Psychological well-being of early and continuously treated phenylketonuria patients

Background Despite enormous advances in therapy, phenylketonuria (PKU) remains an incurable, inherited metabolic disease requiring life-long treatment with potential to negatively impact quality of life and psychological well-being. Therefore, the aim of this study was to screen early diagnosed and continuously treated children with PKU on psychological strengths and behavioral difficulties. Methods Evaluation of psychological strengths and behavioral difficulties in 49 patients with PKU (23f, 2-17 years) by Strengths and Difficulties Questionnaire (SDQ; self-report 11-17 years and parent-report 2-17 years). Comparison to age, sex and BMI-matched healthy controls (n = 98; 46f). Results In patients with PKU and healthy controls median SDQ Total Difficulties Score and median scores of subscales were within the normal range in parent- and self-report, irrespective of sex and age group (children 2-10 years, adolescents 11-17 years). No influence of long-term metabolic control in PKU on SDQ could be revealed. The 2- to 10-year-old boys with PKU showed significantly higher scores in Prosocial Behavior compared to their healthy peers (P = .032). Likewise, adolescent boys with PKU showed fewer Conduct Problems (parent-report, P = .006). Adolescent girls with PKU rated themselves more often as abnormal in the subscale Emotional Problems compared to their healthy peers (P = .041). This subscale was also responsible for a significantly different Total SDQ Difficulties Score between patients and their parents' report (P = .008). Discussion SDQ represents a suitable instrument within the care for patients with PKU. Specific aspects, however, require separate consideration and evaluation with respect to this chronic disease. Special attention should be paid on adolescent PKU girls who seem to be at risk to develop emotional problem

Metabolomics of dietary fatty acid restriction in patients with phenylketonuria

Patients with phenylketonuria (PKU) have to follow a lifelong phenylalanine restricted diet. This type of diet markedly reduces the intake of saturated and unsaturated fatty acids especially long chain polyunsaturated fatty acids (LC-PUFA). Long-chain saturated fatty acids are substrates of mitochondrial fatty acid oxidation for acetyl-CoA production. LC-PUFA are discussed to affect inflammatory and haemostaseological processes in health and disease. The influence of the long term PKU diet on fatty acid metabolism with a special focus on platelet eicosanoid metabolism has been investigated in the study presented here. 12 children with PKU under good metabolic control and 8 healthy controls were included. Activated fatty acids (acylcarnitines C6-C18) in dried blood and the cholesterol metabolism in serum were analyzed by liquid chromatographic tandem mass spectrometry (LC-MS/MS). Fatty acid composition of plasma glycerophospholipids was determined by gas chromatography. LC-PUFA metabolites were analyzed in supernatants by LC-MS/MS before and after platelet activation and aggregation using a standardized protocol. Patients with PKU had significantly lower free carnitine and lower activated fatty acids in dried blood compared to controls. Phytosterols as marker of cholesterol (re-) absorption were not influenced by the dietary fatty acid restriction. Fatty acid composition in glycerophospholipids was comparable to that of healthy controls. However, patients with PKU showed significantly increased concentrations of y-linolenic acid (C18:3n-6) a precursor of arachidonic acid. In the PKU patients significantly higher platelet counts were observed. After activation with collagen platelet aggregation and thromboxane B(2) and thromboxane B(3) release did not differ from that of healthy controls. Long-term dietary fatty acid restriction influenced the intermediates of mitochondrial beta-oxidation. No functional influence on unsaturated fatty acid metabolism and platelet aggregation in patients with PKU was detected

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

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Psychological well-being of early and continuously treated phenylketonuria patients

Background Despite enormous advances in therapy, phenylketonuria (PKU) remains an incurable, inherited metabolic disease requiring life-long treatment with potential to negatively impact quality of life and psychological well-being. Therefore, the aim of this study was to screen early diagnosed and continuously treated children with PKU on psychological strengths and behavioral difficulties. Methods Evaluation of psychological strengths and behavioral difficulties in 49 patients with PKU (23f, 2-17 years) by Strengths and Difficulties Questionnaire (SDQ; self-report 11-17 years and parent-report 2-17 years). Comparison to age, sex and BMI-matched healthy controls (n = 98; 46f). Results In patients with PKU and healthy controls median SDQ Total Difficulties Score and median scores of subscales were within the normal range in parent- and self-report, irrespective of sex and age group (children 2-10 years, adolescents 11-17 years). No influence of long-term metabolic control in PKU on SDQ could be revealed. The 2- to 10-year-old boys with PKU showed significantly higher scores in Prosocial Behavior compared to their healthy peers (P = .032). Likewise, adolescent boys with PKU showed fewer Conduct Problems (parent-report, P = .006). Adolescent girls with PKU rated themselves more often as abnormal in the subscale Emotional Problems compared to their healthy peers (P = .041). This subscale was also responsible for a significantly different Total SDQ Difficulties Score between patients and their parents' report (P = .008). Discussion SDQ represents a suitable instrument within the care for patients with PKU. Specific aspects, however, require separate consideration and evaluation with respect to this chronic disease. Special attention should be paid on adolescent PKU girls who seem to be at risk to develop emotional problem

