Supplementation for Performance and Health in Patients with Phenylketonuria: An Exercise-Based Approach to Improving Dietary Adherence.

Supplementation is crucial for improving performance and health in phenylketonuria (PKU) patients, who face dietary challenges. Proteins are vital for athletes, supporting muscle growth, minimizing catabolism, and aiding muscle repair and glycogen replenishment post-exercise. However, PKU individuals must limit phenylalanine (Phe) intake, requiring supplementation with Phe-free amino acids or glycomacropeptides. Tailored to meet nutritional needs, these substitutes lack Phe but fulfill protein requirements. Due to limited supplement availability, athletes with PKU may need higher protein intake. Various factors affect tolerated Phe levels, including supplement quantity and age. Adhering to supplement regimens optimizes performance and addresses PKU challenges. Strategically-timed protein substitutes can safely enhance muscle synthesis and sports performance. Individualized intake is essential for optimal outcomes, recognizing proteins' multifaceted role. Here, we explore protein substitute supplementation in PKU patients within the context of physical activity, considering limited evidence.

Postauthorization safety study of betaine anhydrous.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 µmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Treatment adherence in tyrosinemia type 1 patients.

BACKGROUND: While therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease. RESULTS: This observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively). CONCLUSIONS: Despite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia.

Pathogenic mutations in NDUFAF4 have been reported in very few cases. Here we present new data to further delineate the phenotypic spectrum of NDUFAF4 deficiency. We describe two siblings presenting with facial dysmorphia and lactic acidosis in the neonatal period. Later on, they developed fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Abnormality of the cerebral white matter was demonstrated in one case, and cardiomyopathy in the other. Urine organic acid profile showed an increased excretion of lactate, Krebs cycle metabolites and 3-methylglutaconate. Whole-exome sequencing identified a novel homozygous nonsense mutation in NDUFAF4 (c.478G > T; p.Glu160Ter), encoding a mitochondrial complex I assembly factor. The disruptive effect of the mutation was corroborated by the absence of NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I-containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. Cellular respiratory capacity in fibroblasts was also markedly reduced. In sum, we provide insights into the physiopathological mechanisms underlying NDUFAF4 deficiency and expand the knowledge about the clinical and biochemical spectrum of this disorder.

Usefulness of urinary glycosaminoglycans assay for a mucopolysaccharidosis-specific screening.

BACKGROUND: Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders characterized by the accumulation of glycosaminoglycans, can be diagnosed early through newborn screening programs. Establishing newborn screening in Morocco is a challenging task for multiple economic and social reasons. Screening in a Moroccan population using 1,9-dimethylmethylene blue urinary glycosaminoglycan (GAG) assays may allow for an earlier diagnosis of MPS. We studied the feasibility of implementing screening in Moroccan children as an alternative to national newborn screening. We determined the reference ranges for GAGs in the Moroccan population, their stability during transport, the effectiveness of this test as a screening procedure for MPS in patients, and its use as a screening test for MPS in the Imssouane region, where the rate of consanguineous marriage is 38%. METHODS: Using dimethylmethylene blue assays, urine samples of 47 MPS patients were analyzed, together with urine samples from healthy controls (n = 368, age ranging from 1 month to 25 years), and from Imssouane region children (n = 350, age ranging from 6 months to 24 month). Precision, linearity, recovery, limits, and stability were tested. RESULTS: Urinary GAGs reference values are age and ethnicity dependent. The validation parameters established displayed great precision and accuracy leading to recoveries according to internationally accepted values for bioanalytical methods. Urinary GAGs were stable for a maximum of 7 weeks at 40 °C. Screening of Imssouane children resulted in the detection of a 6-month-old child, diagnosed with MPS I. CONCLUSIONS: Our results demonstrate the usefulness of quantifying glycosaminoglycans for early screening of MPS.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Implementation of an Affordable Method for MPS Diagnosis from Urine Screening to Enzymatic Confirmation: Results of a Pilot Study in Morocco.

