BACKGROUND:Inborn errors of metabolism (IEMs) are inherited diseases causing significant morbidity and mortality, particularly in childhood. Liver transplantation (LT) can be curative or partially effective for these diseases. LT for IEMs has increased, making IEMs the second most common reason for pediatric LT after biliary atresia. PATIENTS AND METHODS:Between 2001 and 2023, 50 pediatric patients with IEMs underwent LT at Başkent University, Ankara Hospital. Data collected retrospectively included diagnosis, gender, age of diagnosis, age of LT, LT indication, donor data, graft type, rejection episodes, post-transplant complications, and clinical findings of the IEMs before and after LT. Treatment methods, follow-up duration, and survival time were also recorded. RESULTS:Of the 332 pediatric LT patients, 50 (15.1%) had IEMs, with three requiring re-transplantations. Diagnoses included glycogen storage diseases (n = 11), tyrosinemia type 1 (n = 10), primary hyperoxaluria (n = 6), urea cycle disorders (n = 6), homozygous familial hypercholesterolemia (n = 4), propionic acidemia (n = 4), deoxyguanosine kinase deficiency (n = 3), maple syrup urine disease (n = 2), methylmalonic acidemia (n = 1), Niemann-Pick disease type B (n = 1), alkaptonuria with unknown neonatal cholestasis (n = 1), and bile acid synthesis disorder (n = 1). The parental consanguinity rate was 74%. Living-related donors provided organs for 48 (90.5%) patients. The mean age at LT was 75.3 ± 8.2 months (range: 5-218), with a follow-up period of 82.1 ± 10.2 months (range:1 day-229 months). Survival rates at 1, 5, 10, and 15 years were 83.7%, 81%, 81%, and 70.9%, respectively. CONCLUSION:LT is an effective solution for children with IEM causing chronic organ failure and difficult to manage with medical treatment, showing a good long-term prognosis.

Objectives Empagliflozin has been used for the treatment of over 100 glycogen storage disease type Ib (GSDIb) patients worldwide since 2019. We aimed to evaluate the effect of empagliflozin treatment on the laboratory and clinical findings of patients with GSDIb in T & uuml;rkiye.Methods Included in this multicenter study were 10 patients with GSDIb, and whose demographic, clinical and laboratory data were analyzed retrospectively. Further data for the study were garnered through a survey of patients and caregivers to evaluate the effects of empagliflozin treatment on quality of life (QoL).Results The mean age at which the empagliflozin treatment was started was 73.2 (4-239) months. The mean duration of empagliflozin treatment was 16.9 (8-39) months. Glucosuria was identified in eight (80 %) patients undergoing empagliflozin treatment, while urogenital infections were detected in six (60 %) and hypoglycemia in two (20 %). An analysis of neutrophil levels revealed increased absolute neutrophil counts following empagliflozin treatment. Skin and/or mucosal lesions were noted in nine (90 %) patients prior to the initiation of empagliflozin treatment, but persisted in only one patient following empagliflozin treatment (10 %) (p=0.008). Empagliflozin treatment resulted in a decrease in the frequency of hospitalizations due to infection (p=0.0015). Furthermore, 80 % of the patients reported positive impact on their well-being as a result of the empagliflozin treatment, and 70 % of parents reported improvement in physical performance and activities, in the sleep quality of both the patient and parents, and in mobility.Conclusions This study revealed empagliflozin to be effective in improving the neutrophil counts of patients with GSD Ib and in enhancing the QoL of both the patients and their caregivers.

Background/aim:Pompe disease (acid maltase deficiency, glycogen storage disease type II, OMIM #606800) is an autosomal recessive disorder characterized by lysosomal acid-α-glucosidase deficiency. The infantile-onset type of the disease is mainly characterized by cardiomegaly, hypotonia, and a high mortality rate. This study aimed to create a national consensus about infantile-onset Pompe disease (IOPD) to raise awareness among clinicians and standardize diagnosis and treatment approaches in Türkiye. Materials and methods:The Gazi University Division of Metabolic Diseases and Nutrition developed this expert opinion consensus and expanded it to include metabolism specialists across Türkiye. A systematic literature review was performed, and the Delphi method was used to evaluate the results. Results:Seventeen conclusive questions were produced about clinical presentation, diagnosis, and treatment, and 14 reached a consensus. Consensus was reached that general hypotonia is one of the most important findings, and agreement was also achieved on the starting dose of treatment for presymptomatic patients. The contributors agreed that gene therapy is a good treatment option for IOPD in the future. Conclusion:The topics related to this consensus will help physicians in Türkiye and elsewhere with high incidence rates of IOPD, especially regarding diagnosis and treatment decisions.

