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OBJECTIVE: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU). STUDY DESIGN: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed. RESULTS: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile. CONCLUSIONS: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737.
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Trastorno por Déficit de Atención con Hiperactividad , Fenilcetonurias , Adolescente , Humanos , Niño , Lactante , Fenilcetonurias/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Función Ejecutiva , Cognición , Método Doble Ciego , Fenilalanina , Resultado del TratamientoRESUMEN
INTRODUCTION: Whole exome sequencing (WES) has increasingly become integrated into prenatal care and genetic testing pathways. Current studies of prenatal WES have focused on diagnostic yield. The possibility of obtaining a variant of uncertain significance and lack of provider expertise are frequently described as common barriers to clinical integration of prenatal WES. We describe the implementation and workflow for a multidisciplinary approach to effectively integrate prenatal WES into maternal-fetal care to overcome these barriers. METHODS: A multidisciplinary team reviews and approves potential cases for WES. This team reviews WES results, reclassifying variants as appropriate and provides recommendations for postnatal care. A detailed description of this workflow is provided, and a case example is included to demonstrate effectiveness of this approach. Our team has approved 62 cases for WES with 45 patients ultimately pursuing WES. We have achieved a diagnostic yield of 40% and the multidisciplinary team has played a role in variant interpretation in 50% of the reported variants of uncertain significance. CONCLUSIONS: This approach facilitates communication between prenatal and postnatal care teams and provides accurate interpretation and recommendations for identified fetal variants. This model can be replicated to ensure appropriate patient care and effective integration of novel genomic technologies into prenatal settings.
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Feto , Atención Prenatal , Embarazo , Femenino , Humanos , Secuenciación del Exoma , Flujo de Trabajo , Pruebas GenéticasRESUMEN
PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Adolescente , Adulto , Compuestos de Bencidrilo , Niño , Preescolar , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Lactante , Recién Nacido , Neutropenia/tratamiento farmacológico , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.
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Metionina , Vitamina B 12 , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/deficiencia , Adulto , Errores Innatos del Metabolismo de los Aminoácidos , Diagnóstico Precoz , Homocisteína , Humanos , Errores Innatos del Metabolismo , Vitamina B 12/metabolismoRESUMEN
During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.
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Insuficiencia Suprarrenal/genética , ADN Polimerasa II/genética , Retardo del Crecimiento Fetal/genética , Mutación/genética , Osteocondrodisplasias/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Anomalías Urogenitales/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Replicación del ADN/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was -0.5768 with a lower limit of the 95% confidence interval (CI) of -1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of -3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120-360 µmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.
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Biopterinas/análogos & derivados , Fenilalanina/sangre , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/fisiopatología , Biopterinas/administración & dosificación , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Personas con Discapacidades Mentales/rehabilitación , Fenilalanina/genética , Fenilcetonurias/sangreRESUMEN
One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.
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Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/terapia , Metabolismo , Administración Intravenosa , Niño , Dieta Cetogénica , Glucosa/administración & dosificación , Humanos , Lípidos/administración & dosificación , Estado Nutricional , Vitaminas/administración & dosificaciónRESUMEN
BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
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Glicerol/análogos & derivados , Hiperamonemia/tratamiento farmacológico , Fenilbutiratos/administración & dosificación , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Edad de Inicio , Amoníaco/sangre , Preescolar , Femenino , Glicerol/administración & dosificación , Humanos , Hiperamonemia/sangre , Hiperamonemia/patología , Lactante , Recién Nacido , Masculino , Pediatría , Fenilacetatos/administración & dosificación , Diálisis Renal , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/patologíaRESUMEN
BACKGROUND: There is a relative lack of information on the incidence and treatment of vision problems in Prader-Willi syndrome (PWS). Using data from the Global PWS Registry, we performed a cross-sectional study of vision problems in PWS. METHODS: Data, reported by caregivers who completed the Vision Survey in the Global PWS Registry between May of 2015 and March of 2020, were analyzed using descriptive statistics. RESULTS: There were 908 participants in this survey, with a mean age of 14.5 years (range 0-62 years). The prevalence of strabismus in this population was 40 %, with no statistically significant difference in prevalence by genetic subtype. Ninety-one percent of participants with strabismus were diagnosed before 5 years of age. Of those with strabismus, 42 % went on to have strabismus surgery, with 86 % of those having their first strabismus surgery before 5 years of age and 10.1 % having more than one strabismus surgery. Additional vision issues reported included myopia (41 %), hyperopia (25 %), astigmatism (25 %), and amblyopia (16 %). CONCLUSIONS: The prevalence of strabismus, amblyopia, and hyperopia are considerably higher in the PWS population represented in the Global PWS Registry as compared to the general population. People with PWS should be screened early and regularly for vision problems.
