Pterin Profiling in Serum, Dried Blood Spot, and Urine Samples Using LC-MS/MS in Patients with Inherited Hyperphenylalaninemia.

Background: Hyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 µmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA. Methods: The samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study. Results: Among the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values. Conclusion: In this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results.

Endocrinological and metabolic profile of Gaucher disease patients treated with enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) is a lysosomal storage disease caused by glucocerebrosidase (GCase) enzyme deficiency. Gaucher cells transformed from the macrophages by progressive sphingolipid accumulation and infiltrate bone marrow, spleen, liver, and other organs. The accumulation of substrate causes inflammation, compromised cellular homeostasis, and disturbed autophagy. It has been hypothesized that this proinflammatory state of GD leads cytokines and chemokines release. As a result of inflammatory process, the cellular dysfunction caused by disruption of cellular signaling, organelle dysfunction, or autoimmune antibodies may affect endocrine profile of GD patients such as hormone levels, lipid profile, and bone mineral density status. METHODS: A total of 13 patients confirmed to have GD, 12 non-neuronopathic type and one subacute neuronopathic type, were enrolled in our study. RESULTS: The median treatment duration in the enzyme therapy was 13.33 years (9-26 years). At least one endocrinological abnormality was detected in blood tests of nine patients. Hyperinsulinism was the most common finding although fasting blood glucose levels HgbA1c levels were normal in all patients. Two patients had osteopenia, and osteoporosis was detected in two patients. Low HDL levels were detected in six patients, but HDL levels below 23 mg/dL associated with disease severity have been detected in two patients who have not receiving enzyme replacement therapy. None of patients had thyroidal dysfunction. CONCLUSIONS: This study had revealed endocrinological abnormalities in GD patients that have not led any severe morbidity in our patients. However, thyroid hormone abnormalities, insulin resistance, or lipid profile abnormalities may cause unpredictable comorbidities. Endocrinological assessment in GD patients in routine follow-up may prevent possible clinical manifestation in long term as well as can define efficacy of ERT on endocrine abnormalities.

Is lysosomal acid lipase activity associated with the presence and severity of coronary artery disease?

BACKGROUND: Lipid metabolism is considerably complex and there can be many critical steps in atherogenesis. The association between lysosomal acid lipase (LAL) activity and coronary artery disease (CAD) has not been elucidated in detail. We aimed to evaluate the association between LAL activity with the presence and severity of CAD in patients who are seen in daily clinical practice. METHODS: Patients who underwent coronary angiography were divided into groups according to the angiography results. Syntax scores and Gensini scores were calculated. The LAL activity was measured from dried blood spots. RESULTS: Median LAL activity values were similar in all study groups (normal coronary arteries: 0.40 nmol/punch/h; non-obstructive CAD: 0.44 nmol/punch/h; obstructive chronic CAD: 0.40 nmol/punch/h; obstructive acute coronary syndrome: 0.48 nmol/punch/h) and there was no correlation between coronary atherosclerotic burden and LAL activity (correlation coefficients Syntax score and LAL: -0.032; Gensini score and LAL: -0.030). In addition, no relationship between serum lipid levels and LAL activity was detected. CONCLUSION: The presence of CAD and its severity is not associated with the LAL activity in patients encountered in daily clinical practice.

Diagnostic value of plasma lysosphingolipids levels in a Niemann-Pick disease type C patient with transient neonatal cholestasis.

OBJECTIVES: Niemann-Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described. CASE PRESENTATION: A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis. CONCLUSIONS: The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.

Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability.

OBJECTIVES: To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. METHODS: The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. RESULTS: Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had two novel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. CONCLUSIONS: This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.

Clinical and event-based outcomes of patients with mucopolysaccharidosis VI receiving enzyme replacement therapy in Turkey: a case series.

