Hematologic Findings of Inherited Metabolic Disease: They are More Than Expected.

Inherited metabolic diseases are pathologic conditions that generally develop as a result of impairment of the production or breakdown of protein, carbohydrate, and fatty acids. Early determination of hematological findings has a positive effect on the prognosis of metabolic diseases. Three hundred eighteen patients who were being followed-up within the previous 6 months at Department of Pediatric Nutrition and Metabolism, Gazi University, Turkey, were included in the study. The hematological findings were classified under 7 main groups: anemia of chronic disease, iron deficiency anemia, vitamin B12 deficiency anemia, hemophagocytosis, leukocytosis, and thrombocytosis. Nine hundred twenty-two hematological examinations of the 319 patients were included in the study, and 283 hematological findings were determined, 127 anemia of chronic disease, 81 iron deficiency anemia, 56 cytopenia, and 4 vitamin B12 deficiency anemia. Leukocytosis (n=1), thrombocytosis (n=5), and hemophagocytosis (n=9) were also observed. It was determined that, although anemia of chronic disease and nutritional anemia are the most common hematological findings, these may be diagnosed late, whereas neutropenia, thrombocytopenia, pancytopenia, and hemostasis disorders may be diagnosed earlier. Our study is the most comprehensive one in the literature, and we think it would positively contribute to the monitoring and prognosis of congenital metabolic diseases.

Diagnostic dilemma: osteopetrosis with superimposed rickets causing neonatal hypocalcemia.

Osteopetrosis is a rare genetic condition of reduced osteoclastic bone resorption which causes defective bone remodeling and skeletal sclerosis during growth, having effects on many organs and tissues. Mutation of T-cell immune regulator 1 (TCRG1) gene is the most common genetic defect leading to osteopetrosis, with poor prognosis. The autosomal recessive form presents in the infantile period (also known as malignant infantile osteopetrosis--MIOP), and is characterized by fractures, short stature, hepatosplenomegaly, compressive neuropathies, hypocalcemia and pancytopenia. Being a rare disease with non-specific clinical manifestations, the diagnosis is difficult and usually delayed. Rickets is a characteristic feature of MIOP which results from the defect in osteoclasts to provide a normal Ca/P balance resulting in the poor mineralization of the osteoid. Various treatment options have been suggested for osteopetrosis, but hematopoietic stem cell transplantation still remains the only curative treatment option presently. The authors report the case of a 46-day-old girl with late-onset neonatal hypocalcemia and rickets that was later diagnosed as osteopetrosis. This case report emphasizes that infantile osteopetrosis is an important cause of neonatal hypocalcemia. As irreversible complications develop within the first months of life, immediate diagnosis and early intervention are crucial and may be life-saving.

Home sleep study characteristics in patients with mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction may result from multiple causative factors which may impact severely upon morbidity and mortality. METHODS: We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Metabolic Unit. Patients underwent home-based sleep measurements, and sleep respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index (AHI), hypopnea index, oxygen desaturation index, and minimal oxygen saturation were obtained through home sleep study. RESULTS: For 19 children, the disorder was normal in 1, mild (AHI=1.5-5/h) in 5, moderate (AHI=5-10/h) in 2, and severe (AHI>10/h) in 11. The prevalence of OSA was 94.7 % (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients. CONCLUSION: Home sleep study is a quick and accessible screening test to determine the abnormalities of breathing during sleep and enables clinicians to take necessary action for patients with severe manifestations.

Diagnosis of glycine encephalopathy in a pediatric patient by detection of a GLDC mutation during initial next generation DNA sequencing.

Early diagnosis for metabolic encephalopathy caused by inborn errors of metabolism is very important for the initiation of early treatment and also for prevention of sequela. Metabolic encephalopathy in the form of seizures can result from many inborn errors of metabolism and considering the large number of disorders causing metabolic encephalopathy, enzyme assays or conventional molecular tests are expensive and take considerably long period of time which results in delayed treatment. In our center we have used next generation DNA sequencing technology as an initial diagnostic test to look for about 700 disorders at the same time for the etiologic diagnosis of a 4-month-old female infant suffering from intractable seizures. The patient was found to have glycine encephalopathy resulting from a previously defined mutation in the GLDC gene. The diagnostic result was obtained much sooner than other conventional investigations. Up to our knowledge, this would be the first case with glycine encephalopathy in the literature who was approached by this novel panel method initially. Although currently, classical evaluation methods such as physical examination, biochemical and conventional molecular investigations are still accepted as the gold standards to clarify the etiology of the metabolic encephalopathy it is obvious that next generation sequence analysis will play a very significant role in the future.