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Síndrome de Prader-Willi , Estrabismo , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Humanos , Incidencia , Lactante , Recién Nacido , Persona de Mediana Edad , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/epidemiología , Sistema de Registros , Estrabismo/epidemiología , Estrabismo/etiología , Estrabismo/cirugía , Adulto JovenRESUMEN
The National Institutes of Health (NIH) established the Rare Diseases Clinical Research Network to address the unique challenges of performing research on rare diseases. The Urea Cycle Disorders Consortium (UCDC) was one of the original ten consortia established. The UCDC represents a unique partnership among clinicians, patients, and the NIH with a primary goal of increasing the development of therapeutics that improve patient outcomes for persons affected with a UCD. Based in part on financial incentives associated with the Orphan Drug Act biopharmaceutical and investment entities have an intense interest in engaging with research consortia like the UCDC, which have compiled potentially valuable longitudinal data characterizing outcomes in a relatively large number of affected individuals. We describe the UCDC experience and the bases for evaluating partnerships with such private entities. We review early industry interactions, the development of policies and procedures, and describe the establishment of an Industry Relations Committee, including guiding principles. Challenges encountered, particularly in the transition when products are approved, and potential solutions are discussed. By building a framework for industry partnerships that guides us in resolving inevitable challenges, we can enthusiastically pursue novel and promising collaborations that can lead to breakthroughs in therapeutic interventions for patients.
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Producción de Medicamentos sin Interés Comercial/legislación & jurisprudencia , Enfermedades Raras/tratamiento farmacológico , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Industria Farmacéutica , Humanos , National Institutes of Health (U.S.) , Asociación entre el Sector Público-Privado , Estados UnidosRESUMEN
PURPOSE: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces. METHODS: We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images. RESULTS: Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative. CONCLUSION: Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.
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Cara , Imagenología Tridimensional , Cara/diagnóstico por imagen , Humanos , SíndromeRESUMEN
OBJECTIVE: Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs. METHODS: This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years. RESULTS: The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms. INTERPRETATION: Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019.
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Cognición/fisiología , Pruebas de Estado Mental y Demencia , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Femenino , Estudios de Seguimiento , Glicerol/análogos & derivados , Glicerol/farmacología , Glicerol/uso terapéutico , Humanos , Lactante , Recién Nacido , Trasplante de Hígado/métodos , Masculino , Tamizaje Neonatal/métodos , Fenilbutiratos/farmacología , Fenilbutiratos/uso terapéutico , Estudios Prospectivos , Trastornos Innatos del Ciclo de la Urea/psicología , Adulto JovenRESUMEN
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.
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Trastornos del Crecimiento/genética , Fenotipo , Complejo Represivo Polycomb 2/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Mutación , Proteínas de Neoplasias , Factores de TranscripciónRESUMEN
INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12â¯months exposure. Here, we present long-term experience with GPB. METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS: A total of 45 pediatric patients between the ages of 1 to 17â¯years (median 7â¯years) and 43 adult patients between the ages of 19 and 61 years (median 30â¯years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35⯵mol/L) through 24â¯months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.
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Glicerol/análogos & derivados , Fenilbutiratos/uso terapéutico , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Adolescente , Adulto , Canadá , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Glicerol/efectos adversos , Glicerol/uso terapéutico , Humanos , Hiperamonemia/inducido químicamente , Lactante , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenilbutiratos/efectos adversos , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.