BACKGROUND: The objective of this study was to describe clinical manifestations and events of patients with mucopolysaccharidosis (MPS) VI in Turkey who are treated with galsulfase enzyme replacement therapy (ERT). Clinical data of 14 children with MPS VI who were followed up at the Department of Pediatrics of the Gazi University Faculty of Medicine in Ankara, Turkey were retrospectively collected from the patients' medical records. Patients were selected based on availability of a pre-ERT baseline and follow-up clinical data for a similar period of time (1.9-3.2 years). Event data (occurrence of acute clinical events, onset of chronic events, surgeries) collected during hospital visits and telemedicine were available for up to 10 years after initiation of ERT (2.5-10 years). RESULTS: Age at initiation of ERT ranged from 2.8 to 15.8 years (mean age 7.5 years). All patients presented with reduced endurance and skeletal abnormalities (dysostosis multiplex) on radiography. Other common clinical manifestations were cardiac valve disease (N = 13), short stature (N = 11), cranial abnormalities on MRI (N = 10), spinal abnormalities on MRI (N = 7), and mild cognitive impairment (N = 6). School attendance was generally poor, and several patients had urinary incontinence. After 1.9 to 3.2 years of ERT, most patients showed improvements in endurance in the 6-min walk test and 3-min stair climb tests; the frequency of urinary incontinence decreased. ERT did not seem to prevent progression of cardiac valve disease, eye disorders, hearing loss, or bone disease. Long-term event-based data showed a high incidence of respiratory tract infections, adenotonsillectomy/adenoidectomy, reduced sleep quality, sleep apnea, and depression before initiation of ERT. The number of events tended to remain stable or decrease in all patients over 2.5-10 years follow-up. However, the nature of the events shifted over time, with a reduction in the frequency of respiratory tract infections and sleep problems and an increase in ophthalmologic events, ear tube insertions, and depression. CONCLUSIONS: This case series shows the high disease burden of the MPS VI population in Turkey and provides a unique insight into their clinical journey based on real-life clinical and event-based data collected before and after initiation of ERT.

Congenital defects of glycosylation: Novel presentations with mainly neurological involvement and variable dysmorphic features.

The pathophysiology of congenital defects of glycosylation (CDG) is complex and the diagnosis has been a challenge because of the overlapping clinical signs and symptoms as well as a large number of disorders. Isoelectric focusing of transferrin has been used as a screening method but has limitations. Individual enzyme or molecular genetic tests have been difficult to perform. In this study, we aimed to describe CDG patients who were referred to from different departments either without a preliminary diagnosis or suspected to have a genetic disorder other than CDG. The patients were diagnosed mainly with a 450 gene next-generation DNA sequencing panel for inborn errors of metabolism, which also included 25 genes for CDG. A total of 862 patients were investigated with the panel, whereby homozygous (10) or compound heterozygous (4) mutations were found in a total of 14 (1.6%) patients. A total of 13 different mutations were discovered, 10 of them being novel. Interestingly, none of the patients was suspected to have a CDG before referral. This report expands the clinical/laboratory findings in patients with CDG and stresses on the fact that CDG should be in the differential list for pediatric patients presented with nonspecific dysmorphic features and neurological delays/regression. Also, next-generation DNA sequencing with panel approach was noticed to have a significant diagnostic potential in patients presented with nonspecific neurologic and dysmorphic findings.

Two patients from Turkey with a novel variant in the GM2A gene and review of the literature.

OBJECTIVES: GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. CASE PRESENTATION: A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including ß-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. CONCLUSIONS: This case report emphasizes that in the event of normal ß-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.

The first case with FBXL4 mutation successfully treated with a parenteral ketogenic diet for lactic acidosis.

BACKGROUND: The ketogenic diet (KD) is a low-carbohydrate, high-fat diet that has been used as an effective nonpharmacological treatment in many neurological and metabolic disorders for a long time. The effectiveness of the KD is revealed in mitochondrial disorders, mainly in pyruvate dehydrogenase deficiency. CASE REPORT: A 4-year-old girl who was diagnosed with an F-box and leucine-rich repeat protein 4 (FBXL4) gene mutation was hospitalized with sepsis. She was first given standard parenteral nutrition (PN) because of gastrointestinal problems. During the disease course, lactic acidosis became prominent and did not respond to pharmacological treatment; standard PN was gradually switched to parenteral KD, and lactate levels decreased after parenteral KD. The patient was discharged with an enteral KD. CONCLUSION: This is the first case of mitochondrial depletion syndrome effectively treated with parenteral KD for lactic acidosis.

