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1.
Genet Med ; 26(4): 101039, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38054409

RESUMO

PURPOSE: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. METHODS: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into "severe" and "attenuated" categories based on the genotype-specific and validated in vitro enzyme activity. RESULTS: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. CONCLUSION: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx-as currently performed-was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.


Assuntos
Transplante de Fígado , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Distúrbios Congênitos do Ciclo da Ureia/genética , Distúrbios Congênitos do Ciclo da Ureia/cirurgia , Proteínas , Avaliação de Resultados em Cuidados de Saúde
2.
Mol Genet Metab ; 143(1-2): 108566, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39299137

RESUMO

OBJECTIVE: In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes. METHODS: We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model. RESULTS: Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes. INTERPRETATION: The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA. CLINICAL TRIAL REGISTRATION: The UCDC database is recorded at the US National Library of Medicine (https://clinicaltrials.gov).

3.
Mol Genet Metab ; 141(3): 108112, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301530

RESUMO

OBJECTIVE: Liver transplantation (LTx) is an intervention when medical management is not sufficiently preventing individuals with urea cycle disorders (UCDs) from the occurrence of hyperammonemic events. Supplementation with L-citrulline/arginine is regularly performed prior to LTx to support ureagenesis and is often continued after the intervention. However, systematic studies assessing the impact of long-term L-citrulline/arginine supplementation in individuals who have undergone LTx is lacking to date. METHODS: Using longitudinal data collected systematically, a comparative analysis was carried out by studying the effects of long-term L-citrulline/arginine supplementation vs. no supplementation on health-related outcome parameters (i.e., anthropometric, neurological, and cognitive outcomes) in individuals with UCDs who have undergone LTx. Altogether, 52 individuals with male ornithine transcarbamylase deficiency, citrullinemia type 1 and argininosuccinic aciduria and a pre-transplant "severe" disease course who have undergone LTx were investigated by using recently established and validated genotype-specific in vitro enzyme activities. RESULTS: Long-term supplementation of individuals with L-citrulline/arginine who have undergone LTx (n = 16) does neither appear to alter anthropometric nor neurocognitive endpoints when compared to their severity-adjusted counterparts that were not supplemented (n = 36) after LTx with mean observation periods between four to five years. Moreover, supplementation with L-citrulline/arginine was not associated with an increase of disease-specific plasma arithmetic mean values for the respective amino acids when compared to the non-supplemented control cohort. CONCLUSION: Although supplementation with L-citrulline/arginine is often continued after LTx, this pilot study does neither identify altered long-term anthropometric or neurocognitive health-related outcomes nor does it find an adequate biochemical response as reflected by the unaltered plasma arithmetic mean values for L-citrulline or L-arginine. Further prospective analyses in larger samples and even longer observation periods will provide more insight into the usefulness of long-term supplementation with L-citrulline/arginine for individuals with UCDs who have undergone LTx.


Assuntos
Transplante de Fígado , Distúrbios Congênitos do Ciclo da Ureia , Masculino , Humanos , Citrulina/uso terapêutico , Arginina/metabolismo , Projetos Piloto , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Distúrbios Congênitos do Ciclo da Ureia/cirurgia , Suplementos Nutricionais , Ureia/metabolismo
4.
Mol Genet Metab ; 141(1): 108097, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38113552

RESUMO

Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Even though hyperammenomia is considered the major pathomechanistic factor for neurological impairment and cognitive dysfunction, a relevant subset of individuals presents with a neurodegenerative course in the absence of hyperammonemic decompensations. Here we show, that ASS1 deficiency induced by antisense-mediated knockdown of the zebrafish ASS1 homologue is associated with defective neuronal differentiation ultimately causing neuronal cell loss and consecutively decreased brain size in zebrafish larvae in vivo. Whereas ASS1-deficient zebrafish larvae are characterized by markedly elevated concentrations of citrulline - the biochemical hallmark of CTLN1, accumulation of L-citrulline, hyperammonemia or therewith associated secondary metabolic alterations did not account for the observed phenotype. Intriguingly, coinjection of the human ASS1 mRNA not only normalized citrulline concentration but also reversed the morphological cerebral phenotype and restored brain size, confirming conserved functional properties of ASS1 across species. The results of the present study imply a novel, potentially non-enzymatic (moonlighting) function of the ASS1 protein in neurodevelopment.


