Clinical Presentation and Molecular Characterization of 3 Patients with Vici Syndrome: Two Novel Variants in the EPG5 Gene.

Introduction: Vici syndrome is an ultra-rare, congenital disorder of autophagy characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Patients usually present in the neonatal period or infancy with profound hypotonia, based on information available from the nearly 100 cases reported to date. Case Presentation: We present 3 new cases of Vici syndrome confirmed by genetic analysis of EPG5 gene. The 3 male patients had neonatal hypotonia, progressive microcephaly, psychomotor retardation, recurrent respiratory tract infections, optic atrophy, and failure to thrive, but no cataracts or hepatomegaly. Three disease-causing variants in homozygous state were detected in the EPG5 gene: two novel c.1652C>T and c.7557+2T>C forms; and one previously reported c.7447C>T. The patient, who was homozygous for the c.1652C>T mutation, presented with neonatal onset seizures that had not been reported previously. Discussion/Conclusion: The present study provides data for the evaluation of the natural history and genotype-phenotype correlations for treatment options that are expected to be available in the future.

A different perspective into clinical symptoms in CPT I deficiency.

Carnitine palmitoyltransferase I (CPT I) deficiency is an autosomal recessive disorder causing long-chain fatty acid oxidation defect, characterized by metabolic decompensation episodes accompanied by hypoketotic hypoglycemia, hepatomegaly, seizures, renal tubular acidosis, and hyperammonemia. The aim of this study was to investigate the neurological symptoms in CPT I deficiency and different outcomes with respect to predisposing factors for sequela and to draw attention to the neurological impairment that may develop during the course of the disease. The retrospective study reviewed clinical characteristics of 14 patients. Mean follow-up period was 10.3 ± 4.7 (range: 8 months-18.6 years; median: 10 years) years. Three patients were diagnosed with newborn screening. In the symptomatic group (n = 12) most common presenting symptoms were psychomotor retardation (n = 6), seizures (n = 5), encephalopathy (n = 5), dystonia (n = 1), Reye-like syndrome (n = 5), muscle weakness (n = 3), and autism (n = 1). Neurologic findings detected in the follow-up period included speech disorder (n = 9), abnormal cranial MRI findings (n = 5), neuropathy (n = 1), and attention deficit hyperactivity disorder (n = 1). Speech disorders collectively included delayed expressive language development, speech articulation disorder, speech delay, stuttering, and specific speech difficulties. After starting treatment for CPT I deficiency, speech disorders improved in 3 patients. Our findings confirmed that the clinical manifestations of CPT I deficiency is wider than previously thought, causing specific neurologic dysfunction, mainly speech disorders at a large scale, that were unexpected in a fatty acid oxidation disorder. We suggest that early diagnosis and treatment is the key factor to prevent neurologic sequelae while an extensive neurological evaluation is essential in patients with CPT I deficiency both at the time of diagnosis and during the follow-up period.

Evaluation of the risk factors for noncommunicable diseases in patients with inborn errors of amino acid metabolism receiving nutrition therapy.

OBJECTIVES: There is growing concern about the low-protein and high-energy diet therapies used in the treatment of inherited amino acid metabolism disorders. We aimed to identify the risk factors for noncommunicable diseases that may arise from nutritional therapies and suggests approaches that may prevent the development of the noncommunicable diseases. METHODS: The present study evaluates 112 patients, on long-term nutritional therapy for at least the last 2 years with a diagnosis of an inborn error of the amino acid metabolism, and their 28 healthy siblings. The participants are assessed for the development of overweight and metabolic syndrome based on an analysis of anthropometric parameters, body composition and the results of biochemical tests. RESULTS: Anthropometric measurements including BMI, weight Z-score, waist circumference and fat mass were not significantly different between patients and controls. Height Z-scores were similar in phenylketonuria patients compared to controls, but lower in urea cycle disorders, organic acidemia and maple syrup urine disease groups. No increased risk of development of overweight or metabolic syndrome was detected in the patient group, while there were findings suggesting malnutrition in patients diagnosed with urea cycle disorders. There was a correlation between patients' BMI and C3-carnitine levels in organic acidemia patients and leucine levels in maple syrup urine disease patients. CONCLUSIONS: All forms of malnutrition can be prevented in patient groups receiving limited nutrients under a dietary management protocol, based on the findings of anthropometric and biochemical evaluations and analyses of body composition.

