Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients (N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH4) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype–phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico.
Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D.Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico.Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling.Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic.Conclusion: A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.
OBJETIVO: Comunicar los desenlaces de la experiencia con la aplicación de algunas herramientas básicas de telemedicina para la atención de pacientes con errores innatos del metabolismo durante la pandemia de COVID-19 y describir la atención presencial llevada a cabo en el mismo periodo, en un centro pediátrico de tercer nivel de atención.MATERIALES Y MÉTODOS: Estudio retrospectivo de pacientes con errores innatos del metabolismo que recibieron atención presencial o mediante herramientas remotas (correos electrónicos o mensajería instantánea por Whats App®) en el Laboratorio de Errores Innatos del Metabolismo y Tamiz del Instituto Nacional de Pediatría, del 23 de marzo al 23 de julio del 2020.RESULTADOS: Se atendieron 117 pacientes con 26 diferentes errores innatos del metabolismo. Se otorgaron 97 consultas presenciales y se enviaron 308 correos electrónicos y 137 mensajes telefónicos. Solo se registró una descompensación metabólica severa en un paciente con acidemia propiónica, que requirió internamiento urgente. No ocurrió ninguna defunción. Siete pacientes fueron de primera vez, 4 de ellos llegaron por tener tamiz neonatal anormal; todos llegaron tardíamente (4-9 meses de edad). Los principales obstáculos detectados para brindar la atención mediante telemedicina fueron la carencia de la plataforma informática respectiva en la institución y de computadoras con internet por parte de los pacientes.CONCLUSIÓN: Los desenlaces señalan las ventajas de algunas de las herramientas de la telemedicina y revelan la necesidad de contar con una plataforma moderna de telesalud institucional que permita atender e instruir a los pacientes y capacitar al personal de salud implicado en la atención de enfermos con algún error innato del metabolismo.
Los errores innatos del metabolismo intermedio (EIMi) son un grupo heterogéneo de enfermedades monogénicas pertenecientes al grupo de las enfermedades raras (ER), que afectan vías metabólicas de la síntesis o catabolismo de los hidratos de carbono, aminoácidos o lípidos.1 Estas enfermedades conllevan anormalidades bioquímicas que pueden cuantificarse en diferentes fluidos biológicos, lo que permite su diagnóstico.
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