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.

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.

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.

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.

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.

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.

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.

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.

Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia.

Isovaleric acidemia (IVA) is a rare disorder of leucine metabolism. We carried out a multicenter study of IVA patients diagnosed by newborn screening (NBS) or symptoms clinics over a period of 28 years in Spain. Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. Follow-up data included C5 levels, intellectual quotient and correlation genotype-phenotype. IVA was detected by NBS in 8 patients (prevalence of 1/326 629). Except 1, all the 8 patients identified by NBS were asymptomatic at diagnosis and had isovalerylcarnitine (C5) levels of 1.6-6.4 µM and isovalerylglycine (IVG) levels <1100 mmol per mol creatinine; they remained asymptomatic with a natural protein intake ⩾1.5 g kg-1 per day. Symptomatic patients with chronic intermittent or acute neonatal IVA had C5 levels of 3.9-16.3 µM and IVG levels >3400 mmol per mol creatinine. The percentage of isovalerate incorporation in fibroblasts was 64-80% in patients detected by NBS and 4.9-13% in symptomatic patients. Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (-0.592; P<0.05). The genetic analysis revealed nine novel mutations. The clinical/biochemical phenotype correlated fairly well with the phenotype predicted by the mutations found. In conclusion, although blood C5 levels have traditionally been considered the prognostic marker of choice, urine IVG levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of IVA in fibroblasts and a less favorable clinical course.

Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis.

BACKGROUND & AIMS: Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe non-alcoholic fatty liver disease. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. METHODS: We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. RESULTS: We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameliorated liver steatosis. CONCLUSIONS: These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.

Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

LC-QTOF-MS-based targeted metabolomics of arginine-creatine metabolic pathway-related compounds in plasma: application to identify potential biomarkers in pediatric chronic kidney disease.

Chronic kidney disease (CKD) is a major epidemiologic problem which causes several disturbances in adults and in pediatrics. Despite being a worldwide public health problem, information available for CKD in the pediatric population is scarce. For that reason, an ion-pair reversed-phase liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) method has been developed and validated in order to analyze 16 amino acids, amino acid derivatives, and analogous compounds related to the arginine-creatine metabolic pathway that are suspicious of being increased or decreased in plasma from patients with CKD. The analytical method involved the addition of dithiothreitol, a reducing agent which reduces disulfide and thus giving total aminothiol concentration, as well as a simple precipitation of plasma proteins. Moreover, despite amino acids being usually derivatized to improve their retention time and to enhance their signal, for this method, an ion-pairing reagent was used, thus avoiding the need for derivatization. Subsequently, analysis of plasma from pediatric patients suffering from CKD and control pediatrics was carried out. As a result, glycine, citrulline, creatinine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were significantly increased in patients with CKD, regardless of their creatinine level, whereas in addition to these compounds dimethylglycine was also increased when CKD patients had plasma creatinine concentrations above 12 µg mL(-1), thus all are suggested as potential biomarkers for renal impairment.

Vitamin and mineral status in patients with hyperphenylalaninemia.

Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross-sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B12, folic acid, ferritin, 25-OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B12, ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B12 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B12. This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks.

6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

BACKGROUND AND AIMS: Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. METHODS: We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. RESULTS: No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. CONCLUSIONS: Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.

Effects of Maternal Ω-3 Supplementation on Fatty Acids and on Visual and Cognitive Development.

OBJECTIVES: The aim of the present study was to elucidate whether a dairy drink enriched with ω-3 long-chain polyunsaturated fatty acid (LC-PUFA) could have an impact on the lipid profile of the mother and the newborn, and also whether this intervention could affect the newborns' visual and cognitive development. METHODS: A total of 110 pregnant women were randomly assigned to one of the following intervention groups: control group (n = 54), taking 400 mL/day of the control dairy drink, and supplemented group (fish oil [FO]) (n = 56), taking 400 mL/day of the fish oil-enriched dairy drink (including ∼400 mg eicosapentaenoic acid-docosahexaenoic acid [DHA]/day). During the study, the mothers' diets were supervised by a nutritionist to encourage compliance with present recommendations of FA intake. Blood fatty acid profiles were determined in the mother's (at enrollment, at delivery, and at 2.5 and 4 months) and newborn (at delivery and at 2.5 months) placenta and breast milk (colostrum and at 1, 2, and 4 months). Pattern reversal visual evoked potentials (VEPs) (at 2.5 and 7.5 months) and Bayley test (at 12 months) were recorded. RESULTS: DHA percentage was higher in plasma, erythrocyte membranes, and breast milk samples from the FO group. The ratio of nervonic acid was also higher in plasma and erythrocyte lipids of the mother and newborn's blood samples from the FO group. No differences were observed in the Bayley test. No differences were observed in VEPs between both groups. We observed a shorter latency, however, in the lower visual angle (7.5') in the boys of the supplemented group. CONCLUSIONS: Omega-3 LC-PUFA dietary supplement during pregnancy and lactation influenced the mother and newborn's fatty acid profile and nervonic acid content but did not show effects on visual and cognitive/psychomotor development.