Cerebral creatine deficiency syndromes (CCDS) are three metabolic diseases characterized by loss of function in three proteins (GATM, GAMT, and SLC6A8) that required in creatine (Cr) synthesis pathway and transport. In this study, we aimed to identify the causal variant in a male who was 12-year-old manifesting intellectual disability (ID), seizures, expressive dysphasia and autism-like behavior. Urinary Cr metabolite measurements and MRI-spectroscopy (MRS) findings were consistent with CCDS. Molecular analysis revealed de novo hemizygous SLC6A8 (NM_005629.4): c.1400 T > G (p.Met467Arg) variant. The variant was not found in ClinVar, (the date of access: April 23th, 2023) and population databases (ExAC, gnomAD, 1000 Genomes, ESP 6500, Turkish Variome, GenomeAsia, Iranome, GME Variome, TOPMed Bravo and 4.7KJPN), it alters the physicochemical properties of the amino acid, the region is moderately conserved across species and in-silico prediction tools (REVEL, CADD, SIFT, PolyPhen2, Mutation Taster, MetaLR, MCAP, MetaRNN and MutPred) unanimously emphasize pathogenicity. Based on this evidence, the variant was interpreted as "likely pathogenic" according to the ACMG criteria (PS2, PM2,PP3, and PP4-S). This report may further elucidate the nature and phenotypic consequences of SLC6A8 variants.

Introduction: Glycogen storage diseases (GSDs) are inherited metabolic disorders result from impaired glycogen storage, glycogen or glucose breakdown. Liver transplantation (LT) is considered as a treatment option for patients with glycogen storage diseases present with hepatic malignancy, liver failure or metabolic decompensation. GSD type Ia is associated with mutations in the G6PC gene due to deficiency of glucose-6-phosphotase, while glycogen storage disease type 9 results from phosphorylase kinase deficiency, an enzyme necessary for glycogen breakdown. Herein, we present our experience and transplantation outcomes in 7 pediatric patients with GSD who underwent LT. Methods: We retrospectively analyzed data from patients diagnosed with GSD who underwent LT between 1993-2021 years. Results: LT was performed in 6 patients with GSD type 1a and one patient with GSD type 9. Four patients had a family history of consanguinity (3 patients 1st degree, 1 patient 2nd degree). Mean age of diagnosis was 7.28 (1-24) months. Mean age of LT was 128.5 (13-216) months. Transplantation indications were hepatic adenoma (4/7), poor metabolic control (4/7) and cirrhosis (1/7). Extra-hepatic findings included proteinuria (4/7), Focal segmental glomerulosclerosis (1/7), proximal tubulopathy (4/7), nephrolithiasis (2/7), hyperlipidemia (7/7), delayed puberty (3/7), hypertension (2/7), short stature (6/7), epilepsy (2/7) and osteoporosis (4/7). One patient with GSD1a underwent cataract surgery. Three patients with GSD1a incidentally had the same G6PC gene mutations (c.247C>T). Three patients had normal cognitive functions and development (WISC-R Test). Two patients had mild where one patient had moderate mental retardation. One patient had %30 developmental delay (AGTE Test). Six patients underwent LT from living-related donors while one patient had cadaveric donor. Patients who underwent LT from live donors received left lateral segment. Explant liver pathology revealed variable numbers (1-12) of hepatic adenoma in 4 patients. Hepatocellular carcinoma (HCC) was detected in one patient. Serum lactate, uric acid and triglyceride levels normalized after LT. Tubulopathy resolved in one patient while epilepsy continued in two patients. Height SD scores were improved in 4 patients while remained unchanged in one patient after 5-year follow up. Acute graft rejection was detected in 4 patients. Mean follow up time was 80 (3-183) months. All patients are still alive and routinely followed up at our department. Conclusion: LT improved the quality of life in our GSD patients with metabolic decompensation and severe disease manifestations. Biochemical parameters (lactate, uric acid and triglyceride levels) normalized after transplantation. Our patients displayed improved height growth. LT should be considered in GSD patients with poor metabolic control despite dietary management, hepatic malignancy or progressive liver failure.

