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1.
J Inherit Metab Dis ; 47(4): 690-702, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38600724

RESUMEN

Classical galactosaemia (CG) is a hereditary disease in galactose metabolism that despite dietary treatment is characterized by a wide range of cognitive deficits, among which is language production. CG brain functioning has been studied with several neuroimaging techniques, which revealed both structural and functional atypicalities. In the present study, for the first time, we compared the oscillatory dynamics, especially the power spectrum and time-frequency representations (TFR), in the electroencephalography (EEG) of CG patients and healthy controls while they were performing a language production task. Twenty-one CG patients and 19 healthy controls described animated scenes, either in full sentences or in words, indicating two levels of complexity in syntactic planning. Based on previous work on the P300 event related potential (ERP) and its relation with theta frequency, we hypothesized that the oscillatory activity of patients and controls would differ in theta power and TFR. With regard to behavior, reaction times showed that patients are slower, reflecting the language deficit. In the power spectrum, we observed significant higher power in patients in delta (1-3 Hz), theta (4-7 Hz), beta (15-30 Hz) and gamma (30-70 Hz) frequencies, but not in alpha (8-12 Hz), suggesting an atypical oscillatory profile. The time-frequency analysis revealed significantly weaker event-related theta synchronization (ERS) and alpha desynchronization (ERD) in patients in the sentence condition. The data support the hypothesis that CG language difficulties relate to theta-alpha brain oscillations.


Asunto(s)
Electroencefalografía , Galactosemias , Humanos , Femenino , Masculino , Adulto , Adulto Joven , Galactosemias/fisiopatología , Encéfalo/fisiopatología , Encéfalo/metabolismo , Estudios de Casos y Controles , Lenguaje , Tiempo de Reacción , Adolescente , Potenciales Relacionados con Evento P300/fisiología
2.
J Inherit Metab Dis ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39143820

RESUMEN

Long-term outcomes in classic galactosemia (CG) have been studied previously, but all prior studies have relied on cohorts of patients that were small in number, or heavily skewed toward children and young adults, or both. Here, we extend what is known about the health and well-being of maturing adults with CG by analyzing the results of anonymous custom surveys completed by 92 affected individuals, ages 30-78, and 38 unaffected sibling controls, ages 30-79. The median age for patients was 38.5 years and for controls was 41 years. These study participants hailed from 12 different countries predominantly representing Europe and North America. Participants reported on their general life experiences and outcomes in seven different domains including: speech/voice/language, cognition, motor function, cataracts, bone health, psychosocial well-being, and gastrointestinal health. We also queried women about ovarian function. Our results indicated a prevalence of long-term complications across all outcome domains that aligned with levels previously reported in younger cohorts. Given the sample size and age range of participants in this study, these findings strongly suggest that the adverse developmental outcomes commonly linked to CG are not progressive with age for most patients. We also tested four candidate modifiers for possible association with each of the outcomes followed, including: days of neonatal milk exposure, rigor of dietary galactose restriction in early childhood, current age, and home continent. We observed no associations that reached even nominal significance, except for the following: cataracts with neonatal milk exposure (p = 2.347e-04), cataracts with age (p = 0.018), and bone health with home continent (p = 0.03).

3.
Hum Mutat ; 42(12): 1624-1636, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34510628

RESUMEN

N-acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel noncoding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427-222G>A and NM_153006.2:c.427-218A>C reside in the 547 bp-long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor α. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.-3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.-3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing noncoding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.


Asunto(s)
N-Acetiltransferasa de Aminoácidos , Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , N-Acetiltransferasa de Aminoácidos/química , N-Acetiltransferasa de Aminoácidos/genética , Humanos , Hiperamonemia/genética , Intrones , Secuencias Reguladoras de Ácidos Nucleicos , Trastornos Innatos del Ciclo de la Urea/genética
4.
J Inherit Metab Dis ; 39(5): 713-723, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27287710

RESUMEN

INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.


Asunto(s)
Ataxia/patología , Trastornos Congénitos de Glicosilación/patología , Epilepsia/patología , Glucosiltransferasas/genética , Deformidades Congénitas de las Extremidades/patología , Proteínas de la Membrana/genética , Trastornos Mentales/patología , Debilidad Muscular/patología , Adolescente , Adulto , Ataxia/genética , Niño , Preescolar , Trastornos Congénitos de Glicosilación/genética , Epilepsia/genética , Femenino , Estudios de Asociación Genética/métodos , Glicosilación , Humanos , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/genética , Masculino , Trastornos Mentales/genética , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Debilidad Muscular/genética , Fenotipo , Estudios Retrospectivos , Convulsiones/genética , Convulsiones/patología , Adulto Joven
5.
J Inherit Metab Dis ; 38(2): 323-31, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25048386

RESUMEN

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.