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

Triosephosphate Isomerase Deficiency: E105D Mutation in Unrelated Patients and Review of the Literature.

Introduction: Chronic haemolytic anaemia, increased susceptibility to infections, cardiomyopathy, neurodegeneration, and death in early childhood are the clinical findings of triosephosphate isomerase (TPI) deficiency, which is an ultra-rare disorder. The clinical and laboratory findings and the outcomes of 2 patients with TPI deficiency are reported, with a review of cases reported in the literature. Case Presentation: Two unrelated patients with haemolytic anaemia and neurologic findings who were diagnosed as having TPI deficiency are presented. Neonatal onset of initial symptoms was observed in both patients, and the age at diagnosis was around 2 years. The patients had increased susceptibility to infections and respiratory failure, but cardiac symptoms were not remarkable. Screening for inborn errors of metabolism revealed a previously unreported metabolic alteration determined using tandem mass spectrometry in acylcarnitine analysis, causing elevated propionyl carnitine levels in both patients. The patients had p.E105D (c.315G>C) homozygous mutations in the TPI1 gene. Although severely disabled, both patients are alive at the ages of 7 and 9 years. Discussion: For better management, it is important to investigate the genetic aetiology in patients with haemolytic anaemia with or without neurologic symptoms who do not have a definitive diagnosis. The differential diagnosis of elevated propionyl carnitine levels using tandem mass spectrometry screening should also include TPI deficiency.

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Leucine tolerance in children with MSUD is not correlated with plasma leucine levels at diagnosis.

OBJECTIVES: Maple syrup urine disease (MSUD) is an inborn metabolic disease. The nutritional treatment with restricted intake of branched chain amino acids and prevention of leucine toxicity are crucially important for a favorable outcome. The aim of this study is to analyze the relation of blood leucine levels at diagnosis with future leucine tolerances, to determine whether any prediction about the future leucine tolerances or plasma leucine levels is possible by evaluating blood leucine levels at diagnosis. METHODS: The study group consisted of 45 MSUD patients. Leucine levels at diagnosis were compared with age at diagnosis, leucine tolerances, maximum leucine levels/ages, and average blood leucine levels. RESULTS: The mean plasma leucine level at diagnosis was 2,355.47 ± 1,251.7 µmol/L (ref: 55-164 µmol/L). The median age at diagnosis was 17 days. Leucine tolerances per kg body weight declined until the age of 8 years and stabilized subsequently. The average age of maximum leucine level during follow-up was 3.14 ± 1.92 years, and the mean maximum lifetime plasma leucine level on follow-up was 1,452.13 ± 621.38 µmol/L. The leucine levels at diagnosis did not have any significant relationship with lifetime leucine tolerances, maximum plasma leucine levels or mean plasma leucine levels. CONCLUSIONS: The plasma leucine levels at diagnosis did not have a predictive value for later leucine tolerances or plasma leucine levels. The maximum lifetime leucine level is likely to happen within the first 3 years of life, underlining the importance of good metabolic control and compliance to dietary treatment at early ages.

Cardiologic evaluation of Turkish mitochondrial fatty acid oxidation disorders.