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, most cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified 10 bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in sarcoplasmic reticulum function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic reticulum storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare disorder characterized by multiple small intestine ulcers. Patients with CEAS typically present with chronic anemia and gastrointestinal bleeding. Besides CEAS, SLCO2A1 mutations cause primary hypertrophic osteoarthropathy (PHO) which is considered as an extraintestinal manifestation in CEAS patients. Since CEAS and Crohn's disease are clinically indistinguishable, patients are often misdiagnosed with Crohn's disease. Herein, we describe a 4-year-old Turkish girl with CEAS due to homozygous pathogenic variant (c.656C > T) in SLCO2A1 with concomitant hereditary fructose intolerance (HFI) caused by homozygous pathogenic variant (c.1005C > G) in ALDOB. Prompt restriction of fructose, sucrose and sorbitol resulted in hepatomegaly regression and mild amelioration of patient's symptoms. Despite budesonide and azathioprine treatments, patient's protein losing enteropathy and chronic anemia did not improve. Although previous CEAS cases were reported from East Asian countries, it is likely to occur in people from other geographic areas. CEAS seems to be underdiagnosed and high index of suspicion is required for the diagnosis of this rare entity. Patients with prior diagnosis of Crohn's disease with no response to immunosuppressive treatment or anti-TNF therapy should be re-evaluated for possible CEAS diagnosis.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Non-cirrhotic portal hypertension (NCPH) is a rare clinical entity in children. Familial clusters of idiopathic non-cirrhotic portal hypertension (INCPH) were previously reported in cases with deoxyguanosine kinase (DGOUK) and potassium calcium-activated channel subfamily N member 3 (KCNN3) mutations. Herein, we report two siblings who had a novel mutation in mitochondrial tRNA methyltransferase 5 (TRMT5) gene and presented with hepatopulmonary syndrome and later diagnosed as INCPH. Autosomal recessive inheritance of this mutation may suggest a role of TRMT5 mutations in the development of NCPH. Screening of TRMT5 mutations could be considered when familial INCPH is suspected.

OBJECTIVES:X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal inborn error of metabolism caused due to the loss of function variants of ABCD1 gene that leads to accumulation of very long chain fatty acids (VLCFAs) in several tissues including the neurological system. Childhood cerebral X-ALD (CCALD) is the most common and severe form of X-ALD, if left untreated. Allogenic hematopoietic stem cell transplantation (HSCT) is the only available therapy that halts neurological deterioration in CCALD. We present 12 patients with several subtypes of X-ALD that were followed-up in a single center. METHODS:Data of 12 patients diagnosed with X-ALD were documented retrospectively. Demographics, age of onset, initial symptoms, endocrine and neurological findings, VLCFA levels, neuroimaging data, molecular genetic analysis of ABCD1 gene, and disease progress were documented. RESULTS:Mean age of initiation of symptoms was 7.9 years and mean age of diagnosis was 10.45 years. Eight patients had the CCALD subtype, while two had the cerebral form of AMN, one had the adult form of cerebral ALD, and one patient had the Addison only phenotype. The most common initial symptoms involved the neurological system. Loes scores varied between 0 and 12. Seven patients with CCALD underwent HSCT, among them three patients died. The overall mortality rate was 25%. CONCLUSIONS:Patients with X-ALD should be carefully followed up for cerebral findings and progression, since there is no genotype-phenotype correlation, and the clinical course cannot be predicted by family history. HSCT is the only available treatment option for patients with neurological deterioration.

PURPOSE:Obesity has become a very significant health problem in childhood. Fructose taken in an uncontrolled manner and consumed in excessive amounts is rapidly metabolized in the body and gets converted into fatty acids. This single center prospective case-control study aims to investigate the relationship between fructose consumption and obesity and the role of fructose consumption in development of atherosclerotic diseases.METHODS:A total of 40 obese and 40 healthy children who were of similar ages (between 8 and 18 years) and sexes were included in the study. In the patient and control groups, the urine fructose levels, as well as the levels of oxidized low-density lipoprotein (LDL), small dense LDL, Apolipoprotein A and Apolipoprotein B values, which have been shown to play a role in development of atherosclerotic diseases, were measured.RESULTS:The levels of oxidized LDL and small dense LDL and the ratio of Apolipoprotein A/Apolipoprotein B were found to be significantly higher in the patient group.CONCLUSION:We found that urinary fructose levels were higher in the obese children than the healthy children. Our results suggest that overconsumption of fructose in children triggers atherogenic diseases by increasing the levels of small dense LDL and oxidized LDL and the ratio of Apolipoprotein B/Apolipoprotein A.

