RESUMEN
Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Enfermedades Mitocondriales/complicaciones , Acidemia Propiónica/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Cognición , Femenino , Humanos , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Ácido Metilmalónico , Enfermedades Mitocondriales/fisiopatología , Tamizaje Neonatal , Países Bajos , Acidemia Propiónica/fisiopatología , Acidemia Propiónica/terapia , Estudios Retrospectivos , HermanosRESUMEN
PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.
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Aminoacil-ARNt Sintetasas/deficiencia , Enfermedades Genéticas Congénitas/enzimología , Enfermedades Genéticas Congénitas/genética , Aminoacil-ARNt Sintetasas/genética , Enfermedades del Sistema Nervioso Central/enzimología , Enfermedades del Sistema Nervioso Central/genética , Niño , Insuficiencia de Crecimiento/enzimología , Insuficiencia de Crecimiento/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/enzimología , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Femenino , Genes Recesivos , Trastornos del Crecimiento/enzimología , Trastornos del Crecimiento/genética , Humanos , Hepatopatías/enzimología , Hepatopatías/genética , Masculino , FenotipoRESUMEN
BACKGROUND: Patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), a long chain fatty acid oxidation disorder, are traditionally treated with a long chain triglyceride (LCT) restricted and medium chain triglyceride (MCT) supplemented diet. Introduction of VLCADD in newborn screening (NBS) programs has led to the identification of asymptomatic newborns with VLCADD, who may have a more attenuated phenotype and may not need dietary adjustments. OBJECTIVE: To define dietary strategies for individuals with VLCADD based on the predicted phenotype. METHOD: We evaluated long-term dietary histories of a cohort of individuals diagnosed with VLCADD identified before the introduction of VLCADD in NBS and their beta-oxidation (LC-FAO) flux score (rate of oleate oxidation) in cultured skin fibroblasts in relation to the clinical outcome. Based on these results a dietary strategy is proposed. RESULTS: Sixteen individuals with VLCADD were included. One had an LC-FAO flux score >90%, was not on a restricted diet and is asymptomatic to date. Four patients had an LC-FAO flux score <10%, and significant VLCADD related symptoms despite the use of strict diets including LCT restriction, MCT supplementation and nocturnal gastric drip feeding. Patients with an LC-FAO flux score between 10 and 90% (n = 11) showed a more heterogeneous phenotype. CONCLUSIONS: This study shows that a strict diet cannot prevent poor clinical outcome in severely affected patients and that the LC-FAO flux is a good predictor of clinical outcome in individuals with VLCADD identified before its introduction in NBS. Hereby, we propose an individualized dietary strategy based on the LC-FAO flux score.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa/deficiencia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Musculares/tratamiento farmacológico , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Síndromes Congénitos de Insuficiencia de la Médula Ósea/metabolismo , Dieta , Ácidos Grasos/administración & dosificación , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/metabolismo , Masculino , Enfermedades Mitocondriales/metabolismo , Enfermedades Musculares/metabolismo , Tamizaje Neonatal/métodos , Fenotipo , Triglicéridos/administración & dosificaciónRESUMEN
BACKGROUND: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. METHODS: We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. RESULTS AND CONCLUSIONS: Most patients (n = 22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype-phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.
Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Células Endocrinas/metabolismo , Hormonas/metabolismo , Transaldolasa/deficiencia , Niño , Preescolar , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Retrospectivos , Encuestas y Cuestionarios , Transaldolasa/genética , Transaldolasa/metabolismoRESUMEN
To evaluate the Dutch newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency since 2007, a nationwide retrospective, observational study was performed of clinical, laboratory and epidemiological parameters of patients with MCAD deficiency born between 2007 and 2015. Severe MCAD deficiency was defined by ACADM genotypes associated with clinical ascertainment, or variant ACADM genotypes with a residual MCAD enzyme activity <10%. Mild MCAD deficiency was defined by variant ACADM genotypes with a residual MCAD enzyme activity ≥10%. The prevalence of MCAD deficiency was 1/8300 (95% CI: 1/7300-1/9600). Sensitivity of the Dutch NBS was 99% and specificity ~100%, with a positive predictive value of 86%. Thirteen newborns with MCAD deficiency suffered from neonatal symptoms, three of them died. Of the 189 identified neonates, 24% had mild MCAD deficiency. The acylcarnitine ratio octanoylcarnitine (C8)/decanoylcarnitine (C10) was superior to C8 in discriminating between mild and severe cases and more stable in the first days of life. NBS for MCAD deficiency has a high sensitivity, specificity, and positive predictive value. In the absence of a golden standard to confirm the diagnosis, the combination of acylcarnitine (ratios), molecular and enzymatic studies allows risk stratification. To improve evaluation of NBS protocols and clinical guidelines, additional use of acylcarnitine ratios and multivariate pattern-recognition software may be reappraised in the Dutch situation. Prospective recording of NBS and follow-up data is warranted covering the entire health care chain of preventive and curative medicine.
