Electro-clinical features and long-term outcomes in guanidinoacetate methyltransferase (GAMT) deficiency.

OBJECTIVE: To evaluate clinical characteristics and long-term outcomes in patients with guanidinoacetate methyltransferase (GAMT) deficiency with a special emphasis on seizures and electroencephalography (EEG) findings. METHODS: We retrospectively analyzed the clinical and molecular characteristics, seizure types, EEG findings, neuroimaging features, clinical severity scores, and treatment outcomes in six patients diagnosed with GAMT deficiency. RESULTS: Median age at presentation and diagnosis were 11.5 months (8-12 months) and 63 months (18 months -11 years), respectively. Median duration of follow-up was 14 years. Global developmental delay (6/6) and seizures (5/6) were the most common symptoms. Four patients presented with febrile seizures. The age at seizure-onset ranged between 8 months and 4 years. Most common seizure types were generalized tonic seizures (n = 4) and motor seizures resulting in drop attacks (n = 3). Slow background activity (n = 5) and generalized irregular sharp and slow waves (n = 3) were the most common EEG findings. Burst-suppression and electrical status epilepticus during slow-wave sleep (ESES) pattern was present in one patient. Three of six patients had drug-resistant epilepsy. Post-treatment clinical severity scores showed improvement regarding movement disorders and epilepsy. All patients were seizure-free in the follow-up. CONCLUSIONS: Epilepsy is one of the main symptoms in GAMT deficiency with various seizure types and non-specific EEG findings. Early diagnosis and initiation of treatment are crucial for better seizure and cognitive outcomes. This long-term follow up study highlights to include cerebral creatine deficiency syndromes in the differential diagnosis of patients with global developmental delay and epilepsy and describes the course under treatment.

Adult-onset carnitine palmitoyl transferase II (CPT II) deficiency presenting with rhabdomyolysis and acute kidney injury.

Metabolic myopathies are among the treatable causes of rhabdomyolysis and myoglobinuria. Carnitine palmitoyl transferase 2 (CPT II) deficiency is one of the most common causes of recurrent myoglobinuria in adults. It is an inherited disorder of fatty acid oxidation pathway, commonly associated with elevated acylcarnitine levels. In this case report, we present a 49-year-old male patient who developed acute kidney injury after rhabdomyolysis and was thus diagnosed with CPT2 deficiency after his first episode of rhabdomyolysis. Inborn errors of metabolism should be kept in mind in patients with rhabdomyolysis. Acylcarnitine profile may be normal in CPT II deficiency, even during an acute attack, and molecular genetic diagnostics should be applied if there is high index of clinical suspicion.

Validity and reliability of the MetabQoL 1.0 and assessment of neuropsychiatric burden in organic acidemias: Reflections from Turkey.

OBJECTIVES: The MetabQoL 1.0 is the first disease-specific health related quality of life (HrQoL) questionnaire for patients with intoxication-type inherited metabolic disorders. Our aim was to assess the validity and reliability of the MetabQoL 1.0, and to investigate neuropsychiatric burden in our patient population. METHODS: Data from 29 patients followed at a single center, aged between 8 and 18 years with the diagnosis of methylmalonic acidemia (MMA), propionic acidemia (PA) or isovaleric acidemia (IVA), and their parents were included. The Pediatric Quality of Life Inventory (PedsQoL) was used to evaluate the validity and reliability of MetabQoL 1.0. RESULTS: The MetabQoL 1.0 was shown to be valid and reliable (Cronbach's alpha: 0.64-0.9). Fourteen out of the 22 patients (63.6%) formally evaluated had neurological findings. Of note, 17 out of 20 patients (85%) had a psychiatric disorder when evaluated formally by a child and adolescent psychiatrist. The median mental scores of the MetabQoL 1.0 proxy report were significantly higher than those of the self report (p = 0.023). Patients with neonatal-onset disease had higher MetabQoL 1.0 proxy physical (p = 0.008), mental (p = 0.042), total scores (p = 0.022); and self report social (p = 0.007) and total scores (p = 0.043) than those with later onset disease. CONCLUSIONS: This study continues to prove that the MetabQoL 1.0 is an effective tool to measure what matters in intoxication-type inherited metabolic disorders. Our results highlight the importance of clinical assessment complemented by patient reported outcomes which further expands the evaluation toolbox of inherited metabolic diseases.