BCS1L gene mutation causing GRACILE syndrome: case report.

GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder.

Apheresis-inducible cytokine pattern change in children with homozygous familial hypercholesterolemia.

Familial hypercholesterolemia is a genetic disorder that leads to severe atherosclerosis related cardiovascular complications in young adults. Extracorporeal elimination is a method of LDL-lowering procedures effective in patients with homozygous or severe heterozygous FH utilized in cases. The recruitment of leucocytes into the arterial intima is dependent on a cascade of events mediated through a diverse family of adhesion molecules. Several pro-inflammatory adhesion molecules are cleared by various lipid apheresis methods. This study showed that, LDL-apheresis led to several changes in circulating inflammatory factors which induced antiinflammatory and antiatherogenic changes in the plasma profile in homozygous familial hypercholesterolemic patients.

Asymmetric dimethylarginine (ADMA) and L-arginine levels in children with glycogen storage disease type I.

Patients with glycogen storage disease type I (GSD-I) often have marked hyperlipidemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy; therefore, these patients may be at high risk for the development of atherosclerosis. A recently discussed cardiovascular risk factor, asymmetric dimethylarginine (ADMA), a naturally occuring product of asymmetric methylation of proteins, is an endogenous inhibitor of endothelial nitric oxide synthase. ADMA causes endothelial dysfunction, vasoconstriction, blood pressure elevation, atherosclerosis, and kidney disease progression. A high prevalence of elevated plasma ADMA levels is observed in adults with hypercholesterolemia, hypertension, chronic kidney disease, diabetes mellitus, peripheral arterial disease, coronary artery disease, preeclampsia, heart failure, liver disease, stroke, and many other clinical disorders. Therefore, we aimed to evaluate the endothelial function in patients with GSD-I by using ADMA levels. High-performance liquid chromatography - based method was used for measuring ADMA and L-arginine levels in plasma. The ADMA level was similar between children with GSD-I and the age-matched healthy control group (0.9±0.28 vs. 1.1±0.45 µmol/L; p=0.18). The L-arginine plasma levels in patients with GSD-I were found to be 55.7±41.3 and 91.6±50.2 µmol/L in healthy controls. The preservation of normal endothelial function may result from diminished platelet aggregation, increased levels of apolipoprotein E, decreased susceptibility of low-density lipoprotein to oxidation (possibly related to the altered lipoprotein fatty acid profile in GSD-I), and increased antioxidative defenses in plasma protecting against lipid peroxidation.

Oxidized low-density lipoprotein levels and carotid intima-media thickness as markers of early atherosclerosis in prepubertal obese children.

OBJECTIVES: Children with obesity have a high cardiovascular risk and an impaired oxidant-antioxidant status, which may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to investigate the circulating oxidized low-density lipoprotein (LDL) concentrations and the IMT of carotid arteries in prepubertal obese children, and also to search for its possible association with carotid atherosclerosis. METHODS: Twenty-seven prepubertal obese children (age, 7.48±2.05 years; boys, 59%) and 30 healthy children (age, 7.80±2.19 years; boys, 55%) were included in the study. Serum concentrations of oxidized LDL, total cholesterol, triglyceride, high-density lipoprotein, LDL, and glucose were measured, and carotid IMT was determined by ultrasound. RESULTS: Serum oxidized LDL levels were significantly higher in prepubertal obese children than in healthy children (p<0.01). No significant correlation was observed between oxidized LDL levels and carotid IMT measurements. However, a significant positive correlation was found between oxidized LDL levels and body mass index, total cholesterol, and LDL-cholesterol. CONCLUSION: Our findings revealed that the oxidation of LDL starts early in obese children but the carotid IMT is not significantly affected. Also, oxidized LDL levels are more strongly associated with obesity and dyslipidemia than the carotid IMT in prepubertal children.

Quality of life in children treated with restrictive diet for inherited metabolic disease.

