RESUMEN
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.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo/genética , Metilmalonil-CoA Mutasa/deficiencia , Proteínas de Transporte de Membrana Mitocondrial/genética , Vitamina B 12/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Niño , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/etiología , Masculino , Ácido Metilmalónico/sangre , Ácido Metilmalónico/orina , Metilmalonil-CoA Mutasa/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , MutaciónRESUMEN
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.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Trasplante de Riñón , Trasplante de Hígado , Enfermedad de la Orina de Jarabe de Arce/terapia , Acidemia Propiónica/terapia , Trastornos Innatos del Ciclo de la Urea/terapia , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Masculino , Enfermedad de la Orina de Jarabe de Arce/mortalidad , Acidemia Propiónica/mortalidad , Tasa de Supervivencia , Trastornos Innatos del Ciclo de la Urea/mortalidad , Adulto JovenRESUMEN
BACKGROUND: Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data. STUDY DESIGN/METHODS: We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected. RESULTS: The median age of transplantation for subjects with MMA was 7.2â¯years with a median follow up of 4.3â¯years. The median age of transplantation for subjects with PA was 1.9â¯years with a median follow up of 5.4â¯years. The survival rate at 1â¯year and 5â¯years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT. CONCLUSION: In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Trasplante de Hígado , Acidemia Propiónica/terapia , Adolescente , Alelos , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Biomarcadores , Niño , Preescolar , Estudios de Seguimiento , Genotipo , Hospitalización , Humanos , Lactante , Recién Nacido , Pruebas de Función Hepática , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Imagen por Resonancia Magnética , Mutación , Fenotipo , Pronóstico , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/genética , Acidemia Propiónica/mortalidad , Estudios RetrospectivosRESUMEN
BACKGROUND: Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016. RESULTS: During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07). CONCLUSION: MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Trasplante de Hígado/normas , Acidemia Propiónica/fisiopatología , Acidemia Propiónica/terapia , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Cuidadores/psicología , Cuidadores/estadística & datos numéricos , Nutrición Enteral/estadística & datos numéricos , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Recién Nacido , Trasplante de Hígado/mortalidad , Masculino , Mutación , Tamizaje Neonatal , Acidemia Propiónica/genética , Acidemia Propiónica/mortalidad , Taiwán , Resultado del TratamientoRESUMEN
Fatty acid ß-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: ⢠Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders. ⢠Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: ⢠Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening. ⢠Sudden deaths were not avoided by starting treatment precociously.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Tamizaje Neonatal/métodos , Acil-CoA Deshidrogenasa/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Cardiomiopatías/mortalidad , Carnitina/deficiencia , Carnitina O-Palmitoiltransferasa/deficiencia , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Humanos , Hiperamonemia/complicaciones , Hiperamonemia/diagnóstico , Hiperamonemia/mortalidad , Hipoglucemia/complicaciones , Hipoglucemia/diagnóstico , Hipoglucemia/mortalidad , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/mortalidad , Masculino , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/mortalidad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/mortalidad , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/complicaciones , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/diagnóstico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/mortalidad , Enfermedades Musculares/complicaciones , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/mortalidad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