BACKGROUND: Rapid and accurate diagnosis of mucopolysaccharidoses (MPS) is still a challenge due to poor access to screening and diagnostic methods and to their extensive clinical heterogeneity. The aim of this work is to perform laboratory biochemical testing for confirming the diagnosis of mucopolysaccharidosis (MPS) for the first time in Morocco. METHODS: Over a period of twelve months, 88 patients suspected of having Mucopolysaccharidosis (MPS) were referred to our laboratory. Quantitative and qualitative urine glycosaminoglycan (GAG) analyses were performed, and enzyme activity was assayed on dried blood spots (DBS) using fluorogenic substrates. Enzyme activity was measured as normal, low, or undetectable. RESULTS: Of the 88 patients studied, 26 were confirmed to have MPS; 19 MPS I (Hurler syndrome; OMIM #607014/Hurler-Scheie syndrome; OMIM #607015), 2 MPS II (Hunter syndrome; OMIM #309900), 2 MPS IIIA (Sanfilippo syndrome; OMIM #252900), 1 MPS IIIB (Sanfilippo syndrome; OMIM #252920) and 2 MPS VI (Maroteaux-Lamy syndrome; OMIM #253200). Parental consanguinity was present in 80.76% of cases. Qualitative urinary glycosaminoglycan (uGAGs) assays showed abnormal profiles in 31 cases, and further quantitative urinary GAG evaluation and Thin Layer Chromatography (TLC) provided important additional information about the likely MPS diagnosis. The final diagnosis was confirmed by specific enzyme activity analysis in the DBS samples. CONCLUSIONS: The present study shows that the adoption of combined urinary substrate analysis and enzyme assays using dried blood spots can facilitate such diagnosis, offer an important tool for an appropriate supporting care, and a specific therapy, when available.

Oocytes of women who are obese or overweight have lower levels of n-3 polyunsaturated fatty acids compared with oocytes of women with normal weight.

OBJECTIVE: To ascertain whether the oocytes of women who are obese or overweight have a different fatty acid (FA) profile than women with normal weight. DESIGN: Prospective case-control study. SETTING: Two IVF centers. PATIENT(S): A total of 205 women undergoing IVF and intracytoplasmic sperm injection (ICSI) were included in the study, totaling 922 oocytes. INTERVENTION(S): The unfertilized and the immature oocytes from the women who underwent IVF/ICSI were subjected to FA analysis with capillary gas chromatography. Women were classified according their body mass index (BMI) as normal, overweight, or obese. Germinal vesicle oocytes, metaphase I oocytes, and unfertilized metaphase II oocytes were analyzed separately. MAIN OUTCOME MEASURE(S): Fatty acid profile. RESULT(S): A very different oocyte FA pattern was observed for each BMI. Women with normal weight had higher levels of saturated FAs, and lower levels of monosaturated FAs. Women who were obese had lower levels of n-3 polyunsaturated FA, and the lowest n-6:n-3 ratios. Regarding specific FAs, docosahexaenoic acid levels were lower in women with normal weight than in those who are overweight, and in women who are overweight than in those who are obese. The opposite occurred with eicosapentaenoic acid, with the highest levels in women who have normal weight followed by those who are overweight and lower levels in those women who were obese. When FA analysis was restricted to a subset of oocytes, many of these differences persisted. CONCLUSION(S): Our study shows that oocytes from women who are obese or overweight have a different FA composition. This difference in levels could be related to the IVF poor outcome in these women. Therefore, this different composition could suggest that offspring of women who are obese or overweight have an unfavorable milieu even before conception.

New variants in Spanish Niemann-Pick type c disease patients.

Niemann-Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein.

Non-alcoholic fatty liver in hereditary fructose intolerance.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation affecting >5% of the liver volume that is not explained by alcohol abuse. It is known that fructose gives rise to NAFLD and it has been recently described that the ingestion of fructose in low amounts in aldolase B deficient mice is associated with the development of fatty liver. Therefore, it is reasonable that patients with HFI (Hereditary Fructose Intolerance) present fatty liver at diagnosis, but its prevalence in patients treated and with adequate follow-up is not well documented in the literature. The aim of this study is to analyze the association between HFI and NAFLD in treated patients. METHODS: A cross-sectional observational study was conducted. The population comprised 16 genetically diagnosed HFI patients aged from 3 years to 48 and in dietary treatment of fructose, sorbitol and sacarose exclusion at least for two years. Blood samples were obtained for analytical studies and anthropometric measurements of each patient were performed. RESULTS: Patients presented a Body Mass Index (BMI) of 17.9 ± 2.9 kg/m2. The HOMA index and Quick index were in normal range for our population. The S-adenosyl-methionine (SAM)/S-adenosyl-l-homocysteine (SAH) ratio was increased in the patients in whom this analysis was performed. By imaging techniques it was observed that 9 of the 16 patients presented fatty liver (7 by hepatic MRI). Of these 9 patients, only 3 presented hepatomegaly. 7 of 9 patients affected by the c.448G > C mutation had fatty infiltration, of which three of them presented in addition hepatomegaly. CONCLUSIONS: There is a high prevalence of fatty liver in HFI patients and it is not related to obesity and insulin resistance. The diagnosis of fatty liver in HFI patients and, above all, the identification of new therapeutic approaches, can positively impact the quality of life of these patients.

Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ±â€Š4.9 and 10.6 ±â€Š5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ±â€Š4.43 vs 24.30 ±â€Š6.10; P = .08) and those with good pharmacological adherence (21.19 ±â€Š4.68 vs 28.58 ±â€Š213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

Quantification of urinary derivatives of Phenylbutyric and Benzoic acids by LC-MS/MS as treatment compliance biomarkers in Urea Cycle disorders.

PURPOSE: Salts of phenylacetic acid (PAA) and phenylbutyric acid (PBA) have been used for nitrogen elimination as a treatment for hyperammonaemia caused by urea cycle disorders (UCD). A new analytical method for PBA measurement in urine which helps to evaluate the drug adherence has been implemented. METHODS: Urine specimens from UCD patients receiving PBA were analysed by tandem mass spectrometry to measure urine phenylacetylglutamine (PAGln). Some clinical and biochemical data for each patient were collected. RESULTS: Our study included 87 samples from 40 UCD patients. The PAGln levels did not correlate with height, weight or age. However, the PAGln values showed correlation with PBA dose (r = 0.383, P = 0.015). Plasma glutamine and ammonia levels presented a positive correlation (r = 0.537, P < 0.001). The stability for PAGln in urine was determined at different storage temperatures. CONCLUSIONS: We have developed a simple method for the determination of PAGln in urine, which acts as useful biomarker of effective drug delivery. PAGln in urine is stable at room temperature at least for 15 days, and for several months when frozen at -20 °C. This procedure is useful for the optimization and monitorization of the drug dose allowing the use of spot urine samples.

Asymmetric dimethylarginine as a potential biomarker for management and follow-up of phenylketonuria.

Phenylketonuria's (PKU) treatment based on low-protein diet may affect other metabolic pathways, such as that of asymmetric dimethylarginine (ADMA). The aim of this study was to evaluate the reliability of ADMA as a biomarker of adequate metabolic control and possible nutritional risk in a long-term PKU patient population. One hundred and six dietary-treated PKU patients from four hospitals in Spain were enrolled in this cross-sectional study. Their lipid profile, total homocysteine, ADMA, and symmetric dimethylarginine (SDMA) concentrations were analyzed and compared with a control group. Sensitivity, specificity, and likelihood ratios of the proposed biomarker were calculated. PKU patients had statistically significant lower plasmatic ADMA, SDMA, and arginine concentrations as compared with the control group (p < 0.001). Significant correlations were found between ADMA, phenylalanine, and total homocysteine levels. The ADMA/creatinine ratio correlated with phenylalanine levels as metabolic control and nutritional risk in PKU patients. Its reliability as a management biomarker was studied with positive results. The ADMA/creatinine ratio might serve as an independent biomarker in the management of PKU patients, different from blood phenylalanine levels. It could be of particular usefulness to detect those who are following an unbalanced diet that could have long-term negative effects.Conclusion: In this study, we have evaluated the reliability of ADMA as a potential biomarker of adequate metabolic control and possible nutritional risk in a long-term PKU patient population. What is Known: • Although PKU individuals have lower values of ADMA even with blood Phe levels in the recommended range, little attention is payed to other metabolic pathways. What is New: • ADMA could be used as new biomarker for PKU management and follow-up of the diet, after evaluating their reliability in a long-term PKU patient population.

Betaine anhydrous in homocystinuria: results from the RoCH registry.

BACKGROUND: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year. RESULTS: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine ß-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns. CONCLUSIONS: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.

A new metabolic disorder in human cationic amino acid transporter-2 that mimics arginase 1 deficiency in newborn screening.

PURPOSE: We report a patient with a human cationic amino acid transporter 2 (CAT-2) defect discovered due to a suspected arginase 1 deficiency observed in newborn screening (NBS). METHODS: A NBS sample was analyzed using tandem mass spectrometry. Screen results were confirmed by plasma and urine amino acid quantification. Molecular diagnosis was done using clinical exome sequencing. Dimethylated arginines were determined by HPLC and nitrate/nitrite levels by a colorimetric assay. The metabolomic profile was analyzed using 1D nuclear magnetic resonance spectroscopy. RESULTS: A Spanish boy of nonconsanguineous parents had high arginine levels in a NBS blood sample. Plasma and urinary cationic amino acids were high. Arginase enzyme activity in erythrocytes was normal and no pathogenic mutations were identified in the ARG1 gene. Massive parallel sequencing detected two loss-of-function mutations in the SLC7A2 gene. Currently, the child receives a protein-controlled diet of 1.2 g/kg/day with protein-and amino-acid free infant formula, 30 g/day, and is asymptomatic. CONCLUSION: We identified a novel defect in human CAT-2 due to biallelic pathogenic variants in the SLC7A2 gene. The characteristic biochemical profile includes high plasma and urine arginine, ornithine, and lysine levels. NBS centers should know of this disorder since it can be detected in arginase 1 deficiency screening.

