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1.
Genet Med ; 23(1): 13-21, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32981931

RESUMO

PURPOSE: Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. METHODS: Systematic literature search for articles published from 2000 to 2019 was performed using the PRISMA protocol. Studies reporting on more than one individual identified by NBS were included. We investigated effects of interventional and noninterventional variables on neurological outcome. RESULTS: Fifteen publications reporting on 647 GA1 patients were included. In the NBS group (n = 261 patients), 195 patients remained asymptomatic (74.7%), while 66 patients (25.3%) developed a MD. Compared with the NBS group, a much higher proportion of patients (349/386; 90.4%; p < 0.0001) diagnosed after the manifestation of neurologic symptoms had a MD and an abnormal motor development (285/349; 81.7%; p < 0.0001). For NBS patients, deviations from the recommended diet increased the risk of insidious onset MD, while delayed start of emergency treatment increased the risk of acute onset MD. CONCLUSIONS: This meta-analysis demonstrates that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy.

2.
J Inherit Metab Dis ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33274439

RESUMO

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; P = .023) and body length (mean SDS -1.34; P = -.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; P = .016). In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

3.
J Inherit Metab Dis ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33295057

RESUMO

Cystathionine ß-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

4.
Mol Genet Metab ; 131(4): 390-397, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288448

RESUMO

OBJECTIVE: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals. METHODS: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype. RESULTS: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis. CONCLUSION: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33132036

RESUMO

OBJECTIVE: Continuous spikes and waves during sleep (CSWS) is an epileptic encephalopathy characterized by generalised epileptiform activity and neurocognitive dysfunction. Causes and outcome are diverse and treatment is mainly empirical. METHODS: Retrospective descriptive analysis of clinical and EEG data of children with CSWS diagnosed between 1998 and 2018 at the University Hospital Heidelberg. RESULTS: Ninety-five children were included with a median age at diagnosis of 5.4 years. A structural/metabolic aetiology was found in 43.2%, genetic alterations in 17.9%, while it remained unknown in 38.9%. The proportion of patients with genetic aetiology increased from 10.3% (1998-2007) to 22.8% (2008-2018). On average, each patient received 5 different treatments. CSWS was refractory in >70% of cases, steroids and neurosurgery were most effective. No difference was observed between children with CSWS or Near-CSWS (Spike-Wave-Index 40-85%). CONCLUSIONS: Our cohort confirms CSWS as an age-dependent epileptic encephalopathy. Structural brain abnormalities were most frequent, but genetic causes are increasingly identified. More specific criteria for the diagnosis and treatment goals should be elaborated and implemented based on evidence. SIGNIFICANCE: This study is the largest monocentric observational study on treatment effects in children with CSWS, providing data for diagnostic and therapeutic decisions.

6.
Genet Med ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33082561

RESUMO

PURPOSE: TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials. METHODS: Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were age at disease onset, survival, and diagnostic delay. Phenotypical, neuroradiological, and histopathological features were descriptively illustrated. RESULTS: Mean age at disease onset was 4 (TUBA1A) and 6 months (TUBB2B), respectively. Mortality was equally estimated with 7% at 3.2 (TUBA1A) and 8.0 years (TUBB2B). Diagnostic delay was significantly higher in TUBB2B (12.3 years) compared with TUBA1A tubulinopathy (4.2 years). We delineated the isotype-dependent clinical, neuroradiological, and histopathological phenotype of affected individuals and present brain malformations associated with epilepsy and an unfavorable course of disease. CONCLUSION: The natural history of tubulinopathies is defined by the genotype and associated brain malformations. Defined data on estimated survival, diagnostic delay, and disease characteristics of TUBA1A and TUBB2B tubulinopathy will help to raise disease awareness and encourage future clinical trials to optimize genetic testing, family counseling, and supportive care.

7.
Pediatrics ; 146(5)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33051224

RESUMO

BACKGROUND: Although extended newborn screening (NBS) programs have been introduced more than 20 years ago, their impact on the long-term clinical outcome of individuals with inherited metabolic diseases (IMDs) is still rarely investigated. METHODS: We studied the clinical outcomes of individuals with IMDs identified by NBS between 1999 and 2016 in a prospective multicenter observational study. RESULTS: In total, 306 screened individuals with IMDs (115 with phenylketonuria and 191 with other IMDs with a lifelong risk for metabolic decompensation) were followed for a median time of 6.2 years. Although the risk for metabolic decompensation was disease-specific and NBS could not prevent decompensations in every individual at risk (n = 49), the majority did not develop permanent disease-specific signs (75.9%), showed normal development (95.6%) and normal cognitive outcome (87.7%; mean IQ: 100.4), and mostly attended regular kindergarten (95.2%) and primary school (95.2%). This demonstrates that not only individuals with phenylketonuria, serving as a benchmark, but also those with lifelong risk for metabolic decompensation had a favorable long-term outcome. High NBS process quality is the prerequisite of this favorable outcome. This is supported by 28 individuals presenting with first symptoms at a median age of 3.5 days before NBS results were available, by the absence of neonatal decompensations after the report of NBS results, and by the challenge of keeping relevant process parameters at a constantly high level. CONCLUSIONS: NBS for IMDs, although not completely preventing clinical presentations in all individuals, can be considered a highly successful program of secondary prevention.