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Acil-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/metabolismo , Tamizaje Neonatal , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasa/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Femenino , Genotipo , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Masculino , Países Bajos/epidemiología , Prevalencia , Estudios RetrospectivosRESUMEN
Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P < 0.001) of the reference mean. The median LC-FAO flux was 33.2% (95% CI: 22.8-48.3) and 41% (95% CI: 40.8-68; P < 0.05) of the control mean, respectively. Clinical characteristics in 23 pre-NBS and 37 NBS patients revealed hypoglycemic events in 12 vs 2 patients, cardiomyopathy in 5 vs 4 patients and myopathy in 14 vs 3 patients. All patients with LC-FAO flux <10% developed symptoms. Of the patients with LC-FAO flux >10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Tamizaje Neonatal , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Femenino , Genotipo , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Países BajosRESUMEN
BACKGROUND: While clinical observations suggest that many patients with mucopolysaccharidosis (MPS) experience chronic pain, few studies have assessed its extent and impact. We therefore investigated its prevalence in patients with all types of MPS in the Netherlands. We also examined the association between pain and health related quality of life (HRQoL) and other clinical variables. METHODS: We conducted a nationwide MPS survey that used questionnaires on MPS and disease-related symptoms (MPS-specific questionnaire), developmental level (Vineland Screener 0-6 years), quality of life (PedsQl and SF-36), and disability (Childhood Health Assessment Questionnaire). Depending on their age and developmental level, patients or their parents were asked to assess pain by keeping a pain diary for five consecutive days: either the Non-communicating Children's Pain Checklist - Revised (3-18 years intellectually disabled and children <8 years), the VAS-score (> 18 years), or the Faces Pain Scale - Revised (8-18 years). RESULTS: Eighty-nine MPS patients were invited, 55 of whom agreed to participate (response rate 62 %; median age 10.9 years, range 2.9-47.2 years). They covered a wide spectrum in all age groups, ranging from no pain to severe pain. Forty percent scored above the cut-off value for pain. Most reported pain sites were the back and hips. While the MPS III group experienced the highest frequency of pain (52.9 %), 50 % of patients with an intellectual disability seemed to experience pain, versus 30 % of patients with a normal intelligence. MPS patients scored much lower (i.e., more pain) than a random sample of the Dutch population on the bodily pain domain of the SF-36 scale and the PedsQl. CONCLUSION: With or without intellectual disabilities, many MPS patients experience pain. We recommend that standardized pain assessments are included in the regular follow-up program of patients with MPS.