AIM: Newborns with inborn errors of metabolism can present with hyperammonaemic coma. In this study, we evaluated the effect of peritoneal dialysis on plasma ammonium levels and on the short-term outcome in neonatal patients with urea cycle defects and organic acidaemia. METHODS: Data from infants with hyperammonaemia due to urea cycle defects or organic acidaemia treated with dialysis were collected and retrospectively analyzed. The results of patient groups (group I, survived; and group II, died) were compared. RESULTS: Fourteen neonates were enrolled in this study. In group I, plasma ammonium levels before dialysis were median (IQR) 1652 µg/dL (1165-2098 µg/dL); in group II, they were 1289 µg/dL (1070-5550 µg/dL). There was no statistically significant difference. Urea cycle defects were diagnosed in eight, and organic acidaemia in six patients. The duration of a blood ammonia level >200 µg/dL was longer in group II (P = 0.04). A <60.8% decline in the ammonia level from the beginning of dialysis to the 12th hour of dialysis carried a 3.33-fold higher risk of mortality, when compared with a greater decline. Five patients with urea cycle defects, and one with organic acidaemia, died. The mortality risk was 8.33-fold (95% CI = 0.63-90.86) higher for patients with urea cycle defects than for those with organic acidaemia. CONCLUSION: In patients with hyperammonaemia treated with peritoneal dialysis, the rate of ammonia removal and the underlying aetiology appear to be important prognostic factors. Neonates with organic acidaemia who are admitted to centres without continuous renal replacement therapy facilities can be effectively treated with peritoneal dialysis.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Amoníaco/sangre , Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Femenino , Humanos , Hiperamonemia/sangre , Hiperamonemia/diagnóstico , Hiperamonemia/etiología , Hiperamonemia/terapia , Recién Nacido , Masculino , Mortalidad , Diálisis Peritoneal , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Turquía/epidemiología , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/mortalidadAsunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación/genética , Adolescente , Femenino , Ataxia de la Marcha/etiología , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Severe urea cycle defects (UCD), organic acidemias (OA) and maple syrup urine disease (MSUD) are life-threatening disorders presenting in the first days of life. Renal replacement therapy (RRT) is an emergency option in affected newborns, mostly performed as ultima ratio. We report our 10-year experience using emergency RRT in newborns with UCD, OA and MSUD. Twelve newborns (eight with UCD, two with methylmalonic acidemia and two with MSUD) underwent emergency RRT. The overall survival rate to RRT was 58.3%. Hyperammonemic newborns required earlier RRT with respect to MSUD patients (75 (65-102) vs 301 (192-410) h of life, P < 0.01). Hyperammonemic neonates surviving (n = 5) and non-surviving (n = 5) the acute neonatal decompensation showed similar birth weight (P = 0.690), duration of intubation (P = 0.917), ammonia at onset (P = 0.916) and at the start of RRT (P = 0.426), age at RRT (P = 0.999) and duration of coma before RRT (P = 0.691). Remarkably, all survivors quickly responded to RRT, with ammonia concentration less than 300 µmol/L after 8 h of treatment. One patient with UCD successfully treated by neonatal RRT died at 4 months of life because of sepsis. All patients with MSUD had normalized leucine levels after 12 h of RRT, surviving the acute neonatal decompenstation. All long-term survivors (five liver transplanted, one waiting for liver transplantation) currently show normal or near-normal neurological development (48 ± 39 months of age). Early response to RRT was associated with survival irrespective of pre-treatment picture. RRT can be considered even in huge neonatal metabolic decompensations. Early liver transplantation may be an option for select patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Enfermedad de la Orina de Jarabe de Arce/terapia , Terapia de Reemplazo Renal/métodos , Trastornos Innatos del Ciclo de la Urea/terapia , Factores de Edad , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Desarrollo Infantil , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Trasplante de Hígado , Masculino , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/mortalidad , Enfermedad de la Orina de Jarabe de Arce/fisiopatología , Recuperación de la Función , Terapia de Reemplazo Renal/efectos adversos , Terapia de Reemplazo Renal/mortalidad , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/mortalidad , Trastornos Innatos del Ciclo de la Urea/fisiopatologíaRESUMEN
Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/orina , Encefalopatías Metabólicas/metabolismo , Encefalopatías Metabólicas/orina , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/metabolismo , Glutaril-CoA Deshidrogenasa/orina , Humanos , Recién Nacido , Ácido Metilmalónico/metabolismo , Tamizaje Neonatal , Valor Predictivo de las Pruebas , Propionatos/metabolismo , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. METHODS: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. RESULTS: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. CONCLUSIONS: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.
