RESUMEN
The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine ß-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-ß-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Homocistinuria , Tamizaje Neonatal , Acidemia Propiónica , Humanos , Tamizaje Neonatal/métodos , Homocistinuria/diagnóstico , Recién Nacido , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Acidemia Propiónica/diagnóstico , Femenino , Masculino , Alemania , Lactante , Proyectos Piloto , Preescolar , Vitamina B 12/sangre , Niño , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Espasticidad Muscular , Trastornos PsicóticosRESUMEN
Newborn screening (NBS) is one of the most effective measures of secondary prevention. While the benefit of NBS on the clinical long-term outcomes of children with inherited metabolic diseases (IMD) has been demonstrated, the potential burden of families living with an early diagnosed and treated child with an IMD has not been thoroughly investigated. The aim of this longitudinal questionnaire-based study on 369 families living with a child with an IMD was to investigate the psychosocial and financial burden following a true-positive NBS. The reported psychosocial burden differed between children and their parents, and was associated with the child's age, diagnosis, and treatment. At younger ages, parent-reported burden was higher for the parents than for the individual child, while it increased for children and decreased for parents as the child grew older. Furthermore, psychosocial burden increased if the child required a strict dietary treatment and was at risk of metabolic decompensation. Regardless of diagnosis and treatment, the developmental delay of their child independently increased the parental psychosocial burden. Financial burden was reported by 24% of all families, and was higher in low-income families and in families whose children required dietary treatment. In conclusion, a substantial psychosocial and financial burden was revealed for children and their families after true-positive NBS. Since this burden is likely to have a negative impact on the long-term individual health benefits of NBS, this study underlines the importance of regularly assessing the psychosocial and financial needs of these families.
RESUMEN
Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus. We report on a child with classical homocystinuria presenting with acute episodes of dystonia and symmetrical basal ganglia abnormalities mimicking a mitochondrial disease. After starting treatment with vitamin B6, homocysteine levels rapidly normalized and dystonic episodes did not re-occur. Moreover, brain-imaging findings almost completely disappeared. The case illustrates that homocystinuria should be considered as a treatable differential diagnosis of dystonia.
Asunto(s)
Distonía , Trastornos Distónicos , Homocistinuria , Niño , Humanos , Homocistinuria/complicaciones , Homocistinuria/diagnóstico , Homocistinuria/genética , Distonía/diagnóstico , Distonía/etiología , Cistationina betasintasa , Piridoxina/uso terapéutico , Vitamina B 6/uso terapéutico , HomocisteínaRESUMEN
Newborn screening (NBS) for inherited metabolic diseases (IMDs) substantially shortens a patient's journey. It enables the early start of metabolic treatment which might prevent potentially lethal neonatal disease manifestations, while promoting favorable development and long-term clinical outcomes. This study aims to assess growth in screened individuals with IMDs under different dietary regimes. Anthropometric data (3585 prospective measures) of 350 screened individuals with IMDs born between 1999 and 2018 and participating in a German prospective multicenter observational study were evaluated. Overall, birth measures were within the reference ranges, suggesting unaffected prenatal growth, except for phenylketonuria (weight) and glutaric aciduria Type 1 (head circumference). After birth, longitudinal analysis of anthropometric measures revealed a loss of height standard deviation score (SDS; -0.5 SDS; p < 0.0001), head circumference SDS (-0.2 SDS; p = 0.0028), but not for weight SDS (0.1 SDS; p = 0.5097) until the age of 18 years, while BMI SDS increased (0.4 SDS; p < 0.0001). The significant interaction with age and diet groups was pronounced for the linear growth in individuals receiving diets being low in protein, long-chain triglycerides, and galactose (p < 0.001). Identification by NBS and subsequent early (dietary) treatment cannot completely protect against alterations in growths. Disease-specific (e.g., metabolic impairments, neurotoxins) and dietary-specific (e.g., diets reduced in protein) factors may have an amplified impact on longitudinal growth. Therefore, alongside other important follow-ups, the continuous observation of the anthropometric development of screened individuals with IMDs needs special attention to early identify and support individuals at risk.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Enfermedades Metabólicas , Recién Nacido , Femenino , Embarazo , Humanos , Adolescente , Tamizaje Neonatal , Estudios Prospectivos , Enfermedades Metabólicas/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/diagnósticoRESUMEN
Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened individuals with IVA is needed to guide therapeutic decision, prevent life-threatening neonatal disease manifestation in classic IVA and over-medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 µmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = -0.255; slope = -0.869; p = 0.0870) and was lower for the "attenuated" variants compared to classic genotypes [median (IQR; range): 2.6 µmol/L (2.1-4.0; 0.7-6.4) versus 10.3 µmol/L (7.4-13.1; 4.3-21.7); N = 73]. In-silico prediction scores (M-CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease.