BACKGROUND: Mitochondrial fatty acid oxidation disorders (FAODs) cause impairment in energy metabolism and can lead to a spectrum of cardiac pathologies including cardiomyopathy and arrhythmias. The frequency of underlying cardiac pathologies and the response to recommended treatment in FAODs was investigated. METHODS: Sixty-eight children (35 males, 33 females) with the diagnosis of a FAOD were included in the study. Cardiac function was evaluated with 12-lead standard electrocardiography, echocardiography, and 24 h Holter monitoring. RESULTS: Forty-five patients (66%) were diagnosed after disease symptoms developed and 23 patients (34%) were diagnosed in the pre-symptomatic period. Among symptomatic patients (n: 45), cardiovascular findings were detected in 18 (40%) patients, including cardiomyopathy in 14 (31.1%) and conduction abnormalities in 4 (8.8%) patients. Cardiac symptoms were more frequently detected in primary systemic carnitine deficiency (57.1%). Patients with multiple acyl-CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and mitochondrial trifunctional protein deficiencies also had an increased frequency of cardiac symptoms. Patients with medium-chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, and carnitine palmitoyltransferase I deficiencies had a lower prevalence of cardiac symptoms both during admission and during clinical follow up. Cardiomyopathy resolved completely in 8/14 (57%) patients and partially in 2/14 (14.3%) patients with treatment. Two patients with cardiomyopathy died in the newborn period; cardiomyopathy persisted in 1 (7.1%) patient with very long-chain acyl-CoA dehydrogenase deficiency. CONCLUSION: Early diagnosis, treatment and follow up made a significant contribution to the improvement of cardiac symptoms of patients with FAODs.

Risk Factors for Clinical Seizures in Neonates with Hypoxic-ischemic Encephalopathy Treated with Therapeutic Hypothermia.

BACKGROUND: This study aimed to assess the risk factors for clinical seizures in newborns treated with whole body cooling (WBC) for hypoxic ischemic encephalopathy (HIE). METHODS: Infants with gestational age≥36 weeks and birth weight≥2.000 g who were treated with WBC due to HIE were retrospectively enrolled in this study. Patients were assigned to two groups: infants without clinical seizures (Group 1) and infants with clinical seizures (Group 2). The two groups were compared to determine the risk factors for the occurrence of clinical seizures. RESULTS: A total of 25 patients (Group 1=10 and Group 2=15) were included in the study. Prothrombin time (PT) was determined as independent risk factor for clinical seizures (p=0.046) and the odds ratio for the effect of PT was found as 1.475 (%95 CI:1.006-2.299). PT (area under the curve [AUC]=0.764; p=0.041), and increased cardiac troponin-I (cTnI) (AUC=0.935; p=0.002) were found to be significant risk factors for predicting the occurrence of clinical seizures. The optimal PT cut-off value was 22.7 sec, with a sensitivity and specificity of 45.4% and 90%, respectively; as well as positive and negative predictive value of 83.3% and 60.0%, respectively. The chest compression in the delivery room, severely abnormal amplitude integrated electroencephalography and high encephalopathy score were also found risk factors for occurrence of clinical seizures. CONCLUSION: Chest compression in the delivery room, high encephalopathy score, prolonged PT, and increased cTnI are significant factors for clinical seizures in newborns treated with WBC for HIE.

A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report.

Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid α-1,4-glucosidase enzyme (GAA). PD has two forms, namely the infantile-onset and the late-onset form. In untreated cases, infantile-onset form usually leads to cardio-respiratory failure and death in the first year of life. Herein, we report a newborn with infantile-onset PD characterized by muscular hypotonia, respiratory distress, hypertrophic cardiomyopathy, hepatomegaly, elevated serum enzyme levels of aspartate aminotransferase of 117 IU/L (three times the normal value), alanine aminotransferase of 66 IU/L (1.8 times the normal value), lactate dehydrogenase of 558 IU/L (1.2 times the normal value), and creatine kinase >5,000 IU/L (16 times the normal value). Dried blood spot testing was performed and revealed decreased GAA enzymatic activity (0.07 nmol/mL/h, normal 0.93-7.33 nmol/mL/h). GAA gene analysis performed for confirming the diagnosis showed homozygous mutation c.896T >C (p.Leu299Pro). Initiation of enzyme replacement therapy (ERT) (ERT; 20 mg/kg, once every week) at 28 days of age resulted in weaning off from respiratory support within 1 week after treatment, normalization of cardiac abnormalities, and normal neuromotor development in the 16th month of age. Early diagnosis and early treatment with ERT, especially in the neonatal period, is of great importance to improve cardiac function and motor development in infantile-onset PD.

Evaluation of immunization status in patients with cerebral palsy: a multicenter CP-VACC study.