Predictors of eventual requirement of phenylalanine-restricted diet in young infants with phenylalanine hydroxylase deficiency initially managed with sapropterin monotherapy.

BACKGROUND: Phenylalanine (Phe)-restricted diet is associated with lower quality of life for patients with phenylketonuria (PKU), and a concern for caregivers of recently-diagnosed infants. Sapropterin is an oral drug used as an alternative or adjunct to dietary treatment. We have observed that some of the young infants initially managed successfully with sapropterin monotherapy have required dietary treatment in long-term follow-up. We aimed to determine the baseline factors associated with future initiation of dietary treatment in these patients. METHODS: Data were obtained retrospectively from the medical records of 80 PKU patients started on sapropterin monotherapy before 3 months of age between 2011 and 2021. RESULTS: The patients were followed for a median of 3.9 years (Q1-Q3: 2.5-5.75 years). Sapropterin was tapered down and discontinued in 5 patients (6.3%) as their Phe levels remained below 360 µmol/L without treatment. Sapropterin monotherapy was sufficient in 62 patients (77.5%), while 13 (16.2%) required dietary treatment. Phe and tyrosine (Tyr) levels, and Phe:Tyr ratios differed significantly among the patients maintained on sapropterin monotherapy and those started on dietary treatment, but the Phe:Tyr ratio at diagnosis was the most important independent baseline variable (OR: 1.61, 95% CI: 1.15-2.27, p = 0.006), with Phe:Tyr ratio at diagnosis >5.25 associated with dietary treatment (sensitivity: 90.0%, specificity: 81.8%). Genotypic phenotype value (GPV), unavailable at baseline, was also associated with dietary treatment (median GPV 9.2 vs. 3.8, p = 0.006), but some genotypes were not specific to the final treatment modality. DISCUSSION: We propose that the Phe:Tyr ratio at diagnosis is an important indicator to predict dietary requirement in young infants initially managed with sapropterin monotherapy.

COVID-19 in inherited metabolic disorders: Clinical features and risk factors for disease severity.

BACKGROUND: Old age, obesity, and certain chronic conditions are among the risk factors for severe COVID-19. More information is needed on whether inherited metabolic disorders (IMD) confer risk of more severe COVID-19. We aimed to establish COVID-19 severity and associated risk factors in patients with IMD currently followed at a single metabolic center. METHODS: Among all IMD patients followed at a single metabolic referral center who had at least one clinic visit since 2018, those with accessible medical records were reviewed for SARS-CoV-2 tests. COVID-19 severity was classified according to the WHO recommendations, and IMD as per the international classification of IMD. RESULTS: Among the 1841 patients with IMD, 248 (13.5%) had tested positive for COVID-19, 223 of whom gave consent for inclusion in the study (131 children and 92 adults). Phenylalanine hydroxylase (48.4%) and biotinidase (12.1%) deficiencies were the most common diagnoses, followed by mucopolysaccharidoses (7.2%). 38.1% had comorbidities, such as neurologic disabilities (22%) or obesity (9.4%). The majority of COVID-19 episodes were asymptomatic (16.1%) or mild (77.6%), but 6 patients (2.7%) each had moderate and severe COVID-19, and two (0.9%) had critical COVID-19, both of whom died. 3 patients had an acute metabolic decompensation during the infection. Two children developed multisystem inflammatory syndrome (MIS-C). Long COVID symptoms were present in 25.2%. Presence of comorbidities was significantly associated with more severe COVID-19 in adults with IMD (p < 0.01), but not in children (p = 0.45). Compared to other categories of IMD, complex molecule degradation disorders were significantly associated with more severe COVID-19 in children (p < 0.01); such a significant IMD category distinction was not found in adults. DISCUSSION: This is the largest study on COVID-19 in IMD patients relying on real-word data and objective definitions, and not on merely expert opinions or physician surveys. COVID-19 severity and long COVID incidence in IMD are probably similar to the general population, and the risk of acute metabolic decompensation is not likely to be greater than that in other acute infections. Disease category (complex molecule degradation) in children, and comorbidities in adults may be associated with COVID-19 severity in IMD. Additionally, the first documented accounts of COVID-19 in 27 different IMD are recorded. The high occurrence of MIS-C may be coincidental, but warrants further study.

Organic acidemias in the neonatal period: 30 years of experience in a referral center for inborn errors of metabolism.