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Errores Innatos del Metabolismo de los Aminoácidos , Niño , Humanos , Recién Nacido , Acetilcarnitina , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Genotipo , Glicina/genética , Tamizaje Neonatal/métodos , Gravedad del PacienteRESUMEN
Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.
Asunto(s)
Errores Innatos del Metabolismo , Acidemia Propiónica , Humanos , Recién Nacido , Tamizaje Neonatal/métodos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/epidemiología , Espectrometría de Masas en Tándem/métodos , Carnitina/metabolismoRESUMEN
Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.
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Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Humanos , Glutaril-CoA Deshidrogenasa , Lisina/metabolismo , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/terapia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Glutaratos/metabolismoRESUMEN
OBJECTIVE: To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B12 deficiency identified by newborn screening (NBS). STUDY DESIGN: Prospective multicenter observational study on health outcomes of 31 infants with vitamin B12 deficiency identified by NBS. Neurodevelopment was assessed by the Denver Developmental Screening Test. RESULTS: In 285â862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B12 deficiency was 26 in 100â000 newborns, with high seasonal variations (lowest in summer: 8 in 100â000). Infants participating in the outcome study (N = 31) were supplemented with vitamin B12 for a median (range) of 5.9 (1.1-16.2) months. All achieved age-appropriate test results in Denver Developmental Screening Test at age 15 (11-23) months and did not present with symptoms characteristic for vitamin B12 deficiency. Most (81%, n = 25) mothers of affected newborns had a hitherto undiagnosed (functional) vitamin B12 deficiency, and, subsequently, received specific therapy. CONCLUSIONS: Neonatal vitamin B12 deficiency can be screened by NBS, preventing the manifestation of irreversible neurologic symptoms and the recurrence of vitamin B12 deficiency in future pregnancies through adequate treatment of affected newborns and their mothers. The high frequency of mothers with migrant background having a newborn with vitamin B12 deficiency highlights the need for improved prenatal care.
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Deficiencia de Vitamina B 12 , Vitamina B 12 , Adolescente , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Tamizaje Neonatal , Evaluación de Resultado en la Atención de Salud , Embarazo , Estudios Prospectivos , Deficiencia de Vitamina B 12/diagnóstico , Deficiencia de Vitamina B 12/tratamiento farmacológico , Deficiencia de Vitamina B 12/epidemiología , VitaminasRESUMEN
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Isovaleril-CoA Deshidrogenasa/deficiencia , Tamizaje Neonatal , Trastornos Neurocognitivos/etiología , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/clasificación , Niño , Preescolar , Cognición , Femenino , Alemania , Humanos , Lactante , Recién Nacido , Isovaleril-CoA Deshidrogenasa/clasificación , Masculino , Fenotipo , Pronóstico , Estudios Prospectivos , Adulto JovenRESUMEN
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; P = .023) and body length (mean SDS -1.34; P = -.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; P = .016). In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/terapia , Glutaril-CoA Deshidrogenasa/deficiencia , Adolescente , Antropometría , Estatura , Índice de Masa Corporal , Peso Corporal , Niño , Preescolar , Distonía/patología , Tratamiento de Urgencia , Femenino , Alemania , Humanos , Lactante , Recién Nacido , Masculino , Megalencefalia/patología , Tamizaje Neonatal , Estudios Prospectivos , Factores Sexuales , Adulto JovenRESUMEN
Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.
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Errores Innatos del Metabolismo de los Aminoácidos/sangre , Aminoácidos de Cadena Ramificada/deficiencia , Aminoácidos de Cadena Ramificada/metabolismo , Isovaleril-CoA Deshidrogenasa/deficiencia , Acidemia Propiónica/sangre , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Distribución de la Grasa Corporal , Factores de Riesgo Cardiometabólico , Estudios de Casos y Controles , Niño , Análisis por Conglomerados , Metabolismo Energético , Femenino , Humanos , Resistencia a la Insulina , Isovaleril-CoA Deshidrogenasa/sangre , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Músculo Esquelético/metabolismo , Acidemia Propiónica/diagnóstico , Adulto JovenRESUMEN
OBJECTIVE: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. METHODS: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children. RESULTS: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study. INTERPRETATION: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.