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Artralgia/epidemiología , Dolor Crónico/epidemiología , Mucopolisacaridosis/epidemiología , Adolescente , Adulto , Artralgia/diagnóstico , Artralgia/psicología , Niño , Preescolar , Dolor Crónico/diagnóstico , Dolor Crónico/psicología , Costo de Enfermedad , Estudios Transversales , Evaluación de la Discapacidad , Femenino , Encuestas de Atención de la Salud , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/psicología , Masculino , Persona de Mediana Edad , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis/psicología , Países Bajos/epidemiología , Dimensión del Dolor , Personas con Discapacidades Mentales/psicología , Prevalencia , Calidad de Vida , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism caused by phenylalanine hydroxylase enzyme (PAH) deficiency. Treatment constitutes a strict Phe restricted diet with unpalatable amino acid supplements. Residual PAH activity enhancement with its cofactor tetrahydrobiopterin (BH4) is a novel treatment which increases dietary tolerance in some patients and permits dietary relaxation. Relaxation of diet may improve health related quality of life (HRQoL). This prospective cohort study aims to evaluate HRQoL of patients with PKU and effects of BH4 treatment on HRQoL. METHODS: Patients aged 4years and older, diagnosed through newborn screening and early and continuously treated, were recruited from eight metabolic centers. Patients and mothers completed validated generic and chronic health-conditions HRQoL questionnaires (PedsQL, TAAQOL, and DISABKIDS) twice: before and after testing BH4 responsivity. Baseline results were compared to the general population. Data collected after BH4 testing was used to find differences in HRQoL between BH4 unresponsive patients and BH4 responsive patients after one year of treatment with BH4. Also a within patient comparison was performed to find differences in HRQoL before and after treatment with BH4. RESULTS: 69/81 (85%) patients completed the questionnaires before BH4 responsivity testing, and 45/69 (65%) participated again after testing. Overall PKU patients demonstrated normal HRQoL. However, some significant differences were found when compared to the general population. A significantly higher (thus better) score on the PedsQL was reported by children 8-12 years on physical functioning and by children 13-17 years on total and psychosocial functioning. Furthermore, adult patients reported significantly lower (thus worse) scores in the TAAQOL cognitive domain. 10 patients proved to be responsive to BH4 treatment; however improvement in their HRQoL after relaxation of diet could not be demonstrated.
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Biopterinas/análogos & derivados , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/psicología , Adolescente , Adulto , Biopterinas/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Transaldolase deficiency (OMIM 606003) is a multisystem disorder first described in 2001. Transaldolase is an enzyme of the reversible part of the pentose phosphate pathway. Affected patients have abnormal polyol concentrations in body fluids, mostly in urine. The clinical presentation is variable. The leading symptoms are coagulopathy, thrombocytopenia, hepatosplenomegaly, hepatic fibrosis and dysmorphic features. The objective of our study was to attempt to characterize the renal phenotype of patients with transaldolase deficiency. METHODS: Clinical and laboratory data of all nine patients with transaldolase deficiency presently known were gathered by retrospective chart analysis. RESULTS: Nephrological abnormalities were present in seven of the nine patients. The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria. The two oldest patients had moderate chronic kidney failure. In two patients, generalized aminoaciduria was found, two patients had renal phosphate wasting and three patients had hyperchloremic metabolic acidosis. Three patients had anatomical abnormalities. CONCLUSIONS: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure. The combination of unexplained liver dysfunction with LMW proteinuria should prompt metabolic screening for transaldolase deficiency by measuring urinary polyols. In patients with transaldolase deficiency, monitoring of kidney function is mandatory.
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Errores Innatos del Metabolismo de los Carbohidratos/patología , Riñón/anomalías , Adolescente , Errores Innatos del Metabolismo de los Carbohidratos/enzimología , Errores Innatos del Metabolismo de los Carbohidratos/genética , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular , Humanos , Hipercalciuria/etiología , Lactante , Recién Nacido , Riñón/fisiopatología , Fallo Renal Crónico/etiología , Masculino , Vía de Pentosa Fosfato , Proteinuria/etiología , Estudios Retrospectivos , Transaldolasa/deficiencia , Transaldolasa/genéticaRESUMEN
BACKGROUND: Patients suffering from an H1N1 infection mainly suffer from respiratory symptoms but may also develop symptoms in other organ systems, such as the kidneys. CASE-DIAGNOSIS/TREATMENT: A 4 ½ year-old boy was admitted with relatively mild respiratory symptoms of H1N1 infection, but developed severe generalized proximal tubular dysfunction with sterile leucocyturia and a reversible rise in serum creatinine. He made a full recovery with supportive therapy. CONCLUSION: Influenza H1N1 may be associated with acute tubulointerstitial nephritis.
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Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/virología , Nefritis Intersticial/virología , Enfermedad Aguda , Biomarcadores/sangre , Preescolar , Creatinina/sangre , Humanos , Gripe Humana/complicaciones , Masculino , Nefritis Intersticial/sangre , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/terapia , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.