Background. Isolated sulfite oxidase deficiency (ISOD), caused by mutations in SUOX gene, is an autosomal recessive disease manifesting with early onset seizures, developmental delay, microcephaly, and spasticity. It mimics hypoxic-ischemic encephalopathy (HIE) in the neonatal period and is characterized by progressive severe neurological impairment due to accumulation of toxic metabolites. Case. This report presents a late diagnosed male patient with ISOD manifesting with neonatal-onset seizures, developmental delay, microcephaly, and spastic quadriplegia. Brain magnetic resonance imaging of the patient showed bilateral subcortical multi-cystic encephalomalacia involving bilateral parieto-occipital regions. A novel homozygous c.590_595delAGCCTC in-frame deletion in SUOX gene was identified in the patient, while both parents were heterozygous for that mutation. Conclusion. The mutation identified in our patient causes severe ISOD. Early diagnosis of ISOD is essential for accurate genetic counseling and achieving prenatal diagnosis. Screening for urinary sulfite in patients with neonatal or early infantile onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking HIE helps in early diagnosis.

We describe the first child with guanidinoacetate methyltransferase (GAMT) deficiency who developed neuroleptic malignant syndrome (NMS) after the treatment of risperidone without elevated creatine kinase (CK) levels. The patient presented with lethargy, hyperthermia, generalized tremor and rigidity with normal serum CK levels. After cessation of risperidone and adding clonezepam to the supportive treatment, symptoms of NMS were ameliorated. We conclude that although serum CK elevation is a useful indicator for the early detection of NMS, normal serum CK levels may be seen during the NMS course in the presence of GAMT deficiency.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder of creatine biosynthesis. Here, we report 9 and 10-year-old cousins with GAMT deficiency caused by a novel mutation who both exhibited neurodevelopmental retardation, seizures, behavioral problems, and autism that began during early infancy. The patients were diagnosed as having only autism and followed for years without a specific diagnosis although they had very low levels of serum creatinine for several times. A novel nonsense mutation in the GAMT gene that caused cessation of synthesis of the protein encoded by this gene was identified in these patients. GAMT deficiency is a treatable inborn error of metabolism and should be considered for all patients with hypotonia, developmental delay, seizures and autism, particularly if low serum creatinine levels are observed.

Background Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. Case characteristics Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. Outcome Both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems. Message Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify CTD in children with autistic behavior and language disorders.

Objective: Cerebral creatine deficiency syndromes (CDS) cover two autosomal recessive disorders in creatine synthesis and X-linked creatine transporter defect. In all CDS, creatine deficiency in body fluids, muscle and brain are common. Creatine synthesis defects are glycine aminotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies. GAMT deficiency results in accumulation of guanidinoacetate, an intermediary metabolite in creatine synthesis, which is known to be neurotoxic and epileptogenic. GAMT deficiency is characterized with epilepsy, movement disorders and learning disabilities. A number of different mutations in GAMT gene are known to cause GAMT deficiency. Methods: We here present two children (10 years-old-male and 9 years-old female) with GAMT deficiency who were followed up in another health care center with the diagnosis of autism and hyperactivity. They are cousins and both from first-degree cousin marriage. Our patients presented with developmental delay, have epilepsy and speech impairment without movement disorders. Results: The levels of creatine in both were found between 0.01 mg/dl and 0.2 mg/dl on numerous occasions, but had not been recognized as a clue for presumptive diagnosis of creatine synthesis defects. Brain magnetic resonance spectroscopy showed the absence of creatine peak in basal ganglia and white matter. We identified a novel homozygous mutation (1. exon p. Cys*, c.C48A) in the index patient. The parents were found heterogeneous for his mutation. This mutation was a nonsense mutation leading to stop the synthesis of the protein in GAMT gene. Conclusion: The creatine synthesis defects (AGAT and GAMT) are treatable disorders, but they are underdiagnosed. The serum creatinine level should be carefully checked for the diagnosis of creatine synthesis defects in all children with developmental e- delay, epilepsy and autistic features.

Ziad Abassi Shuaib Abdullah William M. Adams O.Y. Addo Peter Aggett N.M. Al-Daghri Carmen Alicia Sanchez-Ramirez Won-Suk An Ann L. Anderson Berry Katsuhiro Arai Shmuel Arnon G. Artioli Halil Ibrahim Aydin Evelien Backx Fereshteh Bahmani C. Baldwin Maria D. Ballesteros-Pomar Maciej Banach Rocco Barazzoni Mariela Bernabe-Garcia A. Buyken Cristina Campoy Dexter Canoy Antonio Gil Castinheiras Neto Ana Carla Cepeda Lopez Colin Cercamondi Semra Cetinkaya A.J. Chambers Hitoshi Chiba Matthys Christophe Roberta Cobas Ion Codreanu Tatienne Costa Jeanne de Vries Tamás Decsi Edgard Delvin Hans Demmelmair Roland N. Dickerson Jan Władyslaw Dlugosz Katarina Dokoupil Jernej Dolinsek Brendon McDermott Masanori Emoto Xabier Escote Simone Eussen Anna Magdalena Fabisiak