Assuntos
Citrulinemia , Hiperamonemia , Animais , Humanos , Citrulinemia/patologia , Peixe-Zebra/genética , Citrulina , Argininossuccinato Sintase/genética , Argininossuccinato Sintase/metabolismo , Fenótipo , Hiperamonemia/genética
5.
J Inherit Metab Dis ; 47(2): 220-229, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38375550

RESUMO

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.


Assuntos
Hiperamonemia , Transplante de Fígado , Doença da Deficiência de Ornitina Carbomoiltransferase , Humanos , Doença da Deficiência de Ornitina Carbomoiltransferase/cirurgia , Hiperamonemia/tratamento farmacológico , Citrulina , Carbamoil-Fosfato/metabolismo , Carbamoil-Fosfato/uso terapêutico , Amônia/metabolismo , Estudos Retrospectivos , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Arginina/uso terapêutico , Ornitina Carbamoiltransferase
6.
BMC Pediatr ; 24(1): 539, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39174957

RESUMO

BACKGROUND: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. METHODS: Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children's Medical Center of Peking University First Hospital from September 2014 to August 2023. RESULTS: Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. CONCLUSIONS: Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.


Assuntos
Carbamoil-Fosfato Sintase (Amônia) , Doença da Deficiência da Carbamoil-Fosfato Sintase I , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem , Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , China , População do Leste Asiático/genética , Mutação
7.
Neurocrit Care ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138714

RESUMO

BACKGROUND: Acute metabolic crises in inborn errors of metabolism (such as urea cycle disorders, organic acidemia, maple syrup urine disease, and mitochondrial disorders) are neurological emergencies requiring management in the pediatric intensive care unit (PICU). There is a paucity of data pertaining to electroencephalograms (EEG) characteristics in this cohort. We hypothesized that the incidence of background abnormalities and seizures in this cohort would be high. Neuromonitoring data from our center's PICU over 10 years are presented in this article. METHODS: Data were collected by retrospective chart review for patients with the aforementioned disorders who were admitted to the PICU at our institution because of metabolic/neurologic symptoms from 2008 to 2018. Descriptive statistics (χ2 test or Fisher's exact test) were used to study the association between EEG parameters and outcomes. RESULTS: Our cohort included 40 unique patients (8 with urea cycle disorder, 7 with organic acidemia, 3 with maple syrup urine disease, and 22 with mitochondrial disease) with 153 admissions. Presenting symptoms included altered mentation (36%), seizures (41%), focal weakness (5%), and emesis (28%). Continuous EEG was ordered in 34% (n = 52) of admissions. Twenty-three admissions were complicated by seizures, including eight manifesting as status epilepticus (seven nonconvulsive and one convulsive). Asymmetry and focal slowing on EEG were associated with seizures. Moderate background slowing or worse was noted in 75% of EEGs. Among those patients monitored on EEG, 4 (8%) died, 3 (6%) experienced a worsening of their Pediatric Cerebral Performance Category (PCPC) score as compared to admission, and 44 (86%) had no change (or improvement) in their PCPC score during admission. CONCLUSIONS: This study shows a high incidence of clinical and subclinical seizures during metabolic crisis in patients with inborn errors of metabolism. EEG background features were associated with risk of seizures as well as discharge outcomes. This is the largest study to date to investigate EEG features and risk of seizures in patients with neurometabolic disorders admitted to the PICU. These data may be used to inform neuromonitoring protocols to improve mortality and morbidity in inborn errors of metabolism.

8.
Mol Genet Metab ; 140(3): 107696, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37690181

RESUMO

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.


Assuntos
Diabetes Mellitus , Hiperamonemia , Transplante de Fígado , Fenilcetonúrias , Distúrbios Congênitos do Ciclo da Ureia , Criança , Humanos , Adulto , Qualidade de Vida , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Hiperamonemia/diagnóstico , Fenilcetonúrias/complicações , Estudos Multicêntricos como Assunto
9.
Mol Genet Metab ; 140(3): 107699, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37717413

RESUMO

Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.


