Lesch-Nyhan Disease and Its Variants: Phenotypic and Mutation Spectrum of Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Argentine Patients

Abstract Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a disorder of purine metabolism responsible for Lesch-Nyhan Disease (LND) and its variants, HPRT-related hyperuricemia with neurologic dysfunction (HND) and HPRT-related hyperuricemia (HRH). The objective of this study was to characterize a cohort of Argentine patients with HPRT deficiency diagnosed in a single center. Results: Twenty nine patients were studied, including 12 LND, 15 HND and 2 HRH. The average onset age was 0.64 years for LND with motor delay as the main manifestation, 8.84 years for HND and 2.5 years for HRH; nephrological manifestations predominated as presenting features in these variants. The average diagnosis age was 3.58 years for LND, 17.21 years for HND and 2.5 years for HRH. Clinical heterogeneity was more evident in HND, even in members of the same family. All patients presented hyperuricemia and no detectable HPRT activity in erythrocyte lysate. The molecular study allowed to identify 9 different mutations in HPRT1 gene from 24 patients (11 independent pedigrees) and to establish genotype-phenotype correlation. In conclusion, this study describes the genotypic/phenotypic spectrum of HPRT deficiency in Argentine patients and highlights the need to increase awareness about the suspicion of these diseases, especially the LND variants with high clinical heterogeneity.

Mutation Spectrum and Genotype-Phenotype Correlation in a Cohort of Argentine Patients with Ornithine Transcarbamylase Deficiency: A Single-Center Experience

Abstract X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Hemizygous males with complete deficiency manifest neonatal acute hyperammonemia, while those with partial deficiency have a late presentation. The symptomatology of heterozygotes depends on the inactivation pattern of X chromosome. Hyperammonemic episodes can cause neurological damage and are potentially fatal. Here, we match clinical, biochemical, and molecular findings with bioinformatics analyses to report genotype-phenotype correlations in 14 Argentine patients with OTCD from 11 unrelated families: 4 hemizygotes with neonatal onset (complete OTC gene deletion, 533C > T, c.540+1G > A, c.697delG); 4 hemizygotes with late onset (c.216+1G > A, c.386G > A, c.622G > A, c.829C > T); and 6 symptomatic heterozygotes (complete OTC gene deletion, c.533C > T, c.452T > G, c.540+1G > A, dupE1-9/delE10). Three of these mutations were previously unreported: c.540+1G > A, c.697delG, and dup1-9/del10. Our data highlight the relevance of combining molecular and bioinformatics analyses for accurate diagnosis and outcome prediction in suspected patients with OTCD and the importance of carrier testing for effective genetic counseling.

Impact of CPS1 Gene rs7422339 Polymorphism in Argentine Patients With Hyperhomocysteinemia

Abstract Carbamoyl phosphate synthetase 1 (CPS1) is a key gene in the first step of urea cycle and has been correlated with nitric oxide level and vascular smooth muscle activity. A functional single-nucleotide polymorphism C/A at position 4217 in CPS1 (National Center for Biotechnology Information SNP database no. rs7422339, T1405N) was reported to be associated with high homocysteine (Hcy) plasma values. Although genetic variants of methylenetetrahydrofolate reductase (MTHFR) gene are known to influence Hcy concentration, other genetic determinants of Hcy remain largely unknown. The association between the CPS1 rs7422339 and the risk of hyperhomocysteinemia in Latin American populations is unknown. Here, we study this association in 100 patients having hyperhomocysteinemia without MTHFR c.677C>T polymorphism and 100 controls. CPS1 rs7422339 was studied using polymerase chain reaction and enzymatic restriction. Comparisons of the CPS1 rs7422339 genotype distributions revealed a significant difference between groups (P = 2.3 × 10−3). Patients carrying polymorphic allele showed almost 3 times higher risk (odds ratio [OR] = 2.47) of hyperhomocysteinemia than wild-type allele, suggesting that rs7422339 SNP is associated with high Hcy levels in the Argentine population.

Actividad de la chitotriosidasa plasmatica en pacientes argentinos con enfermedad de Gaucher, diversas lisosomopatias y en otras metabolopatias geneticas / Plasma chitotriosidase activity in Argentinean patients with Gaucher disease, various lysosomal diseases and other inherited metabolic disorders

Recientemente, una marcada y aparente específica elevación de la actividad de la chitotriosidasa plasmática (Ch-PI) fue demostrada en pacientes con Enfermedad de Gaucher (EG) Tipo 1 (Mc Kusick 230800); este indicador bioquímico contribuiría además, en la detección de la patología y en la valoración de la terapia de suplementación enzimática (TSE). Datos subsecuentes sugirieron que el incremento de la Ch-PI también era marcador de otras patologías de atesoramiento lisosomal (PAL), aunque las actividades fueron menores que los valores más bajos de la EG Tipo 1. Aquí presentamos nuestra experiencia en la investigación de la actividad de la Ch-PI en una población argentina distribuida en tres grupos: a) 25 controles sanos; b) individuos relacionados con la EG: 3 pacientes con EG Tipo 1, 3 heterocigotas obligadas y 1 pacientes con una variante atípica de EG; c) 42 pacientes con precisa definición nosológica de una Enfermedad metabólica Hereditaria (EMH) y 5 pacientes presumibles de padecer una PAL aunque sin confirmación enzimática. La actividad de la metilumbelliferil tri-N-acetilchitotriosa hidrolasa fue de 600-2000 veces mayor en la plasma de las pacientes con EG Tipo 1 respecto del valor medio normal autóctono (17 nmoles/min/ml; rango de 6-60, 4 nmoles/min/ml); en el paciente con EG atípica el incremento de la Ch-PI fue alrededor de 100 veces. El efecto de la TSE en 2 de las pacientes con EG Tipo 1, una de forma moderada y la otra severa, se manifestaron con un descenso del 50 por ciento de la actividad de la Ch-PI a los 10 meses de tratamiento a la dosis de 30 U/kg/mes de alglucerase. En las heterocigotas obligadas de EG Tipo 1 y en la del Tipo 2 como asimismo en el grupo de pacientes con diferentes EMH, la actividad de la Ch-PI resultó normal. Una deficiencia total de la Ch-PI se demostró en el 8 por ciento de los controles sanos y un 10,6 por ciento en el grupo patológico. La relación entre el incremento de varios cientos de veces de la Ch-PI uy la fisiopatología de la EG no está elucidada como tampoco los posibles efectos de la relativamente común deficiencia de la enzima en el ser humano. La demostración del rol de la enzima en la degradación de patógenos contentivos de chitina, la purificación y clonación de cADN de la enzima, abren interesantes aspectos a investigar en este nuevo capítulo de la genética médica.