OBJECTIVES: Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome. METHODS: Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated. RESULTS: Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p<0.001). Metabolic acidosis with increased anion gap was more frequent in MMA and propionic acidemia (PA) (p=0.003). 89.1% of OAs were admitted for recurrent metabolic crisis. 46% had chronic non-neurologic complications; 19.3% of MMA had chronic kidney disease. Abnormal findings were present in 26/34 of EEG, 19/29 of MRI studies, and 32/33 of developmental screening tests. Metabolic acidosis on admission was associated with increased incidence of abnormal EEG (p=0.005) and overall mortality (p<0.001). Severe hyperammonemia in MMA was associated with overall mortality (33.3%) (p=0.047). Patients diagnosed between 2007-2017 had lower overall mortality compared to earlier years (p<0.001). CONCLUSIONS: Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications.

Single Institutional Experience with GM1 Gangliosidosis: Clinical and Laboratory Results of 14 Patients

Background: GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by biallelic mutations in the GLB1 gene. Neurodegeneration, hypotonia, visceromegaly, macular cherry-red spots, skeletal dysplasia, and coarse and dysmorphic face are the major clinical features. Aims: To evaluate the demographic and clinical data of patients with GM1 gangliosidosis in a single center. Study Design: A retrospective clinical study. Methods: This study included patients followed at Hacettepe University Ihsan Dogramaci Children's Hospital Pediatric Metabolism Unit with the diagnosis of GM1 gangliosidosis between 1988 and 2021. Hospital records of the patients were reviewed for demographic, clinical, and laboratory findings. Results: Fourteen patients were included in the study and 10 (71.4%) were male. The age at onset of clinical symptoms was between 0 and 5 months, and the median time to diagnosis after the first symptom was 4.3 (0-13) months. Motor delay (54%) was the most common initial symptom. The median follow-up period was 14.8 (0.4-92.2) months. Twelve patients (85.7%) died, and all deaths occurred before the age of 24 months. The median survival was 21.3 (95% confidence interval, 15.5-24.9) months. Higher leukocyte beta-galactosidase activity correlated with later age at onset (ρ = 0.575), later age at diagnosis (ρ = 0.618), and longer diagnostic delay (ρ = 0.702) (ρ < 0.05). Conclusion: Median survival in patients with GM1 gangliosidosis is less than 24 months. Beta-galactosidase enzyme activity may be associated with clinical onset and time of diagnosis in these patients.

Novel Cranial Imaging Findings and a Splice-Site Variant in a Patient with Tyrosinemia Type III, and a Summary of Published Cases.

Tyrosinemia type III is an extremely rare autosomal recessive disease, with only 19 patients yet reported. It is caused by a deficiency of the 4-hydroxyphenylpyruvate dioxygenase enzyme, resulting from biallelic mutations in the HPD gene. Although the clinical spectrum of the disease is not fully known, most patients present with neurodevelopmental symptoms. We report on a 20-month-old patient who was investigated due to developmental delay and dysmorphic features. The girl had a novel splice-site mutation in the HPD gene and ventriculomegaly in cranial imaging, which was not previously associated with tyrosinemia type III. Our patient had mild subjective improvement in social skills and language development after dietary therapy was started and her tyrosine levels decreased. We also summarize clinical, biochemical, and genetic findings of previously published patients with biallelic HPD mutations.

Hyperinsulinism May Be Underreported in Hypoglycemic Patients with Phosphomannomutase 2 Deficiency

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.

COVID-19-related anxiety in phenylketonuria patients.

BACKGROUND: Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism, the treatment of which often requires a special diet to prevent adverse neuropsychiatric outcomes. In the COVID-19 pandemic, which has had a substantial effect on the whole world since the beginning of 2020, PKU patients represent a vulnerable population because they may be dependent on special nutritional products, have limited access to routine care and display increased levels of anxiety. METHODS: For this reason, an online questionnaire assessing the anxiety levels and various personal opinions and practices regarding the pandemic was sent to the PKU patients managed at our clinic, who were 12 years of age or older. Ninety-eight patients responded to the questionnaire. Median age of the participants was 19 years. RESULTS: Most patients were compliant with the hygiene and social distancing recommendations regarding the spread of COVID-19. Of the patients, 61.2% felt more anxious since the pandemic. The most common concern was the possibility of not being able to obtain special nutritional products (58.2%). Anxiety level was significantly higher in females. CONCLUSIONS: These data suggest that food security is an important issue of concern in PKU patients. In line with the changing world after the pandemic, different strategies should be considered in the management of patients with inborn errors of metabolism, including PKU.

Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant.

BACKGROUND: Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare, autosomal recessive, and highly lethal fatty acid oxidation (FAO) disorder caused by defective acylcarnitine transport across the mitochondrial membrane. CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness. Herein, we described the clinical features, biochemical, and molecular findings of three patients with CACTD, presented with poor feeding, hypoglycemia, liver dysfunctions, and hyperammonemia, but died despite intensive treatment. CASES: All cases had similar signs and symptoms like poor feeding and respiratory failure associated with liver dysfunction. Urinary organic acid profiles in the presence of hypoglycemia and hyperammonemia led us to the possible diagnosis of one of fatty acid ß-oxidation defects. Results of the molecular analyses were compatible with CACTD. In addition to known mutation (c.270delC;p.Phe91Leufs*38) we detected a novel one (c.408C > A;p.Cys136*). CONCLUSIONS: All three cases died despite a very intensive therapy. Based on our experience with these three cases, it can be said that CACTD has a relatively poor prognosis, molecular studies are of most importance in suspected cases for the final diagnosis and such studies might be of help while giving genetic counselling and guidance to parents for future pregnancies.

Correction to: DNAJC12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8.

DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.

Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis.

OBJECTIVES: This study aimed to investigate automatic and voluntary motor control performances, which have an important function in maintaining balance, in children and adolescents with mucopolysaccharidosis (MPS). METHODS: The records of 70 patients were retrospectively analyzed. The results of Computerized Dynamic Posturography (CDP) performed according to the age and development of the individuals were examined. The results of 10 children and adolescents with MPS (mean age: 9.43 ranging from 6 to 14; four males and six females) who completed the sensory analysis, Weight-Bearing Squat Test, and Adaptation Test were retrieved from the database of the CDP. Nine healthy children and adolescents with typical development (mean age: 9.63 ranging from 6 to 14; four males and five females) were included as the control group. RESULTS: In the sensory analysis test, there was a statistically significant difference between the two groups in the visual ratio parameter. In the adaptation test, there was a statistically significant difference between the two groups in the toes up and toes down trials. There was no statistically significant difference between the groups in the Weight-Bearing Squat test at 0° knee extension and various knee flexions. CONCLUSIONS: Children and adolescents with MPS should be directed to the appropriate exercise and therapy programs to develop postural and balance control, which have a significant effect on their quality of life and the ability to independently perform daily activities of living. In addition to routine hearing assessments for patients with MPS, other objective tests used in the differential diagnosis of balance and vestibular system should also be implemented.

Invisible burden of COVID-19: enzyme replacement therapy disruptions.

OBJECTIVES: Lysosomal storage diseases (LSD) constitute an important group of metabolic diseases, consisting of approximately 60 disorders. In some types of lysosomal diseases, enzyme replacement therapy (ERT) is administered intravenously in weekly or biweekly doses. Unfortunately, scheduled ERT during COVID-19 was disrupted. We considered the possibility of adverse outcomes caused by the disruption in the treatment of patients with lysosomal storage disorders. METHODS: During the COVID-19 pandemic, we conducted a questionnaire that was delivered via Internet to assess how this vulnerable patient group was affected by the pandemic in terms of their access to treatment and their disease-related symptoms. RESULTS: The questionnaire was filled out by 75 patients. There were 35 patients whose treatment dose was missed because of COVID-19. The most common reason for skipping treatment was not wanting to go to the hospital for fear of contracting COVID-19. These 35 patients missed a median of four doses of ERT (range: 1-16 dosages). Twenty-one patients (60%) claimed that they were affected physically by not taking ERT (20 mucopolysaccaridoses, 1 Fabry disease), whereas 14 (40%) did not. CONCLUSIONS: Interruption of ERT during the COVID-19 pandemic may have significant consequences. It may be beneficial to switch to home treatment or reserve dedicated facilities. With proper planning and management, the treatment disruptions of this particular group can be avoided.

Oral health status of children and young adults with maple syrup urine disease in Turkey.