Asunto(s)
4-Aminobutirato Transaminasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Flumazenil/uso terapéutico , Estudios de Seguimiento , Moduladores del GABA/uso terapéutico , Humanos , Lactante , Masculino , FenotipoRESUMEN
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Descarboxilasas de Aminoácido-L-Aromático/genética , Terapia Genética , Neuronas/metabolismo , Neurotransmisores/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico por imagen , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Conducta Animal , Presión Sanguínea/genética , Encéfalo/metabolismo , Dependovirus/genética , Modelos Animales de Enfermedad , Dopamina/metabolismo , Activación Enzimática , Fluorodesoxiglucosa F18 , Expresión Génica , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Frecuencia Cardíaca , Inmunohistoquímica , Ratones , Ratones Transgénicos , Actividad Motora , Especificidad de Órganos/genética , Tomografía de Emisión de Positrones , Transducción Genética , Aumento de Peso/genéticaRESUMEN
Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/economía , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Dieta con Restricción de Proteínas/economía , Trasplante de Hígado/economía , Apoyo Nutricional/economía , Acidemia Propiónica/economía , Acidemia Propiónica/terapia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Análisis Costo-Beneficio , Árboles de Decisión , Dieta con Restricción de Proteínas/efectos adversos , Costos de la Atención en Salud , Humanos , Recién Nacido , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Cadenas de Markov , Modelos Económicos , Apoyo Nutricional/efectos adversos , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/mortalidad , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Factores de Riesgo , Sobrevivientes , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: (i) To determine whether clinical features and biochemical parameters help to predict survival of methylmalonic acidemia with homocystinuria; (ii) To find the cutoff values of biochemical parameters for predicting survival of methylmalonic acidemia with homocystinuria. DESIGN: A prospective cohort study. SETTING: A pediatric tertiary hospital in Beijing; all patients were followed until death or June 2013. SUBJECTS: 45 pediatric patients diagnosed with methylmalonic acidemia with homocystinuria between 2006 and 2012. OUTCOME MEASURES: The data of clinical characteristics and pretreatment biochemical parameters were collected. The Cox regression analysis was performed to identify independent risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The best cutoff values for these independent factors were determined by the receiver characteristic curve. RESULTS: Newborn onset (OR=6.856, 95%CI=2.241-20.976, P=0.001), high level of methylmalonic acid in urine (OR=1.022, 95%CI=1.011-1.033, P<0.001), and high level of urea in serum (OR=1.083, 95%CI=1.027-1.141, P=0.003) were independent negative risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The cutoff values of maximum predictive accuracy of methylmalonic acid in urine and urea in serum were respectively 5.41 mmol/mmol creatinine and 7.80 mmol/L by receiver operating characteristic curve analysis. CONCLUSIONS: The patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/epidemiología , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Homocistinuria/complicaciones , Homocistinuria/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Beijing/epidemiología , Femenino , Homocistinuria/diagnóstico , Homocistinuria/epidemiología , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Lysinuric protein intolerance (LPI) is a rare multisystemic metabolic disease. The objective of the study was to describe presentation and course of lung involvement in a cohort of ten children. PATIENTS AND METHODS: Retrospective review of patients followed at Necker-Enfants Malades University Hospital between 1980 and 2012 for a LPI. In patients with lung involvement, clinical data, chest radiographs, pulmonary function tests, bronchoalveolar lavages, and lung biopsies were analyzed. The first and last high-resolution computed tomography (HRCT) were also reviewed. RESULTS: Lung involvement was observed in ten of 14 patients (71 %). Five patients had an acute onset of respiratory symptoms, three had a progressive onset and two were free of symptoms. During the period studied, six patients (60 %) died, all in a context of respiratory failure. Clinical presentation and course were highly variable, even in the same family. HRCT were performed in seven cases, showing in all cases an interstitial pattern and fibrosis in four. All ten patients had pulmonary alveolar proteinosis (PAP) confirmed by histopathological analysis. Five patients had pulmonary fibrosis (at biopsy and/or HRCT scan). Two patients underwent whole lung lavages, without efficiency. CONCLUSION: PAP is a constant feature in children with LPI and lung involvement. Pulmonary fibrosis is frequent and these two pathologies may develop independently. This study shows the heterogeneity of presentation and outcome. Lung injury could be secondary to impaired phagocytic function and abnormal inflammatory and immune responses intrinsic to the SLC7A7 mutant phenotype. HRCT is recommended to detect lung involvement.