Long-Term Neurological Outcomes of Adult Patients with Phenylketonuria before and after Newborn Screening in Japan.
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ABSTRACT:
SUBMITTER: Yamada K
PROVIDER: S-EPMC8167766 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Homocystinuria (HCU) is a rare inherited metabolic disease. In Japan, newborn screening (NBS) for HCU (cystathionine ?-synthase deficiency) was initiated in 1977. We compared the outcomes between patients detected by NBS (NBS group) and clinically detected patients (non-NBS group). METHODS:We administered questionnaires about clinical symptoms and social conditions to 16 attending physicians of 19 adult HCU patients treated with methionine-free formula. RESULTS:Eighteen patients (nine patients each in the NBS and non-NBS groups) participated. The frequency of patients with ocular, vascular, central nervous system, and skeletal symptoms in the NBS group was lower than that in the non-NBS group. Intellectual disability was observed in one and eight patients in the NBS and non-NBS groups, respectively. Concerning their social conditions, all patients in the NBS group were employed or still attending school, while only two patients in the non-NBS group were employed. Three of the four patients who discontinued treatment presented some symptoms, even in the NBS group. CONCLUSION:The social and intellectual outcomes of adult Japanese patients with HCU detected by NBS were favorable. However, even in the patients in the NBS group, some symptoms might not be preventable without continuous treatment.
| S-EPMC7569964 | biostudies-literature
Project description:The objective of this study was to evaluate the cost-effectiveness of newborn screening and treatment for phenylketonuria (PKU) in the context of new data on adherence to recommended diet treatment and a newly available drug treatment (sapropterin dihydrochloride). A computer simulation model was developed to project outcomes for a hypothetical cohort of newborns with PKU. Four strategies were compared: (1) clinical identification (CI) with diet treatment; (2) newborn screening (NBS) with diet treatment; (3) CI with diet and medication (sapropterin dihydrochloride); and (4) NBS with diet and medication. Data sources included published literature, primary data, and expert opinion. From a societal perspective, newborn screening with diet treatment had an incremental cost-effectiveness ratio of $6400/QALY compared to clinical identification with diet treatment. Adding medication to NBS with diet treatment resulted in an incremental cost-effectiveness ratio of more than $16,000,000/QALY. Uncertainty analyses did not substantially alter the cost-effectiveness results. Newborn screening for PKU with diet treatment yields a cost-effectiveness ratio lower than many other recommended childhood prevention programs even if adherence is lower than previously assumed. Adding medication yields cost-effectiveness results unlikely to be considered favorable. Future research should consider conditions under which sapropterin dihydrochloride would be more economically attractive.
| S-EPMC8151371 | biostudies-literature
Project description:ObjectiveTo determine whether the benefits of universal newborn hearing screening (UNHS) seen at age 8 years persist through the second decade.DesignProspective cohort study of a population sample of children with permanent childhood hearing impairment (PCHI) followed up for 17 years since birth in periods with (or without) UNHS.SettingBirth cohort of 100 000 in southern England.Participants114 teenagers aged 13-19 years, 76 with PCHI and 38 with normal hearing. All had previously their reading assessed aged 6-10 years.InterventionsBirth in periods with and without UNHS; confirmation of PCHI before and after age 9 months.Main outcome measureReading comprehension ability. Regression modelling took account of severity of hearing loss, non-verbal ability, maternal education and main language.ResultsConfirmation of PCHI by age 9 months was associated with significantly higher mean z-scores for reading comprehension (adjusted mean difference 1.17, 95% CI 0.36 to 1.97) although birth during periods with UNHS was not (adjusted mean difference 0.15, 95% CI -0.75 to 1.06). The gap between the reading comprehension z-scores of teenagers with early compared with late confirmed PCHI had widened at an adjusted mean rate of 0.06 per year (95% CI -0.02 to 0.13) during the 9.2-year mean interval since the previous assessment.ConclusionsThe benefit to reading comprehension of confirmation of PCHI by age 9 months increases during the teenage years. This strengthens the case for UNHS programmes that lead to early confirmation of permanent hearing loss.Trial registration numberISRCTN03307358.
| S-EPMC4717422 | biostudies-literature
Project description:Gaucher disease (GD) is an autosomal recessive inborn metabolic disorder caused by a glucocerebrosidase (GCase) defect. GD is classified into three main types depending on accompanying neurological symptoms. Enzyme replacement therapy and substrate reduction therapy are limited in the treatment of neurological symptoms, and using genotype and GCase activity to discriminate between non-neuronopathic and neuronopathic GD may be challenging as the two sometimes phenotypically overlap. The number of patients exhibiting neurological symptoms in Japan is significantly higher than that in Europe and the United States, and newborn screening (NBS) is still not actively performed in Japan. Definitive determination of the actual frequency and proportion of the type of GD from the results of NBS remains inconclusive. We performed NBS for Fabry disease, Pompe disease, and GD, mainly in the Kyushu area in Japan. Herein, we discuss the results of NBS for GD, as well as, the insights gained from following the clinical course of patients diagnosed through NBS. A total of 155,442 newborns were screened using an enzyme activity assay using dried blood spots. We found four newborns showing lower GCase activity and were definitively diagnosed with GD by GBA gene analysis. The frequency of GD diagnosis through NBS was 1 in 77,720 when limited to the probands. This frequency is higher than that previously estimated in Japan. In the future, NBS for GD is expected to be performed in many regions of Japan and contribute to detecting more patients with GD. Early screening and diagnosis may have a very significant impact on the quality of life and potentially longevity in infants with GD.
