.