BACKGROUND: The aim of this study was to investigate the quality of life (QoL) of a group of patients with inherited metabolic diseases (IMD) who were treated with restrictive diet. METHOD: A total of 68 patients (35 boys, 51.5%; 33 girls, 48.5%) with IMD (organic acidemia [OA], n = 14; disorder of carbohydrate metabolism [CMD], n = 33; and disorder of amino acid metabolism [AMD], n = 21) and their parents were inteviewed. Both parents completed a QoL Scale for Metabolic Diseases-Parent Form, a KINDL parent questionnaire, and a depression form. All patients aged ≥4 years completed a questionnaire themselves, including the KINDL-Kid and KINDL-Kiddo self-reports. The semi-standardized interviews were carried out with patients and their parents in a clinical setting. RESULTS: The patients with bad diet compliance had lower scores for school labeling and perception of disease on both the parent and child questionnaire forms (P < 0.05). The patients were then divided into three groups (OA, CMD, AMD) for further analysis. Differences were seen between groups with regard to scores of physical function and school performance according to QoL Scale for Metabolic Diseases-Parent Form (P < 0.01). According to parent perceptions, the CMD patients had better QoL with regard to emotional wellbeing. CONCLUSION: As negative effects of the disease increased, the QoL of IMD patients and their parents decreased in terms of emotional, physical, and cognitive function. Application of expanded newborn scanning programs, early diagnosis, regular follow up, and family education would lessen the effects of the disease and improve the QoL of both families and children.

Hypercalcemia in glycogen storage disease type I patients of Turkish origin.

Glycogen storage disease type I (GSD I) is an autosomal recessive disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-a (G6Pase) catalytic unit characterizes GSD IA and defects in the glucose-6-phosphate transporter protein (G6PC) characterize GSD IB. The main clinical characteristics involve fasting hypoglycemia, hyperuricemia, hyperlactatemia, and hyperlipidemia. Hypercalcemia arose as an unknown problem in GSD I patients, especially in those with insufficient metabolic control. The aim of the present study was to obtain the prevalence of hypercalcemia and to draw attention to the metabolic complications of GSD I patients, including hypercalcemia in poor metabolic control. Hypercalcemia frequency and the affecting factors were studied cross-sectionally in 23 GSD I pediatric subjects. Clinical diagnosis of GSD I was confirmed in all patients either through documentation of deficient G6Pase enzyme activity levels on liver biopsy samples or through G6PC gene sequencing of DNA. Hypercalcemia was detected in 78.3% of patients with GSD I. Different from the previous report about hypercalcemia in a GSD IA patient who had R83H and 341delG mutations, we could not identify any genotype-phenotype correlation in our GSD I patients. Hyperlactatemia and hypertriglyceridemia correlated significantly with hypercalcemia. Furthermore, no differences in serum calcium concentrations could be demonstrated between patients with optimal metabolic control. We observed hypercalcemia in our series of GSD I patients during acute metabolic decompensation. Therefore, we speculate that hypercalcemia should be considered as one of the problems of GSD I patients during acute attacks. It may be related with prolonged lactic acidosis or may be a pseudohypercalcemia due to hyperlipidemia that can be seen in GSD I patients with poor metabolic control.

Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.

Hereditary coproporphyria (HCP) is an autosomal dominant acute hepatic porphyria due to the half-normal activity of the heme biosynthetic enzyme, coproporphyrinogen oxidase (CPOX). The enzyme catalyzes the step-wise oxidative decarboxylation of the heme precursor, coproporphyrinogen III, to protoporphyrinogen IX via a tricarboxylic intermediate, harderoporphyrinogen. In autosomal dominant HCP, the deficient enzymatic activity results primarily in the accumulation of coproporphyrin III. To date, only a few homozygous HCP patients have been described, most having Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues D400-K404, most patients described to date having at least one K404E allele. Here, we describe a Turkish male infant, the product of a consanguineous union, who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. He was homoallelic for the CPOX missense mutation, c.980A>G (p.H327R), and had massively increased urinary uroporphyrins I and III (9,250 and 2,910 µM, respectively) and coproporphyrins I and III (895 and 19,400 µM, respectively). The patient expired at 5 months of age from an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site, thereby accounting for the Harderoporphyria phenotype.

N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia.