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Trastornos Innatos del Ciclo de la Urea/diagnóstico , Estudios de Cohortes , Análisis de Datos , Diagnóstico Tardío , Europa (Continente) , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , América del Norte , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/metabolismo , Enfermedades Raras , Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/metabolismoRESUMEN
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2â¯months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN). Pharmacokinetics (PK) of GPB were examined to see if hydrolysis is impaired in very young patients who may lack lipase activity. METHODS: Patients 2â¯months to <2â¯years of age with UCDs from two open label studies (nâ¯=â¯17, median age 10â¯months) predominantly on stable doses of nitrogen scavengers (nâ¯=â¯14) were switched to GPB. Primary assessments included traditional plasma PK analyses of PBA, PAA, and PAGN, using noncompartmental methods with WinNonlin™. UPAGN was collected periodically throughout the study up to 12â¯months. RESULTS: PBA, PAA and PAGN rapidly appeared in plasma after GPB dosing, demonstrating evidence of GPB cleavage with subsequent PBA absorption. Median concentrations of PBA, PAA and PAGN did not increase over time and were similar to or lower than the values observed in older UCD patients. The median PAA/PAGN ratio was well below one over time, demonstrating that conjugation of PAA with glutamine to form PAGN did not reach saturation. Covariate analyses indicated that age did not influence the PK parameters, with body surface area (BSA) being the most significant covariate, reinforcing current BSA based dosing recommendations as seen in older patients. CONCLUSION: These observations demonstrate that UCD patients aged 2â¯months to <2â¯years have sufficient lipase activity to adequately convert the pre-prodrug GPB to PBA. PBA is then converted to its active moiety (PAA) providing successful nitrogen scavenging even in very young children.
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Glicerol/análogos & derivados , Lipasa/sangre , Fenilbutiratos/administración & dosificación , Profármacos/administración & dosificación , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Niño , Preescolar , Femenino , Glutamina/sangre , Glicerol/administración & dosificación , Glicerol/sangre , Glicerol/farmacocinética , Humanos , Lactante , Masculino , Nitrógeno/sangre , Nitrógeno/metabolismo , Fenilacetatos/sangre , Fenilbutiratos/sangre , Fenilbutiratos/farmacocinética , Profármacos/farmacocinética , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/patologíaRESUMEN
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.
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Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Intolerancia a la Fructosa/inducido químicamente , Fructosa-Bifosfato Aldolasa/genética , Fórmulas Infantiles/efectos adversos , Mutación , Femenino , Intolerancia a la Fructosa/complicaciones , Fructosa-Bifosfato Aldolasa/deficiencia , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , PronósticoRESUMEN
Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder. We sought to evaluate the diagnostic sensitivity and variability of the various PDC enzyme assays in females and males at the Center for Inherited Disorders of Energy Metabolism (CIDEM). CIDEM data were filtered by lactic acidosis and functional PDC deficiency in at least one cell/tissue type (blood lymphocytes, cultured fibroblasts or skeletal muscle) identifying 186 subjects (51% male and 49% female), about half were genetically resolved with 78% of those determined to have a pathogenic PDHA1 mutation. Assaying PDC in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1, was highly sensitive irrespective of gender; 97% (95% confidence interval [CI]: 90%-100%) and 91% (95% CI: 82%-100%) in females and males, respectively. In contrast to the fibroblast-based testing, the lymphocyte- and muscle-based testing were not sensitive (36% [95% CI: 11%-61%, p=0.0003] and 58% [95% CI: 30%-86%, p=0.014], respectively) for identifying known PDC deficient females with pathogenic PDHA1 mutations. In males with a known PDHA1 mutation, the sensitivity of the various cell/tissue assays (75% lymphocyte, 91% fibroblast and 88% muscle) were not statistically different, and the discordance frequency due to the specific cell/tissue used for assaying PDC was 0.15±0.11. Based on this data, a practical diagnostic algorithm is proposed accounting for current molecular approaches, enzyme testing sensitivity, and variability due to gender, cell/tissue type used for testing, and successive repeat testing.
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Algoritmos , Pruebas de Enzimas/métodos , Fibroblastos/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Complejo Piruvato Deshidrogenasa/genética , Acidosis Láctica/metabolismo , Bioquímica/métodos , Células Cultivadas , Pruebas de Enzimas/instrumentación , Femenino , Humanos , Linfocitos/metabolismo , Masculino , Mutación , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100µmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development. RESULTS: 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule. CONCLUSION: GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.
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Amoníaco/metabolismo , Glutamina/metabolismo , Glicerol/análogos & derivados , Fenilbutiratos/efectos adversos , Fenilbutiratos/uso terapéutico , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Preescolar , Tos , Manejo de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Fiebre , Glutamina/efectos de los fármacos , Glicerol/efectos adversos , Glicerol/sangre , Glicerol/uso terapéutico , Glicerol/toxicidad , Humanos , Lactante , Masculino , Neutropenia , Fenilbutiratos/sangre , Fenilbutiratos/toxicidad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.