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Enfermedades Autoinmunes/etiología , Pulmón , Proteinosis Alveolar Pulmonar/etiología , Fibrosis Pulmonar/etiología , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Sistema de Transporte de Aminoácidos y+L , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/fisiopatología , Enfermedades Autoinmunes/terapia , Biopsia , Lavado Broncoalveolar , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Cadenas Ligeras de la Proteína-1 Reguladora de Fusión/genética , Predisposición Genética a la Enfermedad , Hospitales Pediátricos , Hospitales Universitarios , Humanos , Lactante , Recién Nacido , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/fisiopatología , Masculino , Mutación , Paris , Valor Predictivo de las Pruebas , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/mortalidad , Proteinosis Alveolar Pulmonar/fisiopatología , Proteinosis Alveolar Pulmonar/terapia , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/mortalidad , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/terapia , Pruebas de Función Respiratoria , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Estudios Retrospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Organic acidemias (OAs) are rare inborn errors of metabolism. The clinical presentations of methylmalonic acidemia (MMA) and propionic acidemia (PA) in Japan have not yet been examined in detail. We aimed to investigate the clinical presentations of OAs in Japan and evaluate current therapies for improving long-term outcomes, especially in MMA and PA cases. Questionnaires were sent to 928 institutions in 2009 inquiring about OAs, and secondary questionnaires were sent to those who confirmed that they had diagnosed and/or treated such cases; 119 cases were eventually included for analysis. In Japan, the majority of OAs was MMA, which was associated with a high mortality rate. The survival rates at 20 years of age in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA and PA patients were 69.8%, 94.4% and 95.8%, respectively. Factors associated with mortality in MMA were failure to thrive, hypoglycemia and pancreatitis. Factors associated with mental retardation in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA, and PA were seizure and liver dysfunction, seizure and failure to thrive, and failure to thrive, respectively. We advocated that avoiding failure to thrive due to too restricted protein diet, hypoglycemia and pancreatitis associated with mortality lead to improve outcome, especially in vitamin B12-unresponsive MMA patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Acidemia Propiónica/tratamiento farmacológico , Vitamina B 12/uso terapéutico , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Acidemia Propiónica/mortalidad , Tasa de Supervivencia , Adulto JovenRESUMEN
We demonstrate that human methylmalonyl-CoA mutase (MUT), delivered using an AAV serotype 8 vector, rescues the lethal phenotype displayed by mice with MMA and provides long-term phenotypic correction. In addition to defining a lower limit of effective dosing, our studies establish that neither a species barrier to mitochondrial processing nor an apparent immune response to MUT limits the murine model as an experimental platform to test the efficacy of human gene therapy vectors for MMA.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Dependovirus/genética , Terapia Genética , Metilmalonil-CoA Mutasa/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/patología , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Vectores Genéticos , Humanos , Metilmalonil-CoA Mutasa/metabolismo , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Fenotipo , Alineación de Secuencia , Tasa de SupervivenciaRESUMEN