Children with chronic neurological diseases, including cerebral palsy (CP), are especially susceptible to vaccine-preventable infections and face an increased risk of severe respiratory infections and decompensation of their disease. This study aims to examine age-appropriate immunization status and related factors in the CP population of our country. This cross-sectional prospective multicentered survey study included 18 pediatric neurology clinics around Turkey, wherein outpatient children with CP were included in the study. Data on patient and CP characteristics, concomitant disorders, vaccination status included in the National Immunization Program (NIP), administration, and influenza vaccine recommendation were collected at a single visit. A total of 1194 patients were enrolled. Regarding immunization records, the most frequently administrated and schedule completed vaccines were BCG (90.8%), hepatitis B (88.9%), and oral poliovirus vaccine (88.5%). MMR was administered to 77.3%, and DTaP-IPV-HiB was administered to 60.5% of patients. For the pneumococcal vaccines, 54.1% of children received PCV in the scope of the NIP, and 15.2% of children were not fully vaccinated for their age. The influenza vaccine was administered only to 3.4% of the patients at any time and was never recommended to 1122 parents (93.9%). In the patients with severe (grades 4 and 5) motor dysfunction, the frequency of incomplete/none vaccination of hepatitis B, BCG, DTaP-IPV-HiB, OPV, and MMR was statistically more common than mild to moderate (grades 1-3) motor dysfunction (p = 0.003, p < 0.001, p < 0.001, p < 0.00, and p < 0.001, respectively). Physicians' influenza vaccine recommendation was higher in the severe motor dysfunction group, and the difference was statistically significant (p = 0.029).Conclusion: Children with CP had lower immunization rates and incomplete immunization programs. Clinicians must ensure children with CP receive the same preventative health measures as healthy children, including vaccines. What is Known: • Health authorities have defined chronic neurological diseases as high-risk conditions for influenza and pneumococcal infections, and they recommend vaccines against these infections. • Children with CP have a high risk of incomplete and delayed immunization, a significant concern given to their increased healthcare needs and vulnerability to infectious diseases. What is New: • Influenza vaccination was recommended for patients hospitalized due to pneumonia at a higher rate, and patients were administered influenza vaccine more commonly. • Children with CP who had higher levels of motor dysfunction (levels 4 and 5) were more likely to be overdue immunizations.

BTD Gene Mutations in Biotinidase Deficiency: Genotype-Phenotype Correlation.

OBJECTIVE: To identify the biotinidase (BTD) gene mutations in patients with biotinidase deficiency in our region; and to determine the phenotype-genotype correlations in the presence of clinical findings. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Medical Genetics and Pediatric Metabolism Outpatient Clinic, Faculty of Medicine, Harran University, between January 2018 and June 2020. METHODOLOGY: Two hundred and nine patients, who were found positive for biotinidase deficiency in heel blood screening, were included. Genomic DNA was isolated from peripheral blood. Next-generation DNA sequencing analysis was performed using primers covering the exon regions of the BTD gene. The results were analysed by the mutation surveyor programme. RESULTS: The most common mutation was c.1330 G>C (p.D444H) and the second most common mutation was c.470 G>A (p.R157H). The majority of the mutations are missense; and they are especially located in the exon 4. The most frequent mutations were found to be D444H and R157H with a rate of 66.66% in symptomatic patients. CONCLUSION: Common mutations in BTD deficiencies were indentified. Associating them with phenotype-genotype data will assist clinicians in better genetic counselling and management in the future by implementing prevention programmes. Key Words: Biotinidase deficiency, BTD gene, Newborn screening, Inherited metabolic disease, Newborn screening programme.

Evaluation of the efficiency of serum biotinidase activity as a newborn screening test in Turkey.