Effects of different arachidonic acid supplementation on psychomotor development in very preterm infants; a randomized controlled trial.

BACKGROUND & AIMS: Nutritional supplementation with polyunsaturated fatty acids is important in preterm infants neurodevelopment, but it is not known if the omega-6/omega-3 ratio affects this process. This study was designed to determine the effects of a balanced contribution of arachidonic acid in very preterm newborns fed with formula milk. METHODS: This was a randomized trial, in which newborns <1500 g and/or <32 weeks gestational age were assigned to one of two groups, based on the milk formula they would receive during the first year of life. Initially, 60 newborns entered the study, but ultimately, group A was composed of 24 newborns, who were given formula milk with an ω-6/ω-3 ratio of 2/1, and Group B was composed of 21 newborns, given formula milk with an ω-6/ω-3 ratio of 1/1. The infants were followed up for two years: growth, visual-evoked potentials, brainstem auditory-evoked potentials, and plasma fatty acids were periodically measured, and psychomotor development was assessed using the Brunet Lézine scale at 24 months corrected age. A control group, for comparison of Brunet Lézine score, was made up of 25 newborns from the SEN1500 project, who were fed exclusively with breast milk. RESULTS: At 12 months, arachidonic acid values were significantly higher in group A than in group B (6.95 ± 1.55% vs. 4.55 ± 0.78%), as were polyunsaturated fatty acids (41.02 ± 2.09% vs. 38.08 ± 2.32%) achieved a higher average. Group A achieved a higher average Brunet Lézine score at 24 months than group B (99.9 ± 9 vs. 90.8 ± 11, p =0.028). The Brunet Lézine results from group A were compared with the control group results, with very similar scores registered between the two groups (99.9 ± 9 vs. 100.5 ± 7). There were no significant differences in growth or evoked potentials between the two formula groups. CONCLUSIONS: Very preterm infants who received formula with an ω-6/ω-3 ratio of 2/1 had higher blood levels of essential fatty acids during the first year of life, and better psychomotor development, compared with very preterm newborns who consumed formula with an ω-6/ω-3 of 1/1. Therefore, formula milk with an arachidonic acid quantity double that of docosahexaenoic acid should be considered for feeding very preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02503020.

Dimethylarginines as biomarkers for the kidney transplant management in methylmalonic aciduria.

Methylmalonic aciduria (MMA) is an inborn error of metabolism associated with many complications despite treatment. Chronic renal failure is the most common problem, and patients may eventually require kidney transplant. Therefore, it is worth investigating whether living donor kidney transplant offers a better option than deceased kidney donors; and the value of novel vascular risk biomarkers in the assessment of transplanted MMA patients. We report a case of a 26-year-old man with MMA, who progressed to end-stage renal disease and received kidney transplant from a heterozygous next-of-kin living donor at 20 years of age. Although post-transplant urinary levels of methylmalonic acid decreased, this reduction was lower than previously reported for deceased donors. No episodes of metabolic decompensation were observed after transplantation. During his clinical progress, vascular complications appeared; and finally, pancreatitis was the cause of death. After kidney transplant, we evaluated novel vascular risk factors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which were used as early biomarkers of progression and metabolic management for this transplanted patient. This case report illustrates the disadvantage of transplantation with an allograft from a heterozygous living donor, and the utility of vascular risk biomarkers in renal transplant assessment.

Sanfilippo syndrome: Overall review.

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow-up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II-thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow-up are discussed.

A new case of maternal phenylketonuria treated with sapropterin dihydrochloride (6R-BH4).

PURPOSE: A woman with phenylketonuria (PKU) was diagnosed through neonatal screening, her PAH mutation was p.V388M/p.I65T, for which she received treatment with phenylalanine restriction, and was administered oral sapropterin dihydrochloride (6R-BH(4)) from the age of thirty. The purpose of this article is to describe the treatment with BH4 during her pregnancy and to evaluate a plan for its use. METHODS: The patient had an unplanned pregnancy at 34 years of age, for which she received a phenylalanine-free supplement enriched with essential fatty acids, vitamins and trace elements. RESULTS: The dose of 6R-BH(4) was reduced from 500 mg/day to 100 mg/day until its suspension in the 28th week of gestation, and was well tolerated. Blood phenylalanine control was easily accomplished during this pregnancy, and no nutritional deficiency was seen. CONCLUSION: The pregnancy had a normal outcome, and so we consider that adaptation of the dose of 6R-BH(4) to the prenatal periods aided a greater efficiency and a lower risk in the treatment of maternal PKU.

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.