Retrospective study to identify risk factors for chronic kidney disease in children with congenital solitary functioning kidney detected by neonatal renal ultrasound screening.

To evaluate the prognostic significance of factors frequently associated with a reduction in renal mass, such as prematurity, low birth weight, and congenital anomalies of kidney and urinary tract (CAKUT), in patients with solitary functioning kidney (SFK) and investigate signs of early renal injury due to glomerular hyperfiltration damage or dysplasia in the remaining kidney.Retrospective observational study of congenital SFK diagnosed and followed at a tertiary care hospital over a period of 10 years in which 32,900 newborns underwent routine neonatal abdominal ultrasound screening. We analyzed age at diagnosis, sex, gestational age, anthropometric measurements at birth and prenatal and neonatal ultrasound findings, in addition to follow-up data corresponding to imaging findings (ultrasound, micturating cystourethrography, dimercaptosuccinic acid renal, and scintigraphy), ipsilateral CAKUT, compensatory hypertrophy, and renal injury in the form of albuminuria, blood pressure, and estimated glomerular filtration rate (eGFR).In total, 128 congenital SFK cases were detected (1 per 257 live births). Of these, 117 (91.4%) were diagnosed by neonatal ultrasound screening and 44.5% of these had been previously identified by prenatal ultrasound. Neonatal ultrasound had a specificity of 100% and a sensitivity of 92.1%. Forty-five patients (35.2%) had ipsilateral CAKUT and the most common type was urinary collecting system anomalies (75.5%). Over a median follow-up of 6.3 years (1-10 years), compensatory renal hypertrophy was observed in 81 patients (63.7%), most of whom had ipsilateral CAKUT (76.1% vs 56.6% of patients without ipsilateral CAKUT). Albuminuria and hypertension were observed in 3.12% and 5% of patients, respectively, and both were associated with ipsilateral CAKUT (P < .05). In addition, 75% of albuminuria cases (P = .031), 83.3% of hypertension cases (P = .004), and 100% of decreased eGFRcases (P = .031) were significantly associated with CAKUT (renal parenchymal anomaly category), being the strongest predictor of GFR the presence or absence of CAKUT.Neonatal ultrasound screening is useful for the early diagnosis of SFK. The presence of ipsilateral CAKUT should be evaluated in all patients with SFK as congenital anomalies of the renal parenchyma are associated with a poorer prognosis. Because morbidity from CAKUTs may not develop until adulthood, patients should be closely followed throughout life.

Carbohydrate status in patients with phenylketonuria.

BACKGROUND: In patients with phenylketonuria (PKU), a low-phenylalanine (Phe) diet supplemented with low-protein foods and a Phe-free amino acid mixture favors a dietary intake rich in carbohydrates, but little is known about how these molecules are metabolized in this setting. The objective of the present study was to analyze carbohydrate metabolism in patients with hyperphenylalaninemia. METHODS: We conducted a multicenter cross-sectional study to investigate biochemical markers of basal and postprandial carbohydrate metabolism in PKU patients according to age, Phe tolerance, waist circumference and body mass index (BMI), diet, tetrahydrobiopterin (BH4) supplementation, and adherence to treatment. Basal biomarkers and anthropometric parameters were also evaluated in patients with mild hyperphenylalaninemia (MHPA) and in healthy controls. RESULTS: A total of 83 patients aged 4-52 years were studied; 68.7% had PKU and 31.3% had MHPA. 68 healthy controls of similar sex and age were also evaluated Metabolic control was adequate in 71.9% of PKU patients. Fasting glucose levels (mean 80.77 ± 8.06 mg/dL) were high in just one patient, but fasting insulin levels, with a mean of 12.74 ± 8.4 mIU/L, were altered in 15 PKU patients (26.3%) and markedly higher than in patients with MPHA (p = 0.035). Fasting insulin levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were significantly higher than in healthy controls and correlated with body mass index, waist circumference, age, and also showed statistically significant differences according to diagnosis and Phe tolerance (p < 0.05). Patients under BH4 therapy had lower insulin levels and HOMA-IR. A higher mean carbohydrate intake from AA mixtures was observed in classic PKU patients. The caloric intake in the form of carbohydrates was also higher in PKU than MHPA patients (p = 0.038) and it was correlated with basal insulin (rho = 0.468, p = 0.006), HOMA-IR (rho = 0.423, p = 0.02), BMI (rho 0.533, p = 0.002), and waist circumference (rho 0.584, p = 0.0007). CONCLUSIONS: This study shows that PKU patients are at risk of carbohydrate intolerance and insulin resistance, more evident in adults and overweight patients, probably related to their higher caloric intake in form carbohydrate content. A higher dependency of AA mixtures was demonstrated in PKU patients.