Hyperammonemia occurs mainly in patients with branched-chain organic acidemias such as propionic, methylmalonic, and isovaleric acidemias. Its pathophysiological process is mainly via the competitive inhibition of N-acetylglutamate synthetase. Oral carglumic acid (N-carbamylglutamate) administration can correct hyperammonemia in neonates with propionic and methylmalonic acidemias, thus avoiding dialysis therapy. Isovaleric acidemia is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase. For the first time, we report a neonate with isovaleric acidemia, whose plasma ammonia concentration dropped dramatically after one oral load of carglumic acid. This experience suggests that carglumic acid could be considered for acute hyperammonemia resulting from isovaleric acidemia. However, trials with more patients are needed.

Analysis of acylcarnitine levels by tandem mass spectrometry in epileptic children receiving valproate and oxcarbazepine.

This prospective study was designed to investigate whether or not monotherapy with sodium valproate (VPA) or oxcarbazepine (OXC) affects plasma levels of fatty acylcarnitine esters in children with epilepsy. A total of 56 children with idiopathic partial or generalised epilepsy were included in the study. Patients were assigned to receive either VPA or OXC monotherapy. Free carnitine (C0) and acylcarnitine profiles of the patients were investigated using tandem mass spectrometry at baseline and at six and 18 months after commencement of therapy. For patients receiving VPA or OXC monotherapy, there were no significant differences in plasma levels of C0, compared with baseline, at six and 18 months (p>0.05). Treatment with VPA for six and 18 months correlated with a significant increase in 3-hydroxy-isovalerylcarnitine (C5-OH) (six months: +23%; 18 months: +73%), and significant decreases in the following acylcarnitines: C6-acylcarnitine (six months: -60%; 18 months: -66%), C14-acylcarnitine (six months: -25%; 18 months: -38%), C16-acylcarnitine (six months: -73%; 18 months: -73%), and C18:1-OH-acylcarnitine (six months: -60%; 18 months: -70%), compared with baseline (p<0.05). In patients receiving OXC monotherapy, on the other hand, plasma concentrations (µmol/L) of acylcarnitines (from C2 to C18:1-OH) fell within the normal reference range. The results of this study indicate that there are significant biochemical changes in acylcarnitines in ambulatory children on VPA monotherapy but these are not clinically significant. OXC monotherapy had no effect on acylcarnitine metabolism in ambulatory children.

Frequency of vitamin D insufficiency in healthy children between 1 and 16 years of age in Turkey.

BACKGROUND: The aim of this study was to establish the frequencies of vitamin D deficiency and insufficiency among healthy children aged 1-16 years and also to determine the factors affecting the levels of vitamin D in Turkey. METHODS: A total of 849 healthy individuals whose ages ranged from 1 to 16 years were included in the study. Serum 25(OH)D, calcium, phosphorous and alkaline phosphatase l levels were measured at the end of the winter period. The approximate daily calcium intake was calculated by using a 1-week diet history. RESULTS: We determined that the prevalence of vitamin D deficiency (<20 ng/mL) was 8% and that of vitamin D insufficiency (20-29 ng/mL) was 25.5% in the population investigated. The average daily intake of calcium was especially low in the >8-year-old age group (<1300 mg/day). CONCLUSION: Vitamin D insufficiency was found to be very common in the population investigated. The daily calcium intake was below the adequate levels especially in school children. Vitamin D supplementation after the first year of life could be beneficial especially for school children and adolescents. The government must develop public policies for the fortification of milk, milk products, and fruit juices with vitamin D.

The levels of asymmetric dimethylarginine, homocysteine and carotid intima-media thickness in hypercholesterolemic children.

The aim of this study was to examine the intima-media thickness (IMT) of carotid arteries and endothelial function parameters such as plasma asymmetric dimethylarginine (ADMA) and homocysteine levels in hypercholesterolemic children and to investigate the relations of these parameters with hypercholesterolemia. Fifty-seven hypercholesterolemic and 37 healthy children were included in the study. Hypercholesterolemia was defined as 155 mg/dl and above for low-density lipoprotein (LDL)-cholesterol. Plasma concentrations of ADMA and homocysteine were measured and the measurement of carotid IMT was determined. Both carotid IMT and plasma ADMA levels were significantly higher in hypercholesterolemic children than healthy children (p<0.01). No significant difference was determined in homocysteine concentration between hypercholesterolemic children and the control group (p>0.05). No significant correlation was observed between lipid profiles and the levels of ADMA and homocysteine. However, a significant positive correlation was found between carotid IMT and total and LDL-cholesterol levels and between the levels of ADMA and LDL-cholesterol. In conclusion, the progressive increase in ADMA levels and carotid IMT and the positive relationship between carotid IMT and serum cholesterol levels support that plasma ADMA levels and carotid IMT can be indicators of early atherosclerosis in hypercholesterolemic children.

