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.

Novel GALT variations and genetic spectrum in Turkish population with the correlation of genotype and phenotype.

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the GALT gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype-phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs* 19), c.533T>G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs* 30), c.467C>A/p.(Ser156* )). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases.

Nutritional aspects of commercial infant and toddler food products sold in Turkey.

Background: In recent years, there has been an increase in the variety and consumption of commercial infant and toddler food products. Aim: The aim of this study is to evaluate the nutritional profiles of commercial infant and toddler food products sold in Turkey. Methods: A cross-sectional survey of the nutritional composition of products available at in-store and online supermarkets in Turkey was derived from the nutritional information panel on the product label or information provided on manufacturer websites in March 2023. The targeted age group, package type, serving size, ingredients list, and nutrition information (energy [kcal], protein [g], total fat [g], carbohydrate [g], dietary fiber [g], total sugar [g], and sodium [mg] per 100 g) were recorded. Results: Of the 189 products identified, more than 90% (n = 47) of the first foods were fruit-based, while 2% (n = 4) contained only vegetables. Almost half of the products (n = 89, 49%) contained added sugar or sweeteners, 41 (22%) had added sugar, and 1 in 3 products (n = 68, 36%) had sugar from fruit-based sources. One in 10 products (n = 18, 9.5%) contained added salt while 40% of the products (n = 76) were above the WHO Europe sodium standards. Almost half of the products (n = 6, 46%) targeting the 12 months older age group were pureed foods using squeeze pouch packaging. Conclusions: The majority of commercial infant and toddler food products did not adhere to nutrition guidelines. There is a need for stronger composition standards for commercial infant and toddler food products by reducing sugar and sodium content, reducing the use of fruits and sweet vegetables, and increasing the variety of products containing different types of vegetables.

Expert opinion on patient journey, diagnosis and clinical monitoring in acid sphingomyelinase deficiency in Turkey: a pediatric metabolic disease specialist's perspective.

This review by a panel of pediatric metabolic disease specialists aimed to provide a practical and implementable guidance document to assist clinicians in best clinical practice in terms of recognition, diagnosis and management of patients with acid sphingomyelinase deficiency (ASMD). The participating experts consider the clinical suspicion of ASMD by the physician to be of utmost importance in the prevention of diagnostic delay and strongly suggest the use of a diagnostic algorithm including/starting with dried blood spots assay in the timely diagnosis of ASMD in patients presenting with hepatosplenomegaly and a need for increased awareness among physicians in this regard to consider ASMD in the differential diagnosis. In anticipation of the introduction of enzyme replacement therapy, raising awareness of the disease among physicians to prevent diagnostic delay and further investigation addressing natural history of ASMD across the disease spectrum, potential presenting characteristics with a high index of suspicion, as well as biomarkers and genotype-phenotype correlations suggestive of poor prognosis seem important in terms of implementation of best practice patterns.

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.

Reanalysis of exome sequencing data reveals a treatable neurometabolic origin in two previously undiagnosed siblings with neurodevelopmental disorder.

Neurodevelopmental disorders (NDDs) have broad heterogeneity both clinically and genetically. Inborn errors of metabolism can be one of the reasons of neurodevelopmental disruption causing specific NDDs. Although there is tremendous advance in molecular identification via next-generation sequencing (NGS), there are still many unsolved patients with NDD. Reanalysis of NGS data with different pipelines can at least partially accomplish this challenge. Herein, we report clinic and genetic components of an adult sib-pair with an undiagnosed NDD condition, which has been solved through reanalysis of whole-exome sequencing (WES). Parallel analysis of SNP-based genotyping and WES was performed to focus on variants only in loci with positive logarithm of the odds scores. WES data was analyzed through three different pipelines with two distinct bed files. Reanalysis of WES data led us to detect a homozygous FOLR1 variant (ENST00000393676.5:c.610C > T, p.(Arg204Ter), rs952165627) in the affected sib-pair. Surprisingly, the variant could not be detected in the first analysis as the variant region is not included in the first bed file which may frequently be used. Biochemical tests of CSF have confirmed the genetic analysis, CSF folic acid levels were detected low in sib-pair, and intravenous folinic acid treatment improved the disease course for the first 6 months of follow-up even at late diagnosis age. Although combined analysis of SNP-based genotyping and WES is a powerful tool to reveal the genetic components of heterogeneous diseases, reanalysis of genome data still should be considered in unsolved patients. Also, biochemical screening helps us to decipher undiagnosed NDD that may be a treatable neurometabolic condition.

Expert-opinion-based guidance for the care of children with lysosomal storage diseases during the COVID-19 pandemic: An experience-based Turkey perspective.