Psychological well-being of early and continuously treated phenylketonuria patients

Background Despite enormous advances in therapy, phenylketonuria (PKU) remains an incurable, inherited metabolic disease requiring life-long treatment with potential to negatively impact quality of life and psychological well-being. Therefore, the aim of this study was to screen early diagnosed and continuously treated children with PKU on psychological strengths and behavioral difficulties. Methods Evaluation of psychological strengths and behavioral difficulties in 49 patients with PKU (23f, 2-17 years) by Strengths and Difficulties Questionnaire (SDQ; self-report 11-17 years and parent-report 2-17 years). Comparison to age, sex and BMI-matched healthy controls (n = 98; 46f). Results In patients with PKU and healthy controls median SDQ Total Difficulties Score and median scores of subscales were within the normal range in parent- and self-report, irrespective of sex and age group (children 2-10 years, adolescents 11-17 years). No influence of long-term metabolic control in PKU on SDQ could be revealed. The 2- to 10-year-old boys with PKU showed significantly higher scores in Prosocial Behavior compared to their healthy peers (P = .032). Likewise, adolescent boys with PKU showed fewer Conduct Problems (parent-report, P = .006). Adolescent girls with PKU rated themselves more often as abnormal in the subscale Emotional Problems compared to their healthy peers (P = .041). This subscale was also responsible for a significantly different Total SDQ Difficulties Score between patients and their parents' report (P = .008). Discussion SDQ represents a suitable instrument within the care for patients with PKU. Specific aspects, however, require separate consideration and evaluation with respect to this chronic disease. Special attention should be paid on adolescent PKU girls who seem to be at risk to develop emotional problem

Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders

This single-center study aims to determine the time, diagnostic procedure, and cost saving potential of early exome sequencing in a cohort of 111 individuals with genetically confirmed neurodevelopmental disorders. We retrospectively collected data regarding diagnostic time points and procedures from the individuals' medical histories and developed criteria for classifying diagnostic procedures in terms of requirement, followed by a cost allocation. All genetic variants were re-evaluated according to ACMG recommendations and considering the individuals' phenotype. Individuals who developed first symptoms of their underlying genetic disorder when Next Generation Sequencing (NGS) diagnostics were already available received a diagnosis significantly faster than individuals with first symptoms before this cutoff. The largest amount of potentially dispensable diagnostics was found in genetic, metabolic, and cranial magnetic resonance imaging examinations. Out of 407 performed genetic examinations, 296 (72.7%) were classified as potentially dispensable. The same applied to 36 (27.9%) of 129 cranial magnetic resonance imaging and 111 (31.8%) of 349 metabolic examinations. Dispensable genetic examinations accounted 302,947.07€ (90.2%) of the total 335,837.49€ in potentially savable costs in this cohort. The remaining 32,890.42€ (9.8%) are related to non-required metabolic and cranial magnetic resonance imaging diagnostics. On average, the total potentially savable costs in our study amount to €3,025.56 per individual. Cost savings by first tier exome sequencing lie primarily in genetic, metabolic, and cMRI testing in this German cohort, underscoring the utility of performing exome sequencing at the beginning of the diagnostic pathway and the potential for saving diagnostic costs and time

Multigene panel next generation sequencing in a patient with cherry red macular spot: identification of two novelmutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings

Background: Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid. Methods: Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out. Case report and results: Cherry red macular spotswere first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations aswell as cerebralMRIwere unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to b1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699CNA, p.S233R in exon 4 and c.803ANG; p.Y268C in Exon 5 in NEU1 transcriptNM_000434.3), leading to amino acid changes predicted to impair protein function. Discussion: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family