Assuntos
Fenilbutiratos , Distúrbios Congênitos do Ciclo da Ureia , Criança , Humanos , Estudos Retrospectivos
10.
Mol Genet Metab ; 138(4): 107558, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37004302

RESUMO

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3 min after the formulation was prepared and remaining palatable when taken within 5 min.


Assuntos
Hiperamonemia , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Fenilbutiratos , Paladar , Pós/uso terapêutico , Hiperamonemia/tratamento farmacológico , Nitrogênio , Doenças Raras/tratamento farmacológico , Ureia
11.
Arch Biochem Biophys ; 736: 109526, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36702451

RESUMO

Urea cycle disorders (UCD) are inborn errors of metabolism that occur due to a loss of function in enzymes and transporters involved in the urea cycle, causing an intoxication by hyperammonemia and accumulation of metabolites. Patients can develop hepatic encephalopathy (HE), severe neurological and motor disabilities, and often death. The mechanisms involved in the pathophysiology of UCD are many and complex, but there are strong indications that oxidative stress and inflammation are present, being responsible for at least part of the cellular damage that occurs in these diseases. The aim of this study was to evaluate oxidative and nitrosative damage and inflammation in UCD, to better understand the pathophysiology mechanisms of these diseases. We evaluated the nitrite and nitrate content, thiobarbituric acid-reactive substances (TBARS), carbonyl protein content and a panel of cytokines in plasma sample of 14 patients. The UCD patients group consisted of individuals affected with ornithine transcarbamylase deficiency (n = 8), carbamoyl phosphate synthetase deficiency (n = 2), argininosuccinate synthetase deficiency (n = 2); arginase 1 deficiency (n = 1) and argininosuccinate lyase deficiency (n = 1). Patients mean age at diagnosis was 5.25 ± 9.86 years-old and mean concentrations were compared with healthy individuals of matched age and gender. We found a significant reduction in nitrogen reactive species in patients when compared to controls. TBARS was increased in patients, indicating lipid peroxidation. To evaluate protein oxidative damage in UCD, the carbonyl content was measured, and the results also demonstrated an increase in this biomarker. Finally, we found that UCD patients have enhanced concentrations of cytokines, with pro-inflammatory interleukins IL-6, IL-8, interferon-γ and TNF-α, and anti-inflammatory IL-10 being increased when compared to the control group. In conclusion, our results demonstrate that oxidative stress and inflammation occurs in UCD and probably contribute to the severe brain damage present in patients.


Assuntos
Distúrbios Congênitos do Ciclo da Ureia , Adolescente , Criança , Pré-Escolar , Humanos , Citocinas/metabolismo , Inflamação , Estresse Oxidativo , Substâncias Reativas com Ácido Tiobarbitúrico , Ureia , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Recém-Nascido , Lactente
12.
Am J Med Genet A ; 191(6): 1492-1501, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36883293

RESUMO

Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 µM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.


Assuntos
Doenças Mitocondriais , ATPases Mitocondriais Próton-Translocadoras , Triagem Neonatal , Humanos , Recém-Nascido , ATPases Mitocondriais Próton-Translocadoras/genética , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Citrulina/sangue , Linhagem , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico
13.
J Inherit Metab Dis ; 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38069502

RESUMO

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

14.
J Inherit Metab Dis ; 46(6): 1007-1016, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37702610

RESUMO

The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long-term follow-up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease-immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long-term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.