BACKGROUND: Maple syrup urine disease (MSUD) is an inherited disorder clinically characterized by ketoacidosis, seizures, coma, psychomotor delay, and intellectual disability. The treatment requires a life-long protein-restricted diet, rich in carbohydrates and fats, supplemented with a medical amino acid formula. Diet, oral health and general health influence each other in a vicious cycle. The aim of this study was to investigate the oral health status of children and young adults with MSUD in Turkey. METHODS: A descriptive study was conducted on patients with MSUD who applied for routine follow-up to the pediatric metabolic diseases clinic at Hacettepe University, Children's Hospital in Ankara, Turkey in a 12-month period. Patients with any other concomitant genetic diseases and acute infection were excluded. A total of twenty-five patients were enrolled and underwent oral examination including DMFT/S, dmft/s (decayed/missing/filled teeth/surfaces for deciduous and primary teeth, respectively), plaque and gingival indices. Panoramic radiographs were obtained in 12 cooperative patients. RESULTS: Mean age was 9.88 ± 5.68 s.d years. More than half of the parents had only primary school level education, and low income. Fourteen patients consumed medical formula during or right before sleep. Fourteen patients reported caries-associated pain. Gingival inflammation was present in all 15 patients who cooperated for evaluation. Seven out of twelve patients had at least one dental anomaly or alterations in mandibular morphology. Five patients had previously been treated for caries under general anesthesia. To our knowledge, this is the first study to document oral clinical and radiologic findings in patients with MSUD. CONCLUSIONS: Impaired oral health was observed in this rare disease population. Regular dental referral by physicians, preventive measures and dental treatments should be included in multidisciplinary management of maple syrup urine disease to promote oral health.

Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.

INTRODUCTION: Glutaric aciduria type 1 (GA1) is a rare and inherited autosomal-recessive metabolic disorder that occurs in the deficiency of glutaryl-co-enzyme A dehydrogenase (GCDH) enzyme encoded by GCDH gene. In this study, we aim to retrospectively investigate the clinical, biochemical, and neuroradiological parameters and examine the spectrum of GCDH gene variants in Turkish patients with glutaric aciduria type 1. METHODS: This is a descriptive cross-sectional study. The study was conducted in fifty-three patients from 39 unrelated Turkish families who were diagnosed with GA1 based on their clinical presentation, neuroimaging, and biochemical measurements, at the department of pediatric metabolism of a university hospital between June 1998 and August 2019. Pathogenic variants screening of GCDH gene was performed by direct DNA sequence analysis in forty-six patients with GA1. Pathogenicity of the novel variants was predicted via computational programs. RESULTS: A total of 53 patients were diagnosed with GA1. Of those, 32 (60.3%) had encephalopathic crisis and 33 (62.3%) had macrocephaly. Twenty different pathogenic variants were detected, 7 of which are novel (p.Glu57Lys, p.Ser145Profs*79, p.Ser246Glyfs*96 p.Ala293Val, p.His348Gln, p.His417Tyr, p.Asp418Val). The p.Arg402Trp, p.Pro248Leu and p.Leu340Phe variants were the most common in Turkish patients, with a frequency of 21.2%, 18.2% and 12.1% respectively. CONCLUSION: This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the GCDH gene. The identification of common variants and hot spot regions of the GCDH gene is important for genetic counselling and the prenatal diagnosis of Turkish patients with GA1.

Retrospective evaluation of 85 patients with urea cycle disorders: one center experience, three new mutations.

Objectives Urea cycle disorders (UCDs) are rare hereditary diseases. This study was conducted to help identify the characteristics of UCDs in Turkey. Methods The primary outcome was to determine patient characteristics. Investigating the relationships between the patient outcomes and ammonia levels were the secondary outcomes. Eighty five patients from 79 families, diagnosed with UCD at a single metabolic referral center between 1979 and 2017, were included. Clinical and laboratory data were retrieved retrospectively from hospital records. Results Classical citrullinemia was the most common type of UCD; citrin deficiency and carbamoyl phosphate synthase 1 deficiency (CPS1D) were the rarest. One thirty one hyperammonemic episodes were recorded. The peak ammonia levels were found to be significantly associated with polycythemia and hypocalcemia at presentation. The median peak ammonia values of the patients who died were higher than those of the survivors. The highest mortality rate was in the classical citrullinemia group. The mortality rate of the first hyperammonemic crisis was 28.6%, while it was 6.7% in subsequent episodes with an odds ratio of 4.28 (95% CI: 1.67-11.0) (p=0.001). Forty-four patients underwent genetic analysis and genetic variants were detected in 42 patients (95%). Three of the detected variants have not been previously reported. Conclusions This is the largest UCD series in Turkey and may serve as a guide to clinical, biochemical and genetic features of UCDs in our country. Prevention of hyperammonemia may be the most influential measure to improve long term survival.