Low allelic heterogeneity in a sample of Mexican patients with classical galactosaemia

Abstract

Classical galactosaemia is an autosomal recessive disease of galactose metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). Galactosaemia is not included in the neonatal screening programme in Mexico and it is necessary to implement methodologies for prompt diagnosis of these patients to establish treatment. To date, more than 190 mutations in the GALT gene have been reported, most in caucasian populations, but there have been no reports of mutations in Latin-American populations. We report here the mutational spectrum in 19 Mexican galactosaemic patients. The most frequent mutations were p.Q188R, p.N314D and IVS2-2A>G, which together represented 71% of detected mutations. The mutation IVS2-2A>G, which has been detected only in Hispanics, was thought to generate a null allele; we identified one patient with a homozygous IVS2-2A>G mutation who showed a mild deficiency of enzyme value in erythrocytes. One patient homozygous for Duarte 2 (p.N314D, IVS5+62G>A) is probably due to a partial uniparental disomy of chromosome 9. In addition, a novel mutation c.336T>C (p.S112R) was detected in one patient with severe enzymatic deficiency. Despite the small number of patients studied, our results suggest that classical galactosaemia shows low allelic heterogeneity in Mexican patients, in contrast what is observed in other Mendelian disorders such as cystinosis or autosomal dominant hypercholesterolaemia. This low allelic heterogeneity might be explained by a "population of origin" effect in the central region of Mexico, as has been described for phenylketonuria.

A Review of Disparities and Unmet Newborn Screening Needs over 33 Years in a Cohort of Mexican Patients with Inborn Errors of Intermediary Metabolism

“…The evolution of our technological platform could explain this, mainly the implementation of MS/MS in 2010 and the consolidation of a specialized interdisciplinary team composed of metabolic pediatricians, dietitians, biochemists, geneticists, and other professionals, such as quality-of-life experts. This team exerts joint efforts to increase the knowledge and awareness of health personnel to promote continuous training and diffusion of knowledge about NBS throughout the country [ 20 , 21 , 22 , 23 , 26 , 27 , 28 , 55 , 56 , 57 ]. Another reason could be the increase in private laboratories, including the expanded NBS service following the U.S. RUSP panel [ 12 , 31 ].…”

“…At our institution, Sanger sequencing is the only methodology available for genotyping [ 75 ]. This is the main reason why we have only performed the genetic studies of six groups of conditions (HPA/PKU [ 27 ], TYR-1 [ 76 ], GALAC [ 20 ], tetrahydrobiopterin defects (BH 4 D) [ 28 ], cystinosis (CTNS) [ 22 ], and MMA [ 21 ]) at our center and only under research protocols, not as permanently available routine tests ( Table S2 ); thus, molecular studies of the patients were not always performed at the same time of their arrival to our institution. Technological modernization and investment in adequate genotyping methods are needed to fill this gap.…”

“…Few works have been published on the epidemiology of IEiM in Mexico, and most cover regional or local experiences regarding specific disorders [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Therefore, Mexican patients with IEiM are under-represented in the current literature.…”