Assuntos
Doenças Metabólicas , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Distúrbios Congênitos do Ciclo da Ureia/terapia , Doenças Raras , Sistema de Registros , Fenótipo
15.
J Inherit Metab Dis ; 46(5): 906-915, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37395264

RESUMO

Organic acidurias (OAs), urea-cycle disorders (UCDs), and maple syrup urine disease (MSUD) belong to the category of intoxication-type inborn errors of metabolism (IT-IEM). Liver transplantation (LTx) is increasingly utilized in IT-IEM. However, its impact has been mainly focused on clinical outcome measures and rarely on health-related quality of life (HRQoL). Aim of the study was to investigate the impact of LTx on HrQoL in IT-IEMs. This single center prospective study involved 32 patients (15 OA, 11 UCD, 6 MSUD; median age at LTx 3.0 years, range 0.8-26.0). HRQoL was assessed pre/post transplantation by PedsQL-General Module 4.0 and by MetabQoL 1.0, a specifically designed tool for IT-IEM. PedsQL highlighted significant post-LTx improvements in total and physical functioning in both patients' and parents' scores. According to age at transplantation (≤3 vs. >3 years), younger patients showed higher post-LTx scores on Physical (p = 0.03), Social (p < 0.001), and Total (p =0.007) functioning. MetabQoL confirmed significant post-LTx changes in Total and Physical functioning in both patients and parents scores (p ≤ 0.009). Differently from PedsQL, MetabQoL Mental (patients p = 0.013, parents p = 0.03) and Social scores (patients p = 0.02, parents p = 0.012) were significantly higher post-LTx. Significant improvements (p = 0.001-0.04) were also detected both in self- and proxy-reports for almost all MetabQoL subscales. This study shows the importance of assessing the impact of transplantation on HrQoL, a meaningful outcome reflecting patients' wellbeing. LTx is associated with significant improvements of HrQol in both self- and parent-reports. The comparison between PedsQL-GM and MetabQoL highlighted that MetabQoL demonstrated higher sensitivity in the assessment of disease-specific domains than the generic PedsQL tool.


Assuntos
Transplante de Fígado , Doença da Urina de Xarope de Bordo , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Qualidade de Vida , Estudos Prospectivos , Doença da Urina de Xarope de Bordo/cirurgia , Pais
16.
Mol Genet Metab ; 135(4): 327-332, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35279366

RESUMO

Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency. Herein, we report ten subjects with positive NBS for a mild elevation of citrulline (<100 µmol/L), in whom molecular investigations revealed carriers status for argininosuccinate synthase deficiency, a milder form of argininosuccinate lyase deficiency and two other diseases, lysinuric protein intolerance and dihydrolipoamide dehydrogenase deficiency, not primarily affecting the urea cycle. To guide the diagnostic process, we have designed an algorithm for mild citrulline elevation (<100 µmol/L) at NBS, which expands the list of disorders to be included in the differential diagnosis.


Assuntos
Citrulina , Distúrbios Congênitos do Ciclo da Ureia , Citrulinemia , Humanos , Recém-Nascido , Triagem Neonatal , Ureia , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/genética
17.
Mol Genet Metab ; 137(1-2): 153-163, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36049366

RESUMO

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.


Assuntos
Hiperargininemia , Deficiência Intelectual , Recém-Nascido , Humanos , Pré-Escolar , Arginase/genética , Hiperargininemia/diagnóstico , Hiperargininemia/epidemiologia , Hiperargininemia/genética , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/etiologia , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/genética , Arginina/uso terapêutico , Aminoácidos Essenciais , Progressão da Doença , Nitrogênio
18.
Mol Genet Metab ; 135(4): 320-326, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35221207

RESUMO

OBJECTIVES: Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. PATIENTS AND METHODS: We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. RESULTS: Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. CONCLUSION: Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.


Assuntos
Acidose , Doenças Metabólicas , Síndrome de Reye , Amônia , Criança , Pré-Escolar , Humanos , Estudos Retrospectivos , Síndrome de Reye/metabolismo
19.
Mol Genet Metab ; 137(4): 436-444, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34183250

RESUMO

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.


Assuntos
Erros Inatos do Metabolismo , Degeneração Retiniana , Paraplegia Espástica Hereditária , Criança , Humanos , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo , Fenótipo , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Proteínas/genética
20.
Cell Mol Neurobiol ; 42(8): 2593-2610, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34665389

RESUMO

Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.


Assuntos
Hiperamonemia , Doenças Metabólicas , Amônia/metabolismo , Ácidos Graxos , Humanos , Hiperamonemia/complicações , Hiperamonemia/diagnóstico , Recém-Nascido , Ureia/metabolismo
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