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Errores Innatos del Metabolismo de los Aminoácidos/terapia , Encefalopatías Metabólicas/terapia , Diagnóstico Precoz , Glutaril-CoA Deshidrogenasa/deficiencia , Tamizaje Neonatal , Niño , Preescolar , Femenino , Alemania , Glutaril-CoA Deshidrogenasa/análisis , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , Fenotipo , Estudios ProspectivosRESUMEN
UNLABELLED: Malonic aciduria is an extremely rare autosomal recessive inborn error of metabolism. We present clinical, biochemical and genetic information for several years of follow-up of new malonic aciduria patients who were diagnosed by newborn screening. These data are discussed with regard to treatment options and possible diagnostic pitfalls. The cases presented here show that the course of malonic aciduria is unpredictable and can even significantly differ in two siblings harbouring identical mutations. Early treatment can lead to the rapid improvement of cardiomyopathy in the course of malonic aciduria. Biochemical parameters seem to be variable and can intermittently be undetectable in the blood or urine samples of affected patients. Therefore, confirmatory tests following a positive newborn screening should be taken with caution and include both malonyl carnitine detection in dried blood spots and urinary organic acid analysis as initial measures. CONCLUSION: Patients with a suspected or confirmed diagnosis of malonic aciduria should undergo thorough diagnostic procedures and be regularly screened for complications such as cardiomyopathy even when they are asymptomatic in order to ensure early therapy of treatable complications.
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Carboxiliasas/deficiencia , Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal/métodos , Hermanos , Niño , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Malonil Coenzima A , Ácido Metilmalónico , Factores de TiempoRESUMEN
OBJECTIVE: Maple syrup urine disease (MSUD), a life-threatening metabolic disorder, is included in newborn screening (NBS) programs worldwide. The study aims to evaluate the impact of NBS on the long-term outcome of MSUD patients. METHODS: We performed a prospective, national, multicenter, observational study. RESULTS: In the studied NBS cohort (N = 33; 22 classic MSUD [cMSUD], 11 variant MSUD [vMSUD]; median age at last visit 10.4 years), 32 (97%) patients survived, 58% of them had normal cognitive functions (median IQ 87). Initial peak leucine increased linearly with age in cMSUD (median: 1712 µmol/L), but not in vMSUD. Global IQ correlated inversely with the initial peak leucine concentration (P = .04; ß = -0.0081) and the frequency of decompensations (P = .02; ß = -9.133). A cluster analysis identified 2 subgroups differing in their long-term metabolic control (median leucine concentration: 162 vs 278 µmol/L; P < .001). In cMSUD, lower leucine concentrations were associated with a higher IQ (95.5 vs 80; P = .008). Liver transplantation (median age 5.8 years) was not associated with better cognitive outcome. NBS is highly sensitive for cMSUD, but vMSUD might be missed (N = 2 missed by NBS). CONCLUSIONS: NBS and the early start of treatment improve survival and long-term outcome in individuals with cMSUD. Disease severity is an important modifier of outcome; however, the time to NBS report and the quality of long-term metabolic control had an independent impact on cognitive outcome, highlighting the importance of an early diagnosis and the quality of treatment.
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Enfermedad de la Orina de Jarabe de Arce , Tamizaje Neonatal , Humanos , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/terapia , Tamizaje Neonatal/métodos , Recién Nacido , Masculino , Femenino , Estudios Prospectivos , Niño , Resultado del Tratamiento , Preescolar , Leucina/sangre , Adolescente , LactanteRESUMEN
OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.
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Cardiomiopatías , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial , Enfermedades del Sistema Nervioso , Rabdomiólisis , Humanos , Recién Nacido , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/terapia , Errores Innatos del Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Proteína Trifuncional Mitocondrial/metabolismo , Proteína Trifuncional Mitocondrial/deficiencia , Lactante , Preescolar , NiñoRESUMEN
Aim of the study was the evaluation of health-related quality of life (HRQoL) and the detection of deviant behavior in early-treated children and adolescents with PKU in comparison with healthy peers. Special focus was laid on the impact of compliance with treatment as defined by the national recommendations on HRQoL. Our investigation in 50 children and adolescents and their parents for the first time demonstrates that despite an overall normal HRQoL in our PKU patient collective, parents are concerned about performance in school especially when phenylalanine concentrations in their children are mainly above the therapeutic range. Adherence to target phenylalanine concentrations ameliorated markedly in patients above 10 years in comparison to younger patients due to relaxed treatment recommendations. Interestingly, this alleged improvement in metabolic control has an impact on the parent assessed but not on the patient assessed appraisal of HRQoL. However, a positive correlation between poor metabolic control and conduct problems was identified by patients' self-assessment. In conclusion, lacking adherence to the strict treatment recommendations in infancy results in significant concern about school success and success in life in parents of PKU patients. With relaxation of dietary phenylalanine restriction at 10 years of age, these concerns diminish.
