Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU

Living with phenylketonuria in adulthood: the PKU ATTITUDE study

Dietary treatment is the cornerstone of therapy for phenylketonuria (PKU), but adherence to low- phenylalanine diet progressively decreases after adolescence. We designed a survey to characterize the dietary habits of Italian adult PKU patients and to identify psychological factors influencing disease perception and adherence to diet. Participants to the survey (n = 111; response rate 94%) were asked to complete a structured questionnaire. Patients appeared to have an altered perception and awareness of the disease. About 40% of them did not consider PKU a disease and, despite declaring regular monitoring of phenylalanine levels (85%), nearly half of them reported a high plasma value over the last 6 months (>600 μmol/L, 48%) or were unable to specify it (31%). Adherence to PKU diet was unsatisfactory, with increased consumption of natural protein sources and reduced daily use of amino-acid supplements (<4–5 times/day in 82% patients). In addition to the intrinsic characteristics of AA formula (palatability, ease of use), the most important factor influencing their consumption was the increased social pressure associated with their use (55%). Plasma phenylalanine periodical measurements (61%) and examinations at metabolic centers (49%) were considered relevant for compliance to diet. In Italian adult PKU patients dietary management was found to be inadequate, likely due to inappropriate perception and knowledge of the disease, and lack of awareness of the negative impact of poor metabolic control in adult life. Clinicians should consider implementing more intense and tailored educational measures, as well as structured transitional care processes

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: Findings from the Fabry Registry

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. Methods: the SF-36 (R) Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/2 weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men. Genet Med 2010:12(11):703 712.Genzyme CorporationGenzymeNatl Univ Hosp, Dept Endocrinol, DK-2100 Copenhagen, DenmarkSan Bassano Hosp, Dept Neurol, Bassano Del Grappa, ItalyUniv Padua, Dept Neurosci, Padua, ItalyUniv Wurzburg, Dept Med, Wurzburg, GermanyColumbia Univ, Dept Pediat, Div Clin Genet, Coll Phys & Surg, New York, NY 10027 USACincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilMassachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USAGenzyme Corp, Dept Biomed Data Sci & Informat, Cambridge, MA USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilWeb of Scienc

Valutazione della qualità di vita in pazienti con malattie metaboliche rare in età adulta. Analisi delle variabili che maggiormente influenzano la percezione soggettiva di benessere fisico e psicologico, con particolare attenzione ad un gruppo di pazienti affetti da Galattosemia

Genetic metabolic diseases or congenital defects of metabolism, are a large and diverse sub-group of genetic diseases characterizad by the dysfunction of an enzima, a protein or other more complex molecules involved in cell metabolism, with a consequent disruption of it. In medicine, the assesment of quality of life perceived by the subject, is a very important aspect in order to emphasize by the importance of the needs perceived by each patient. The objective of this study was initially born of the desire to analyse the variables witch might influence a subjective perception of a good quality of life in patients suffering from a metabolic disorder. During the course of this study, the focus shifted mainly on cognitive functioning , considered asa variable significantly affecting the perception that every patients has in regard to their physical and psychological well-being. Here is the analysis on a group of patients affected by Galactosemia , with the aim of: - assess and quality the cognitive functions, find a possible correlations between the type of mutation and the phenotype, asses the relationship between the biochemical context of each patient ( levels of total plasma galactose) and the neurological and neuropsychological framework. it was analysed the clinical history of 7 patients with Galactosemia, 3 children and 4 adults. The cognitive changes highlighted in the adults are: Verbal apraxia, constructive apraxia,attention deficits,change in perception-gnosis capacities. A careful analysis of the patients also revealed the presence of specific aspects of personality.Le malattie metaboliche ereditarie (MME), o difetti congeniti del metabolismo, rappresentano un vasto ed eterogeneo sottogruppo di malattie genetiche caratterizzate dalla disfunzione di un enzima, di una proteina o di altre molecole più complesse coinvolte nel metabolismo cellulare, con conseguente perturbazione dello stesso. La valutazione della qualità  della vita percepita dal soggetto rappresenta in medicina un aspetto molto importante al fine di enfatizzare l'importanza dei bisogni percepiti da ciascun paziente. L'obiettivo del presente studio inizialmente è nato dalla volontà  di analizzare quali variabili potessero influenzare maggiormente la percezione soggettiva di una buona qualità  di vita, in pazienti affetti da una patologia metabolica. Durante il corso dello studio l'attenzione si è spostata principalmente sull'analisi della funzionalità  cognitiva, intesa come variabile notevolmente influenzante la percezione che ogni paziente ha relativamente, al proprio benessere fisico e psicologico. A questo proposito si riporta l'analisi compiuta su di un gruppo di pazienti affetti da Galattosemia, con l'obiettivo di : valutare e quantificare le funzioni cognitive, stabilire una possibile correlazione tra genotipo e fenotipo del campione, valutare l'eventuale relazione esistente tra il quadro biochimico di ogni singolo paziente (livelli di galattosio totale plasmatico) ed il quadro neuropsicologico e neurologico. E' stata analizzata in modo retrospettivo la storia clinica di 7 pazienti con galattosemia, 3 in età  pediatrica e 4 in età  adulta. Le alterazioni cognitive evidenziate in modo eterogeneo nel campione adulti sono: aprassia verbale, aprassia costruttiva,deficit delle capacità  attentive,alterazioni delle capacità percettivo gnosiche. Ad un'attenta analisi dei pazienti inoltre, emerge la presenza di specifici aspetti di personalità

Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria

Background: The effect of long-term N-carbamylglutamate (NCG) treatment on the rate and severity of decompensations due to propionic aciduria (PA) and methylmalonic aciduria (MMA) is unknown. This paper presents clinical experience from a single-centre cohort of patients with PA and MMA who received continuous long-term treatment with NCG. Methods: The effect of oral NCG treatment (initial dose: 50 mg/kg/day) was investigated in patients with PA or MMA who were experiencing frequent progressive episodes of metabolic decompensation, who had pathological levels of ammonia, and who were referred to the Division of Metabolic Diseases, University Hospital of Padova between August 2014 and December 2015. Clinical and biochemical data, including the number of metabolic decompensations, lactic acid, uric acid and plasma ammonia levels, protein intake and body weight, were collected before and after the initiation of NCG treatment. Results: Eight patients with PA (n = 4) and MMA (n = 4) aged 2–20 years were treated with NCG (50 mg/kg/day) for 7–16 months. Metabolic decompensation episodes decreased in number and severity, with three of the patients having no episodes (pre-treatment: 24 episodes; post-treatment: 9 episodes). After NCG treatment, all episodes were treated at home and none required hospitalisation, lactic acid values were 1.3–2.1 mmol/L and uric acid values were 0.21–0.36 mmol/L. Significant reductions in blood ammonia levels after NCG initiation were observed in five patients, whereas levels were reduced or maintained in the normal range in the remainder. Over the treatment period, patients had an increase in natural protein intake of 20–50% and gained 0–6.5 kg in bodyweight. Conclusion: These observations suggest that, in addition to short-term benefits for the acute treatment of hyperammonaemia, NCG may be effective and well tolerated as a long-term treatment in patients with severe PA and MMA, and that further prospective studies are warranted

A new strategy of desensitization in mucopolysaccharidosis type II disease treated with idursulfase therapy: A case report and review of the literature

Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme replacement therapy (ERT) with recombinant idursulfase is the main treatment available to decrease morbidity and improve quality of life. However, infusion-associated reactions (IARs) are reported and may limit access to treatment. When premedication or infusion rate reductions are ineffective for preventing IARs, desensitization can be applied. To date, only two MPS II patients are reported to have undergone desensitization. We report a pediatric patient with recurrent IARs during infusion successfully managed with gradual desensitization. Our protocol started at 50% of the standard dosage infused at concentrations from 0.0006 to 0.06&nbsp;mg/ml on weeks 1 and 2, followed by 75% of the standard dosage infused at concentrations from 0.0009 to 0.09&nbsp;mg/ml on weeks 3 and 4, and full standard dosage thereafter, infused at progressively increasing concentrations until the standard infusion conditions were reached at 3&nbsp;months. Our experience can be used in the management of MPS II patients presenting IARs to idursulfase infusion, even when general preventive measures are already administered

Variant in the allosteric domain of CPS1 protein associated with effectiveness of N-carbamoyl glutamate therapy in neonatal onset CPS1 deficiency

OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. CASE PRESENTATION: We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake. CONCLUSIONS: Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy

Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency

We report the first case of late-onset isolated sulfite oxidase deficiency (ISOD) presenting with a stroke-like episode. Clinical, biochemical and neuroradiological features at diagnosis and during follow-up after dietary treatment intervention are described. Furthermore, pathogenic mechanisms possibly leading to stroke in ISOD are discussed

Report of Five Years of Experience in Neonatal Screening for Mucopolysaccharidosis Type I and Review of the Literature

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disease, with neurological and visceral involvement, in which early diagnosis through newborn screening (NBS) and early treatment can improve outcomes. We present our first 5 years of experience with laboratory and clinical management of NBS for MPS I. Since 2015, we have screened 160,011 newborns by measuring alpha-L-iduronidase (IDUA) activity and, since 2019, glycosaminoglycans (GAGs) in dried blood spot (DBS) as a second-tier test. Positive screening patients were referred to our clinic for confirmatory clinical and molecular testing. We found two patients affected by MPS I (incidence of 1:80,005). Before the introduction of second-tier testing, we found a high rate of false-positives due to pseudodeficiency. With GAG analysis in DBS as a second-tier test, no false-positive newborns were referred to our clinic. The confirmed patients were early treated with enzyme replacement therapy and bone-marrow transplantation. For both, the clinical outcome of the disease is in the normal range. Our experience confirms that NBS for MPS I is feasible and effective, along with the need to include GAG assay as a second-tier test. Follow-up of the two positive cases identified confirms the importance of early diagnosis through NBS and early treatment to improve the outcome of these patients