BACKGROUND: In glutaric aciduria type 1 (GA1), dietary treatment with emergency management (EM) is essential to prevent encephalopathic crisis (EC). In the present study, dietary practices were examined in a single UK centre without access to newborn screening. METHODS: Twenty GA1 patients (11 males, median age: 10.2 years, range 2.2-24.1 years) were evaluated. Nine presented without EC (median diagnosis age: 1.1 years, range 4 days to 8 years) and 11 with EC (median diagnosis age 10 months, range 6 months to 1.7 years). Dietary treatment, neurological outcome, anthropometry and biochemical/haematological markers were assessed. RESULTS: Diet treatment varied according to age of diagnosis and symptom severity. Four of six pre-encephalopathic children diagnosed before 2 years of age were treated with carnitine, protein restriction (medium l.2 g kg day(-1)) and lysine-free/low tryptophan protein substitute (PS) (medium dose: 1.6 g kg day(-1)). EM consisted of natural protein cessation and glucose polymer with PS delivered via an enteral feeding tube. Older children (>3 years) without EC were given carnitine and protein restriction, and seven of nine EC patients had PS via an enteral feeding tube. Clinical deterioration occurred in two patients without EC; one taking PS and protein restriction (with a second untreatable pathology) and one after protein restriction only. In patients presenting with EC, four died and one had some improvement in movement, with the rest remaining stable but with severe disability. Patients taking PS had better nutritional markers [serum vitamin B(12) (P < 0.001), albumin (P < 0.001), haemoglobin (P < 0.001) and essential plasma amino acids]. CONCLUSIONS: Early diagnosis of GA1 before EC is essential because PS and protein restriction with meticulous EM prevents EC. PS also improves nutritional status irrespective of clinical condition.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Encefalopatías Metabólicas/dietoterapia , Dieta con Restricción de Proteínas , Proteínas en la Dieta , Lisina/administración & dosificación , Pautas de la Práctica en Medicina , Triptófano/administración & dosificación , Adolescente , Adulto , Factores de Edad , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Biomarcadores/sangre , Encefalopatías/etiología , Encefalopatías/prevención & control , Encefalopatías Metabólicas/complicaciones , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/mortalidad , Encefalopatías Metabólicas/terapia , Carnitina/uso terapéutico , Niño , Preescolar , Proteínas en la Dieta/efectos adversos , Proteínas en la Dieta/uso terapéutico , Dietética/métodos , Personas con Discapacidad , Diagnóstico Precoz , Nutrición Enteral , Femenino , Glucosa/uso terapéutico , Glutaril-CoA Deshidrogenasa/deficiencia , Humanos , Lisina/efectos adversos , Masculino , Índice de Severidad de la Enfermedad , Triptófano/efectos adversos , Reino Unido/epidemiología , Adulto JovenRESUMEN
Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of methylmalonyl-CoA mutase (MCM). MMA is associated with significant morbidity and mortality, thus therapies are necessary to help improve quality of life and prevent renal and neurological complications. Transgenic mice carrying an intact human MCM locus have been produced. Four separate transgenic lines were established and characterised as carrying two, four, five or six copies of the transgene in a single integration site. Transgenic mice from the 2-copy line were crossed with heterozygous knockout MCM mice to generate mice hemizygous for the human transgene on a homozygous knockout background. Partial rescue of the uniform neonatal lethality seen in homozygous knockout mice was observed. These rescued mice were significantly smaller than control littermates (mice with mouse MCM gene). Biochemically, these partial rescue mice exhibited elevated methylmalonic acid levels in urine, plasma, kidney, liver and brain tissue. Acylcarnitine analysis of blood spots revealed elevated propionylcarnitine levels. Analysis of mRNA expression confirms the human transgene is expressed at higher levels than observed for the wild type, with highest expression in the kidney followed closely by brain and liver. Partial rescue mouse fibroblast cultures had only 20% of the wild type MCM enzyme activity. It is anticipated that this humanised partial rescue mouse model of MMA will enable evaluation of long-term pathophysiological effects of elevated methylmalonic acid levels and be a valuable model for the investigation of therapeutic strategies, such as cell transplantation.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Modelos Animales de Enfermedad , Ratones , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Animales , Dosificación de Gen , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Orden Génico , Vectores Genéticos/genética , Genotipo , Humanos , Metaboloma , Metilmalonil-CoA Mutasa/genética , Metilmalonil-CoA Mutasa/metabolismo , Ratones Noqueados , Ratones Transgénicos , TransgenesRESUMEN
BACKGROUND: Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation. METHODS: Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality. RESULTS: 57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days. CONCLUSIONS: Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.