Assuntos
Doenças Metabólicas/diagnóstico , Triagem Neonatal , Feminino , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/complicações , Fenilcetonúrias/diagnóstico , Estudos Prospectivos , Fatores de Tempo
8.
Biomedicines ; 8(11)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126500

RESUMO

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

9.
J Inherit Metab Dis ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32996606

RESUMO

BACKGROUND: This study provides a general overview on liver and/or kidney transplantation in patients with an amino and organic acid-related disorder (AOA) with the aim to investigate patient characteristics and global outcome in Europe. This study was an initiative of the E-IMD and the AOA subnetwork of MetabERN. METHODS: A questionnaire was sent to all clinically active European Society for the Study of Inborn Errors of Metabolism (SSIEM) members. The questionnaire focused on transplanted individuals with methylmalonic acidemia (MMA), propionic acidemia (PA), maple syrup urine disease (MSUD), and urea-cycle disorders (UCDs). RESULTS: We identified 280 transplanted AOA patients (liver transplantation in 20 MMA, 37 PA, 47 MSUD, and 111 UCD patients, kidney or combined liver and kidney transplantation in 57 MMA patients and undefined transplantation type in 8 MMA patients), followed by 51 metabolic centers. At a median follow-up of 3.5 years, posttransplant survival ranged between 78% and 100%, being the lowest in PA patients. Overall, the risk of mortality was highest within 14 days posttransplantation. Neurological complications were mainly reported in Mut0 type MMA (n = 8). Nonneurological complications occurred in MMA (n = 28), PA (n = 7), and UCD (n = 14) patients, while it was virtually absent in MSUD patients. Only 116/280 patients were psychologically tested. In all, except MSUD patients, the intelligence quotient (IQ) remained unchanged in the majority (76/94, 81%). Forty-one percentage (9/22) of MSUD patient showed improved IQ. CONCLUSION: The survival in AOA individuals receiving liver and/or kidney transplantation seems satisfactory. Evidence-based guidelines, systematic data collection, and improved cooperation between transplantation centers and European Reference Networks are indispensable to improve patient care and outcomes.

10.
Brain ; 143(10): 2929-2944, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32979048

RESUMO

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

11.
J Inherit Metab Dis ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32754920

RESUMO

INTRODUCTION: Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult. METHOD: Cross-sectional analysis of data from the European Registry and Network for Intoxication type Metabolic Diseases (Chafea no. December 1, 2010). RESULTS: Data from 28 cblA and 95 mut patients in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval, six patients from the mut group died, while all cblA patients survived. CONCLUSION: Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients.

12.
Eur J Med Genet ; 63(11): 104046, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858208

RESUMO

BACKGROUND: ECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia. PATIENTS/METHODS: We used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented. RESULTS: We identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients' fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual. Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis. CONCLUSIONS: In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes.

13.
J Inherit Metab Dis ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32845020

RESUMO

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

14.
Sci Rep ; 10(1): 13584, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788680

RESUMO

Warburg effect or aerobic glycolysis provides selective growth advantage to aggressive cancers. However, targeting oncogenic regulators of Warburg effect has always been challenging owing to the wide spectrum of roles of these molecules in multitude of cells. In this study, we present ADP-dependent glucokinase (ADPGK) as a novel glucose sensor and a potential onco-target in specifically high-proliferating cells in Burkitt's lymphoma (BL). Previously, we had shown ADPGK to play a major role in T-cell activation and induction of Warburg effect. We now report ADPGK knock-out Ramos BL cells display abated in vitro and in vivo tumour aggressiveness, via tumour-macrophage co-culture, migration and Zebrafish xenograft studies. We observed perturbed glycolysis and visibly reduced markers of Warburg effect in ADPGK knock-out cells, finally leading to apoptosis. We found repression of MYC proto-oncogene, and up to four-fold reduction in accumulated mutations in translocated MYC in knock-out cells, signifying a successful targeting of the malignancy. Further, the activation induced differentiation capability of knock-out cells was impaired, owing to the inability to cope up with increased energy demands. The effects amplified greatly upon stimulation-based proliferation, thus providing a novel Burkitt's lymphoma targeting mechanism originating from metabolic catastrophe induced in the cells by removal of ADPGK.