OBJECTIVES: Biotinidase Deficiency (BD) is an autosomal recessive metabolic disorder. However, the relationship between genotype and biochemical phenotype has not been completely elucidated yet. But still, some mutations are accepted to be associated with profound or partial deficiency. We aimed to evaluate the results of biochemical enzyme activity in accordance with the presence of genetic mutations and investigate the correlation between genotype and biochemical phenotype together in the study. METHODS: This retrospective study was carried out using data from medical records of 133 infants detected by the newborn screening followed by serum biotinidase activity (BA) detection with semi-quantitative colorimetric method. Mutation analysis was performed to confirm the diagnosis. In addition, the expected biochemical phenotype based on the known mutant alleles were compared with the observed biochemical phenotype. RESULTS: When confirmed with mutation analysis results, the diagnostic sensitivity and specificity of serum BA with spectrophotometric method was 93.1% and 95.1%, respectively. In 93.98% of the cases conformity was observed between the biochemical phenotype and the genotype. The c.1330 G>C(p.D444H) and c.470 G>A (p.Arg157His) were the most common allelic variants with frequencies of 63.69% and 33.75%, respectively. CONCLUSIONS: The diagnostic test is supposed to have a high sensitivity to identify asymptomatic BD patients. Apparently healthy cases with almost normal enzyme activity and a variant allele in the genetic analysis were reported to present symptoms under stress conditions, which should be kept in mind. This study can be accepted as an informative report as it may contribute to the literature in terms of the allelic frequency and determination of the relation between genotype and biochemical phenotype. Also, method verification including the assessment of possible effects of non-genetic factors on BA according to the certain mutation types is warranted.

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.

Pseudohypoaldosteronism Type 1 Newborn Patient with a Novel Mutation in SCNN1B.

Pseudohypoaldosteronism is a rare disease characterized by resistance to aldosterone-targeted organs, hyponatremia, hyperkalemia, metabolic acidosis, and severe salt loss in hyperaldosteronism. Homozygous mutations in SCNN1A , SCNN1B, and SCNN1G genes were found to be responsible for the etiology. About 80 cases with molecular basis have been reported to date. In this case, a newborn patient admitted to our neonatal intensive care unit due to feeding problems was examined. The parents of the patient had a consanguineous marriage, and they had lost their three sons due to hyperkalemia. Since she had hyponatremia and hyperkalemia, congenital adrenal hyperplasia was primarily considered. Although the initial evaluation was made in this direction, the patient was diagnosed as pseudohypoaldosteronism type 1 with the findings obtained during the process such as dehydration, cortisol levels, adrenocorticotropic hormone levels, and negative CYP21A2 analysis result. This clinical diagnosis was confirmed by the novel homozygous frame-shift variant c.1245_1246insC (p.N416Qfs*35) in SCNN1B shown by gene analysis. In this report, we seek to emphasize that aldosterone deficiency should be one of the first diagnoses to be considered in neonatal patients with hyponatremia, hyperkalemia, metabolic acidosis, and dehydration.

The first Turkish family with Rotor syndrome diagnosed at the molecular level.

Rotor syndrome is defined as a self-limiting hyperbilirubinemia characterized by jaundice that does not need treatment, cause any morbidity or affect life expectancy. As far as the literature is evaluated, the number of patients with Rotor syndrome diagnosed at the molecular level is less than 20 until today. In this case presentation, we aimed to present two siblings with Rotor syndrome who were diagnosed at the molecular level. To the nest of our knowledge, these patients are the first Turkish patients with Rotor syndrome diagnosed at the molecular level.

A novel homozygous GALC variant has been associated with Krabbe disease in a consanguineous family.

Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal storage disorder involving the white matter of the peripheral and the central nervous systems. It is caused by a deficiency of galactocerebrosidase enzyme activity. The most common manifestation is the classical early onset KD that leads to patient's loss before the age of 2. Herein, we report the evaluation of a consanguineous family with three affected children manifesting severe neurological findings that ended with death before the age of 2, in an attempt to provide genetic diagnosis to the family. One of the children underwent detailed physical and neurological examinations, including brain magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) evaluations. GALC genetic testing on this child enabled identification of a novel homozygous variant (NM_000153.3: c.1394C>T; p.(Thr465Ile)), which confirmed diagnosis as KD. Familial segregation of this variant was performed by PCR amplification and Sanger sequencing that revealed the parents as heterozygous carriers. We believe this novel GALC variant will not only help in genetic counseling to this family but will also aid in identification of future KD cases.