An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation.

INTRODUCTION: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder characterized by severe gastrointestinal dysmotility and leads to cachexia, ptosis, external ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy. RESULTS AND DISCUSSION: It is often misdiagnosed as anorexia nervosa or intestinal pseudoobstuctions and are unnecessarily treated with surgery. It has been established that MNGIE is caused by mutations in the gene encoding thymidine phosphorylase, which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine and deoxyuridine. CONCLUSION: We present herein the clinical, neuroimaging, and molecular findings of a patient with MNGIE caused by a novel homozygous TYMP gene mutation (c.112G>T which convert codon 38 from glutamate to a stop codon [p.38E>X]).

Homocysteine, fibrinogen and anti-ox-LDL antibody levels as markers of atherosclerosis in prepubertal obese children.

BACKGROUND: Homocysteine, fibrinogen and antibodies to oxidised LDL were shown to be important markers of atherosclerosis in adults. AIM: To investigate the levels of these three risk factors in prepubertal obese children. METHODS: Fasting homocysteine, fibrinogen and antibodies to oxidised LDL, plasma lipids, insulin, HbA1c and blood glucose levels were investigated in 30 prepubertal obese and 28 control children 6-9 years old. Investigations in the obese group were repeated after an oral glucose tolerance test. RESULTS: Fasting fibrinogen levels of the obese children were found to be significantly higher than those in the controls. Anti-ox-LDL antibody levels increased significantly after an oral glucose tolerance test. CONCLUSION: Fasting fibrinogen and postload ox-LDL levels which could act as important markers of coronary heart disease in later life could also be important risk factors in prepubertal obese children.

High incidence of co-existing factors significantly modifying the phenotype in patients with Fabry disease.

Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ±â€¯12,1 Range 8-46) and 16 males (Age 24,56 ±â€¯15,04 Range 2-48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co-existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.

Asymmetric dimethylarginine and coronary collateral vessel development.

INTRODUCTION: Nitric oxide (NO) plays a major role in collateral vessel development. Asymmetric dimethylarginine (ADMA) that is an endogenous inhibitor of NO synthesis may impair the effective coronary collateral vessel development. The aim of this study was to evaluate the relationship between plasma ADMA level and coronary collateral vessel development. METHODS: The patients with a greater than or equal to 95% obstruction in at least one epicardial coronary artery were included in the study. Degree of coronary collateral development was determined according to Rentrop method. Patients with grade 2-3 collateral development were regarded as good collateral group and formed group I. The patients with grade 0-1 collateral development were regarded as poor collateral group and were included in group II. Group III that had been formed as a control group included the patients with a normal coronary angiogram. We compared the plasma ADMA, symmetric dimethylarginine, L-arginine/ADMA ratio among three groups. RESULTS: Seventy-four patients have been included in the study. Patients with good collateral development had lower plasma ADMA level in comparison with patients with poor collateral development (0.41+/-0.25 micromol/l vs. 0.70+/-0.23 micromol/l, P=0.001) and had similar plasma ADMA levels with the patients who have normal coronary arteries. When we compared L-arginine/ADMA ratio between good and poor collateral groups, we found that the patients with higher L-arginine/ADMA ratio have significantly better collateral development (270.8+/-168.0 vs. 120.9+/-92.1, P<0.001). In the analyses comparing Rentrop score with ADMA level and L-arginine/ADMA ratio, there were significant correlations (r=-0.444, P=0.008 and r=0.553, P=0.001, respectively). In multivariate analysis, ADMA level (odds ratio, 0.009; 95% confidence interval, 0.000-0.466, P=0.020) and L-arginine/ADMA ratio (odds ratio, 1.010; 95% confidence interval, 1.001-1.020, P=0.032) were independent predictors of collateral development. CONCLUSION: Increased plasma ADMA levels are related with poor coronary collateral development. ADMA may be responsible for the difference in coronary collateral vessel development among different patients with coronary artery disease. NO inhibitors that have a determinative relation with endothelial cell functions may be integral prerequisite in all steps of collateral development.