Assuntos
Proliferação de Células/genética , Glucoquinase/genética , Neoplasias Hematológicas/genética , Peixe-Zebra/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Técnicas de Inativação de Genes , Glucoquinase/metabolismo , Glicólise/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Células Jurkat , Macrófagos/metabolismo , Macrófagos/patologia , Linfócitos T/metabolismo , Células THP-1 , Transplante Heterólogo , Peixe-Zebra/metabolismo
15.
J Inherit Metab Dis ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785952

RESUMO

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and - in acute diseases - metabolic decompensations nevertheless. Research on the subjective burden of IT-IEM remains sparse. Studies with appropriate sample sizes are needed to make valid statements about health-related quality of life (HrQoL) in children and adolescents with IT-IEM. Six international metabolic centres contributed self-reports and proxy reports of HrQoL (assessed with the Paediatric Quality of Life Inventory) to the final data set (n = 251 patients; age range 2.3-18.8 years). To compare HrQoL of the patient sample with norm data and between acute and non-acute IT-IEM, t tests were conducted. To examine the influence of child age, sex, diagnosis and current dietary treatment on HrQoL, multiple linear regression analyses were conducted. Self-reports and proxy reporst showed significantly lower HrQoL total scores for children with IT-IEM compared to healthy children. Current dietary treatment significantly predicted lower proxy reported total HrQoL. Children with non-acute IT-IEM reported significantly lower psychosocial health and emotional functioning than children with acute IT-IEM. The patient sample showed significantly impaired HrQoL and a diet regimen remains a risk factor for lower HrQoL. Differences in HrQoL between acute and non-acute IT-IEM subgroups indicate that factors beyond symptom severity determine the perception of disease burden. Identifying these factors is of crucial importance to develop and implement appropriate interventions for those in need.

16.
Genet Med ; 22(11): 1863-1873, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32699352

RESUMO

PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

17.
Sci Rep ; 10(1): 11948, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686765

RESUMO

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.


Assuntos
Peso Corporal , Desenvolvimento Humano , Distúrbios Congênitos do Ciclo da Ureia/epidemiologia , Biomarcadores , Criança , Pré-Escolar , Bases de Dados Factuais , Gerenciamento Clínico , Feminino , Humanos , Lactente , Masculino , Vigilância em Saúde Pública , Avaliação de Sintomas , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/etiologia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Pesos e Medidas
18.
J Inherit Metab Dis ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412122

RESUMO

Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work-up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence-based recommendations have improved neonatal survival and short-term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post-translational short-chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short-chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

19.
Exp Neurol ; 331: 113330, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32339612

RESUMO

Chronic hyperammonemia is a common condition affecting individuals with inherited urea cycle disorders resulting in progressive cognitive impairment and behavioral abnormalities. Altered neurotransmission has been proposed as major source of neuronal dysfunction during chronic hyperammonemia, but the molecular pathomechanism has remained incompletely understood. Here we show that chronic exposure to ammonium acetate induces locomotor dysfunction and abnormal feeding behavior in zebrafish larvae, indicative for an impairment of higher brain functions. Biochemically, chronically elevated ammonium concentrations cause enhanced activity of glutamate decarboxylase isoforms GAD1 and GAD2 with increased formation of GABA and concomitant depletion of glutamate, ultimately leading to a dysfunctional hypoglutamatergic and hyperGABAergic metabolic state. Moreover, elevated GABA concentrations are accompanied by increased expression of GABAA receptor subunits alpha-1, gamma-2 and delta, supporting the notion of an increased GABA tone in chronic hyperammonemia. Propionate oxidation as major anaplerotic reaction sufficiently compensates for the transamination-dependent withdrawal of 2-oxoglutarate, thereby preventing bioenergetic dysfunction under chronic hyperammonemic conditions. Thus, our study extends the hypothesis of alterations in the glutamatergic and GABAergic system being an important pathophysiological factor causing neurobehavioral impairment in chronic hyperammonemia. Given that zebrafish larvae have already been successfully used for high-throughput identification of novel compounds to treat inherited neurological diseases, the reported zebrafish model should be considered an important tool for systematic drug screening targeting altered glutamatergic and GABAergic metabolism under chronic hyperammonemic conditions in the future.

20.
PLoS One ; 15(4): e0230898, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267884

RESUMO

PURPOSE: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). METHODS: Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. RESULTS: Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N = 23) months. CONCLUSIONS: The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included "me-too"-enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.


Assuntos
Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Produção de Droga sem Interesse Comercial/estatística & dados numéricos , United States Food and Drug Administration , Estudos Transversais , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Regulamentação Governamental , Humanos , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
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