Asunto(s)
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 Joven
6.
Mol Genet Metab Rep ; 38: 101057, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38469096

RESUMEN

The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and negative galactosemia screening. This report underlines the value of neonatal screening and the importance of further diagnostic testing in case of late-onset manifestations.

7.
J Inherit Metab Dis ; 35(2): 279-86, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21779791

RESUMEN

BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.


Asunto(s)
Galactosemias/diagnóstico , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Galactosemias/enzimología , Galactosemias/genética , Genotipo , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Tamizaje Neonatal/métodos , Enfermedades Neurodegenerativas/enzimología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Fenotipo , UTP-Hexosa-1-Fosfato Uridililtransferasa/deficiencia , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética , Adulto Joven
8.
J Inherit Metab Dis ; 34(2): 357-66, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20978943

RESUMEN

Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose. In this review we explore the complexities of timing and detection of galactosemia-associated POI and discuss potential underlying mechanisms. Finally, we offer recommendations for follow-up care with current options for intervention.


Asunto(s)
Galactosemias/diagnóstico , Galactosemias/genética , Adolescente , Adulto , Animales , Niño , Epigénesis Genética , Escherichia coli/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Galactosa/metabolismo , Humanos , Ovario/patología , Insuficiencia Ovárica Primaria/genética , Pubertad , Sepsis/genética
10.
JIMD Rep ; 61(1): 76-88, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34485021

RESUMEN

BACKGROUND: Classical galactosemia (CG) (OMIM #230400) is a rare disorder of carbohydrate metabolism, due to deficiency of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological, and female infertility remains poorly understood. OBJECTIVES: This study investigated (a) the association between specific IgG N-glycosylation biomarkers (glycan peaks and grouped traits) and CG patients (n = 95) identified from the GalNet Network, using hydrophilic interaction ultraperformance liquid chromatography and (b) a further analysis of a GALT c.563A-G/p.Gln188Arg homozygous cohort (n = 49) with correlation with glycan features with patient Full Scale Intelligence Quotient (FSIQ), and (c) with galactose intake. RESULTS: A very significant decrease in galactosylation and sialylation and an increase in core fucosylation was noted in CG patients vs controls (P < .005). Bisected glycans were decreased in the severe GALT c.563A-G/p.Gln188Arg homozygous cohort (n = 49) (P < .05). Logistic regression models incorporating IgG glycan traits distinguished CG patients from controls. Incremental dietary galactose intake correlated positively with FSIQ for the p.Gln188Arg homozygous CG cohort (P < .005) for a dietary galactose intake of 500 to 1000 mg/d. Significant improvements in profiles with increased galactose intake were noted for monosialylated, monogalactosylated, and monoantennary glycans. CONCLUSION: These results suggest that N-glycosylation abnormalities persist in CG patients on dietary galactose restriction which may be modifiable to a degree by dietary galactose intake.

11.
J Inherit Metab Dis ; 33 Suppl 3: S181-5, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20300853

RESUMEN

Two young girls without a notable medical history except for asthma presented with an acute toxic encephalopathy with very low serine concentrations both in plasma and cerebrospinal fluid (CSF) comparable to patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. Clinical symptoms and enzyme measurement (in one patient) excluded 3-PGDH deficiency. Deficiencies in other serine biosynthesis enzymes were highly unlikely on clinical grounds. On basis of the fasting state, ketone bodies and lactate in plasma, urine and CSF, we speculate that reduced serine levels were due to its use as gluconeogenic substrate, conversion to pyruvate by brain serine racemase or decreased L-serine production because of a lack of glucose. These are the first strikingly similar cases of patients with a clear secondary serine deficiency associated with a toxic encephalopathy.