This expert-opinion-based document was prepared by a group of specialists in pediatric inherited metabolic diseases and infectious diseases including administrative board members of Turkish Society for Pediatric Nutrition and Metabolism to provide guidance for the care of children with lysosomal storage disorders (LSDs) during the COVID-19 pandemic in Turkey. The experts reached consensus on key areas of focus regarding COVID-19-based risk status in relation to intersecting immune-inflammatory mechanisms and disease patterns in children with LSDs, diagnostic virus testing, particularly preventive measures and priorities during the pandemic, routine screening and diagnostic interventions for LSDs, psychological and socioeconomic impact of confinement measures and quarantines and optimal practice patterns in managing LSDs and/or COVID-19. The participating experts agreed on the intersecting characteristics of immune-inflammatory mechanisms, end-organ damage and prognostic biomarkers in LSD and COVID-19 populations, emphasizing the likelihood of enhanced clinical care when their interaction is clarified via further studies addressing certain aspects related to immunity, lysosomal dysfunction and disease pathogenesis. In the context of the current global COVID-19 pandemic, this expert-opinion-based document provides guidance for the care of children with LSDs during the COVID-19 pandemic based on the recent experience in Turkey.

Special low protein foods for phenylketonuria in Turkey: An examination of their nutritional composition compared to regular food.

Background: Special low protein foods (SLPF) that are phenylalanine (Phe)-free or have a low Phe content are an integral part of PKU diet therapy. Aim: The aim of this study is to determine the nutritional profiles of SLPFs used in Turkey and to compare their contents with equivalent products in the "regular" category, in order to evaluate nutritional and metabolic risks. Methods: Between February and March 2022, the information concerning the nutritional contents of "special low protein products" recommended for PKU and available in Turkey were obtained from the websites of producers/suppliers. Results: A total of 148 SLPFs were identified in Turkey. Compared to regular products, SLPFs were determined to contain less sugar and high carbohydrate content in the Turkish market (p < 0.001). Overall, SLPF products had higher dietary fiber compared to products with regular protein content (p < 0.001). In SLPF subgroups, meat substitutes, rice and pasta, and soup products had significantly less total fat than regular products; low protein bread, sweet snacks, and salted crackers were found to contain less saturated fat (p < 0.05). Moreover, all SLPFs contained significantly more salt than regular products, especially the salt content of subgroups of low protein bread, flour, pasta, and rice was significantly higher than regular products (p < 0.05). Conclusion: Including detailed nutritional information on the Turkish SLPFs' food labels will be effective for patients with PKU to follow themselves on their own.

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.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

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.

Functional Connectivity Analysis in Heterozygous Glucocerebrosidase Mutation Carriers.

BACKGROUND: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD. METHODS: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. RESULTS: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

Measurement of serum vitamin B12-related metabolites in newborns: implications for new cutoff values to detect B12 deficiency.

OBJECTIVE: Our aim was to determine the prevalence of maternal and neonatal vitamin B12 (vit-B12) and folate deficiencies, a new cutoff value of serum vit-B12 in newborns using vit-B12-related metabolites and also cutoff values of homocysteine (Hcy), propionyl (C3) carnitine, and methyl malonic acid (MMA) in newborns using a vit-B12 cutoff value of 200 pg/mL. METHODS: Healthy pregnant women (without iron deficiency) and 98 healthy, term, singleton babies were included. Blood samples were obtained from women 0-8 h before birth and from cord blood during birth for hemogram and to measure serum vit-B12, folate, and Hcy levels. Maternal and cord blood serum vit-B12 levels were classified as low < 200 pg/mL, marginal 200-300 pg/mL, and normal ≥ 300 pg/mL. Neonatal urine MMA levels were analyzed in mothers with a vit-B12 concentration < 300 pg/mL. C3 carnitine levels of newborns were acquired from extended newborn screening. Receiver operating characteristics curve (ROC) analysis was used for serum vit-B12, urine MMA, C3 carnitine, and Hcy. RESULTS: Of total, 98 pregnant women (28.6 ± 5.5-year-old) and 98 newborn were included. Vit-B12 level was lower than 300 pg/mL in 93% of the pregnant women and 61% of cord blood samples. Folate deficiency was not found in either group. There was statistically significant negative correlation between baby C3 carnitine, cord blood folate (r = -0.265, p = .008) and cord blood vit-B12 (r = -0.220, p = .029). In backward stepwise linear regression analysis, maternal vit-B12 level exerted the most marked effect on cord blood vit-B12 level (adjusted R2 = 0.457). In ROC analysis, the Hcy cutoff value was 4.77 µmol/L (68.4% sensitivity, 58.3% specificity, p = .012) for the detection of vit-B12 deficiency. CONCLUSION: Vit-B12 deficiency remains an important health issue for pregnant women and newborns. Our study revealed a cutoff value for Hcy for the detection of nutritional vit-B12 deficiency that could be used in practice for newborns.

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study.

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.