| S-EPMC8866142 | biostudies-literature
Project description:BackgroundThe diagnostic yield of coeliac disease could be improved by screening in at-risk groups, but long-term benefits of this approach are obscure.ObjectiveTo investigate health, quality of life and dietary adherence in adult coeliac patients diagnosed in childhood by screening.MethodsAfter thorough evaluation of medical history, follow-up questionnaires were sent to 559 adults with a childhood coeliac disease diagnosis. The results were compared between screen-detected and clinically-detected patients, and also between originally asymptomatic and symptomatic screen-detected patients.ResultsIn total, 236 (42%) patients completed the questionnaires a median of 18.5 years after childhood diagnosis. Screen-detected patients (n?=?48) had coeliac disease in the family and type 1 diabetes more often, and were less often smokers and members of coeliac societies compared to clinically-detected patients, whereas the groups did not differ in current self-experienced health or health concerns, quality of life or dietary adherence. Screen-detected, originally asymptomatic patients had more anxiety than those presenting with symptoms, whereas the subgroups were comparable in other current characteristics.ConclusionComparable long-term outcomes between screen-detected and clinically-detected patients support risk-group screening for coeliac disease. However, asymptomatic patients may require special attention.
| S-EPMC6137595 | biostudies-literature
Project description:Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD?=?2.0) and again in adulthood (T2, mean age 25.8 years, SD?=?2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ?360 µmol/L from age 13 onwards (n?=?11) had better cognitive flexibility and executive motor control than those who had phenylalanine ?360 µmol/L throughout life (n?=?7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.
| S-EPMC5574956 | biostudies-literature
Project description:Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5-5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.
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Project description:The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.
| S-EPMC6835503 | biostudies-literature
Project description:Research over the past decades has demonstrated that adult brain produces neural progenitor cells which proliferate and differentiate to newborn neurons that integrate into the existing circuit. However, detailed differentiation processes and underlying mechanisms of newly generated neurons are largely unknown due to the limitation of available methods for labeling and manipulating neural progenitor cells and newborn neurons. In this study, we designed a tightly controlled, noninvasive system based on Cre/loxP recombination to achieve long-term tracing and genetic manipulation of adult neurons in vivo. In this system, tamoxifen-inducible recombinase, CreER(T2), was driven by BAC-based promoter of doublecortin (DCX, a marker of newborn neurons). By crossing this Cre line with reporter mouse, we found that newborn neurons in the dentate gyrus (DG) could be selectively pulse-labeled by tamoxifen-induced expression of yellow fluorescent protein (YFP). YFP-positive neurons were identified by coimmunostaining with cell type-specific markers and characterized by electrophysiological recording. Furthermore, analysis of the migration of these neurons showed that the majority of these labeled neurons migrated to the inner part of granule cell layer. Moreover, spine growth of inner molecular layer of newborn granule neurons takes a dynamic pattern of invert U-shape, in contrast to the wedge-shaped change in the outer molecular layer. Our transgenic tool provides an efficient way to selectively label and manipulate newborn neuron in adult mouse DG.
| S-EPMC3193432 | biostudies-literature
Project description:The Houston West Nile Cohort (HWNC) was founded in 2002 when West Nile virus (WNV) reached Houston, TX. The long-term outcomes following WNV infection are still mostly unknown, though neurological abnormalities up to 1 year postinfection have been documented. We report an observational study of neurological abnormalities at 1-3 and 8-11 years following WNV infection in the HWNC. We conducted standard neurological examinations at two separate time points to assess changes in neurological status over time. The majority of patients (86%, 30/35) with encephalitis had abnormal neurological exam findings at the time of the first assessment compared with uncomplicated fever (27%, 3/11) and meningitis (36%, 5/14) cases. At the time of the second assessment, 57% (4/7) of West Nile fever (WNF), 33% (2/6) of West Nile meningitis (WNM), and 36% (5/14) of West Nile encephalitis (WNE) had developed new neurological complications. The most common abnormalities noted were tandem gait, hearing loss, abnormal reflexes, and muscle weakness. Long-term neurological abnormalities were most commonly found in patients who experienced primary WNV encephalitis. New abnormalities may develop over time regardless of initial clinical infection. Future studies should aim to differentiate neurological consequences due to WNV neuroinvasive infection versus neurological decline related to comorbid conditions.
| S-EPMC4426557 | biostudies-literature