Autism: Screening of inborn errors of metabolism and unexpected results.

In this study, the aim was to examine patients with inborn errors of metabolism (IEM) who presented with only autism, without any other findings, to suggest any other neurological and genetic disorders. To investigate IEM, data of the hospital records of 247 patients who were referred from pediatric psychiatric to pediatric metabolism outpatient clinics due to further evaluation of autism spectrum disorders (ASD) were examined. Among them, 237 patients were evaluated for IEM leading to ASDs. Organic acidemias, phenylketonuria, tetrahydrobiopterin and neutrotransmitter disorders, biotinidase deficiency, Smith-Lemni-Opitz syndrome, disorders of cerebral creatine metabolism, urea cycle defects, homocystinuria, purine-pyrimidine metabolism disorders, mitochondrial disorders, cerebrotendinous xantomatosis, mucopolysaccaridosis, and glucose 6 phosphate dehydrogenase deficiency were screened with complete blood counts, complete biochemical analyses, homocysteine levels, an arterial blood gase, and metabolic investigations. Six patients were diagnosed as follows: one with phenylketonuria (PKU), one with cerebral creatine deficiency, one with hypobetalipoproteinemia, one with glycogen storage disease type IX-a, one with dihydropyrimidine dehydrogenase deficiency, and one with succinic semialdehyde dehydrogenase deficiency (SSADHD). Forty-six patients screened for IEM were from consanguineous families, among them, one was diagnosed with FKU and the other was with SSADHD. It would not be expected to find PKU in a 5-year-old patient as a result of newborn screening, but she could not been screened due to being a refugee. The diagnosed diseases were rare presentations of the diseases and furthermore, the diagnosis of hypobetalipoproteinemia and glycogen storage disease type IX-a were surprising with the only presentation of ASDs. LAY SUMMARY: It is well-known that some types of inborn errors of metabolism (IEM) may present with that of autism spectrum disorders (ASDs). This study suggests that in countries where consanguinity marriages are common such as Turkey and refugees whose escaped from neonatal screening are present, patients with ASD should be screened for IEMs. The results can surprise the physicians with a very rare cause of autism that has never been thought. Autism Res 2021, 14: 887-896. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

INTRODUCTION: Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. MATERIALS AND METHODS: Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. RESULTS: Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. DISCUSSION: Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

Un trastorno poco frecuente del ciclo de la urea en un recién nacido: deficiencia de N-acetilglutamato sintasa / A rare urea cycle disorder in a neonate: N-acetylglutamate synthetase deficiency

Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency.The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG).NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia

A rare urea cycle disorder in a neonate: N-acetylglutamate synthetase deficiency. / Un trastorno poco frecuente del ciclo de la urea en un recién nacido: deficiencia de N-acetilglutamato sintasa.

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency. The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG). NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia.

Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia.

Beneficial Effects of Modified Atkins Diet in Glycogen Storage Disease Type IIIa.

INTRODUCTION: Glycogen storage disease Type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen debranching enzyme, encoded by the AGL gene. Two clinical types of the disease are most prevalent: GSD IIIa involves the liver and muscle, whereas IIIb affects only the liver. The classical dietetic management of GSD IIIa involves prevention of fasting, frequent feeds with high complex carbohydrates in small children, and a low-carb-high-protein diet in older children and adults. Recently, diets containing high amount of fat, including ketogenic and modified Atkins diet (MAD), have been suggested to have favorable outcome in GSD IIIa. METHODS: Six patients, aged 3-31 years, with GSD IIIa received MAD for a duration of 3-7 months. Serum glucose, transaminases, creatine kinase (CK) levels, capillary ketone levels, and cardiac parameters were followed-up. RESULTS: In all patients, transaminase levels dropped in response to MAD. Decrease in CK levels were detected in 5 out of 6 patients. Hypoglycemia was evident in 2 patients but was resolved by adding uncooked cornstarch to diet. CONCLUSION: Our study demonstrates that GSD IIIa may benefit from MAD both clinically and biochemically.