Asunto(s)
Edema Encefálico/etiología , Encéfalo/metabolismo , Síndromes de Neurotoxicidad/etiología , Serina/líquido cefalorraquídeo , Serina/deficiencia , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Glucemia/metabolismo , Edema Encefálico/sangre , Edema Encefálico/líquido cefalorraquídeo , Edema Encefálico/diagnóstico , Niño , Preescolar , Metabolismo Energético , Resultado Fatal , Femenino , Humanos , Cuerpos Cetónicos/sangre , Ácido Láctico/sangre , Síndromes de Neurotoxicidad/sangre , Síndromes de Neurotoxicidad/líquido cefalorraquídeo , Síndromes de Neurotoxicidad/diagnóstico , Valor Predictivo de las Pruebas , Ácido Pirúvico/metabolismo , Serina/sangre
12.
Orphanet J Rare Dis ; 13(1): 164, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30231941

RESUMEN

BACKGROUND: Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17-51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. RESULTS: Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = - 0.68) and (rs = - 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). CONCLUSIONS: These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.


Asunto(s)
Galactosa/metabolismo , Galactosemias/sangre , Galactosemias/fisiopatología , Infertilidad/sangre , Infertilidad/fisiopatología , Adolescente , Adulto , Femenino , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Galactosemias/metabolismo , Humanos , Infertilidad/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Leptina/sangre , Persona de Mediana Edad , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Insuficiencia Ovárica Primaria/sangre , Insuficiencia Ovárica Primaria/metabolismo , Insuficiencia Ovárica Primaria/fisiopatología , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Septinas/genética , Septinas/metabolismo , Adulto Joven
14.
PLoS One ; 11(12): e0167884, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28002426

RESUMEN

Neurite orientation dispersion and density imaging (NODDI) enables more specific characterization of tissue microstructure by estimating neurite density (NDI) and orientation dispersion (ODI), two key contributors to fractional anisotropy (FA). The present work compared NODDI- with diffusion tensor imaging (DTI)-derived indices for investigating white matter abnormalities in a clinical sample. We assessed the added value of NODDI parameters over FA, by contrasting group differences identified by both models. Diffusion-weighted images with multiple shells were acquired in a group of 8 healthy controls and 8 patients with an inherited metabolic disease. Both standard DTI and NODDI analyses were performed. Tract based spatial statistics (TBSS) was used for group inferences, after which overlap and unique contributions across different parameters were evaluated. Results showed that group differences in NDI and ODI were complementary, and together could explain much of the FA results. Further, compared to FA analysis, NDI and ODI gave a pattern of results that was more regionally specific and were able to capture additional discriminative voxels that FA failed to identify. Finally, ODI from single-shell NODDI analysis, but not NDI, was found to reproduce the group differences from the multi-shell analysis. To conclude, by using a clinically feasible acquisition and analysis protocol, we demonstrated that NODDI is of added value to standard DTI, by revealing specific microstructural substrates to white matter changes detected with FA. As the (simpler) DTI model was more sensitive in identifying group differences, NODDI is recommended to be used complementary to DTI, thereby adding greater specificity regarding microstructural underpinnings of the differences. The finding that ODI abnormalities can be identified reliably using single-shell data may allow the retrospective analysis of standard DTI with NODDI.


Asunto(s)
Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Sustancia Blanca/diagnóstico por imagen , Adolescente , Estudios de Casos y Controles , Humanos , Procesamiento de Imagen Asistido por Computador , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/patología , Estudios Retrospectivos , Sustancia Blanca/anatomía & histología , Sustancia Blanca/química , Adulto Joven
15.
Orphanet J Rare Dis ; 10: 99, 2015 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-26289392

RESUMEN

BACKGROUND: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine ß-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. PURPOSE OF THE STUDY: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. RESULTS AND DISCUSSION: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 µM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Heterocigoto , Homocigoto , Metionina Adenosiltransferasa/genética , Adolescente , Adulto , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven
16.
Orphanet J Rare Dis ; 8: 103, 2013 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-23842451

RESUMEN

BACKGROUND: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. METHODS: Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with ≥30% phenylalanine reduction at ≥1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term ≥30% reduction in mean phenylalanine concentration and/or ≥4 g/day and/or ≥50% increase of natural protein intake. Genotype was collected if available. RESULTS: 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with ≥1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. CONCLUSIONS: The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.


Asunto(s)
Biopterinas/análogos & derivados , Fenilcetonurias/tratamiento farmacológico , Adolescente , Adulto , Biopterinas/uso terapéutico , Niño , Femenino , Genotipo , Humanos , Masculino , Mutación , Fenilcetonurias/genética , Adulto Joven
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