Asunto(s)
Fenilalanina/metabolismo , Fenilcetonurias/psicología , Fenilcetonurias/terapia , Rendimiento Escolar Bajo , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Padres , Grupo Paritario , Fenilcetonurias/metabolismo , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors.
Asunto(s)
Coenzima A Transferasas/genética , Cetosis/genética , Proteínas Mutantes/genética , Mutación Missense/genética , Acidosis/genética , Preescolar , Coenzima A Transferasas/deficiencia , Femenino , Genotipo , Homocigoto , Humanos , Lactante , Recién Nacido , Cetosis/patología , Masculino , Proteínas Mutantes/metabolismo , Fenotipo , Conformación ProteicaRESUMEN
OBJECTIVE: The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations. METHODS: We here assess the neurocognitive development using standardized psychometric test batteries with respect to cognition, motor abilities and speech in nine early-treated patients with HT I under long-term NTBC treatment. RESULTS: High plasma tyrosine concentrations were frequently documented resulting in elevated 12-month median plasma tyrosine concentrations in seven out of nine patients. Plasma NTBC concentrations were generally in the lower therapeutic range. Five out of seven patients (71%) above 3 years of age had a total IQ score below the average. In addition, five out of seven patients above 3 years showed an inhomogenous test profile with significant differences between the different testing scales. Motor abilities were subnormal in four out of seven patients(57%). Cerebral MRI revealed no abnormalities. Logopedic evaluation in children at school age documented dysfunction or retardation in language development in all but one of the tested patients (80%), however, all but one patients had a migration background. CONCLUSIONS: A high number of patients performed below normal in the assessment of development, motor function and speech. We propose intellectual impairment as long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias. These findings remain to be reproduced in greater patient numbers.
Asunto(s)
Trastornos del Conocimiento/etiología , Cognición/efectos de los fármacos , Ciclohexanonas/efectos adversos , Ciclohexanonas/uso terapéutico , Nitrobenzoatos/efectos adversos , Nitrobenzoatos/uso terapéutico , Tirosinemias/tratamiento farmacológico , Tirosinemias/psicología , Cerebro/efectos de los fármacos , Niño , Preescolar , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Lactante , Desarrollo del Lenguaje , Cuidados a Largo Plazo/métodos , Masculino , Actividad Motora/efectos de los fármacos , Psicometría/métodos , Tiempo , Resultado del Tratamiento , Tirosina/sangre , Tirosinemias/sangreRESUMEN
OBJECTIVE: Psychomotor impairment has been described in hypertyrosinemia types II and III (HT III). Only recently cognitive deficits have also been reported in hypertyrosinemia type I (HT I). The pathogenic mechanisms responsible are unknown. Since implementation of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, Nitisinone (Swedish Orphan International)) in the treatment of HT I, plasma tyrosine elevation is a common finding as known from the other hypertyrosinemias. PATIENTS AND METHODS: With elevated tyrosine as suspected pathogenic factor in the development of cognitive deficits, we here investigated tyrosine in the cerebrospinal fluid (CSF) and serotonergic and dopaminergic neurotransmitter levels in three patients with HT I during long-term treatment with Nitisinone. In addition, Nitisinone concentrations in plasma and CSF were measured. We also assessed psychomotor and cognitive development by standardized test systems and brain morphology by magnetic resonance imaging. RESULTS: All patients presented with high tyrosine concentrations in CSF correlating with increased plasma tyrosine levels and a reduced CSF serotonin turnover. MRI revealed no structural abnormalities in the brain. All patients presented with either impaired cognitive development or behavioural abnormalities. CONCLUSIONS: We here outline the need to further study the exact pathogenic mechanisms responsible for the neurotransmitter changes observed in HT type I in order to possibly prevent cognitive dysfunction. Nitisinone has significantly improved outcome and quality of life in HT type I; however, it is also accompanied by elevated plasma and CSF tyrosine. Further studies are essential to identify the necessary dietary tyrosine restriction and the optimal Nitisinone dose.
Asunto(s)
Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Nitrobenzoatos/uso terapéutico , Serotonina/metabolismo , Tirosina/líquido cefalorraquídeo , Tirosinemias/tratamiento farmacológico , Tirosinemias/enzimología , Encéfalo/anatomía & histología , Niño , Ciclohexanonas/sangre , Ciclohexanonas/líquido cefalorraquídeo , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/líquido cefalorraquídeo , Humanos , Lactante , Masculino , Nitrobenzoatos/sangre , Nitrobenzoatos/líquido cefalorraquídeo , Desempeño Psicomotor , Serotonina/análisis , Tirosina/sangreRESUMEN
SUMMARY: Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5-12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1. LEARNING POINTS: Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia. If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected. Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects. The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.