Vitamin D Levels and Bone Mineral Density in Inborn Errors of Metabolism Requiring Specialised Diets.

OBJECTIVE: To evaluate vitamin D levels and bone mineral density in patients with dietary limitations due to inborn errors of metabolism (IEM) and its correlation with diets. STUDY DESIGN: Retrospective study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Gazi University Hospital, Turkey, from March to Semtember 2016. METHODOLOGY: The study is a retrospective review of 115 patients. Information about vitamin D status, bone mineral density (BMD) measurement and anthropometric parametres were collected. Patients were divided into two major groups, receiving protein-restricted diets (n=83) and lactose-restricted diets (n=32). Data of 110 healthy children were used as the control group. RESULTS: Mean vitamin D level of patients with special diets 28.1 ±14.9 ng/ml while mean level of healthy controls was 26.6 ±12.27 ng/ml. Levels of 26.8% (n=26/97) patients were found to be deficient and 34% (n=33/97) were found to be insufficient. No statistically significant differences were found between vitamin D levels and BMD of patients and healthy controls. BMD was not influenced by vitamin D levels. CONCLUSION: Low BMD may be encountered in IEM, independent of vitamin D levels and revision of diet for adequacy of essential nutrients; and follow-up for dietary compliance is inevitable.

A possible biomarker of neurocytolysis in infantile gangliosidoses: aspartate transaminase.

Gangliosidoses (GM1 and GM2 gangliosidosis) are rare, autosomal recessive progressive neurodegenerative lysosomal storage disorders caused by defects in the degradation of glycosphingolipids. We aimed to investigate clinical, biochemical and molecular genetic spectrum of Turkish patients with infantile gangliosidoses and examined the potential role of serum aspartate transaminase levels as a biomarker. We confirmed the diagnosis of GM1 and GM2 gangliosidosis based on clinical findings with specific enzyme and/or molecular analyses. We retrospectively reviewed serum aspartate transaminase levels of patients with other biochemical parameters. Serum aspartate transaminase level was elevated in all GM1 and GM2 gangliosidosis patients in whom the test was performed, along with normal alanine transaminase. Aspartate transaminase can be a biochemical diagnostic clue for infantile gangliosidoses. It might be a simple but important biomarker for diagnosis, follow up, prognosis and monitoring of the response for the future therapies in these patients.

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.

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.

Vitamin A status and factors associated in healthy school-age children.

BACKGROUND & AIMS: Vitamin A deficiency (VAD) is one of the most widespread vitamin deficiencies. Vitamin A is essential for children in order to ensure a healthy life span and sustain the normal growth and development. Aim of this study is to examine vitamin A status, and factors associated with it, in healthy school-age children. METHODS: The study was carried out in schools in Altindag, the district of Ankara, from April to May 2009. 585 girls and 478 boys, a total of 1063 healthy children aged 5-16 years were taken into the study. Serum retinol, ferritin and hs-CRP levels and complete blood count of each case were measured. A questionnaire was developed to collect socio-economic and demographic information of the participants. RESULTS: Any subclinical VAD (SRL <0.7 µmol/L) was not detected in the children attending the study. However, SRLs were suboptimal in 2.2% of cases and these children were under a high risk of developing subclinical, and subsequently clinical VAD. There were significant positive correlations between serum retinol and hemoglobin values, and statistically significant negative correlation between serum retinol level and ferritin and hsCRP. CONCLUSIONS: Vitamin A deficiency does not constitute an important public health problem for Altindag, Ankara, Turkey. Frequency of such vitamin deficiencies should be revealed before launching nationwide public health programs to fight with these deficiencies.