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Ondas Encefálicas , Encéfalo/fisiopatología , Coenzimas/deficiencia , Electroencefalografía , Epilepsia/diagnóstico , Errores Innatos del Metabolismo de los Metales/diagnóstico , Metaloproteínas/deficiencia , Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Ondas Encefálicas/efectos de los fármacos , Coenzimas/genética , Imagen de Difusión por Resonancia Magnética , Epilepsia/tratamiento farmacológico , Epilepsia/enzimología , Epilepsia/fisiopatología , Humanos , Recién Nacido , Masculino , Errores Innatos del Metabolismo de los Metales/enzimología , Errores Innatos del Metabolismo de los Metales/genética , Errores Innatos del Metabolismo de los Metales/fisiopatología , Metaloproteínas/genética , Cofactores de Molibdeno , Molibdoferredoxina/genética , Valor Predictivo de las Pruebas , Pteridinas , Sulfitos/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Maple syrup urine disease (MSUD) leads to severe neurological deterioration unless diagnosed early and treated immediately. We have evaluated the effectiveness of 11 years of MSUD newborn screening (NBS) in the Netherlands (screening >72 hours, referral if both total leucine (Xle) and valine ≥400 µmol/L blood) and have explored possibilities for improvement by combining our data with a systematic literature review and data from Collaborative Laboratory Integrated Reports (CLIR). Dutch MSUD NBS characteristics and accuracy were determined. The hypothetical referral numbers in the Dutch population of additional screening markers suggested by CLIR were calculated. In a systematic review, articles reporting NBS leucine concentrations of confirmed patients were included. Our data showed that NBS of 1 963 465 newborns identified 4 MSUD patients and led to 118 false-positive referrals (PPV 3.28%; incidence 1:491 000 newborns). In literature, leucine is the preferred NBS parameter. Total leucine (Xle) concentrations (mass-spectrometry) of 53 detected and 8 false-negative patients (sampling age within 25 hours in 3 patients) reported in literature ranged from 288 to 3376 (median 900) and 42 to 325 (median 209) µmol/L blood respectively. CLIR showed increasing Xle concentrations with sampling age and early NBS sampling and milder variant MSUD phenotypes with (nearly) normal biochemical profiles are causes of false-negative NBS results. We evaluated the effect of additional screening markers and established the Xle/phenylalanine ratio as a promising additional marker ratio for increasing the PPV, while maintaining high sensitivity in the Dutch MSUD NBS.
RESUMEN
BACKGROUND: Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes. METHODS: We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007-2010. Clinical, molecular, and enzymatic data were integrated. RESULTS: Eighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant ACADM genotype. In patients with classical ACADM genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant ACADM genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210-1/11,130). CONCLUSIONS: Determination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification. Subjects with variant ACADM genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical ACADM genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant ACADM genotypes and >10% residual MCAD enzyme activity.
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Acil-CoA Deshidrogenasa/metabolismo , Errores Innatos del Metabolismo Lipídico/enzimología , Tamizaje Neonatal , Acil-CoA Deshidrogenasa/deficiencia , Acil-CoA Deshidrogenasa/genética , Estudios de Cohortes , Genotipo , Humanos , Recién Nacido , Fenotipo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetic heterogeneous autosomal recessive disorder. We report two siblings with FHLH caused by a PRF1 mutation. The first child died in utero with hydrops fetalis and the second presented soon after birth with fatal multiple organ failure. Post-mortem DNA analysis showed a homozygous c.666C>A (p.His222Gln) mutation in the PRF1 gene in both cases, with their non-consanguineous parents being heterozygous for the same mutation. Review of the literature shows that perinatal presentation of FHLH is rare. Diagnosis is difficult because in most cases histologic examination reveals no hemophagocytosis and the disease is rapidly fatal. The association between hydrops fetalis and FHLH has been reported in four previous reports. We present the first case of hydrops fetalis caused by FHLH, confirmed by DNA analysis. FHLH should be included in the differential diagnosis of non-immune hydrops fetalis and neonatal multiple organ failure.
Asunto(s)
Hidropesía Fetal/patología , Linfohistiocitosis Hemofagocítica/complicaciones , Insuficiencia Multiorgánica/complicaciones , Resultado Fatal , Femenino , Heterocigoto , Humanos , Recién Nacido , Linfohistiocitosis Hemofagocítica/genética , Masculino , MutaciónRESUMEN
Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.