Mucopolysaccharidosis Type I in Mexico: Case-Based Review.

INTRODUCTION: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease present in 1:100,000 newborns. Variants in the IDUA (alpha-L-iduronidase) gene decrease the enzyme activity for glycosaminoglycans metabolism. MPS I patients exhibit clinical manifestations that fall on the Hurler, Hurler-Scheie, and Scheie syndrome spectrum. CASE PRESENTATION: We present a male Mexican patient with respiratory exacerbations requiring recurrent hospitalizations. He showed macrocephaly, coarse facies, hepatomegaly, umbilical hernia, and dorsal kyphosis. The sequencing of the IDUA gene revealed the following genotype: c.46_57del12/c.1205G>A. He received combined therapy with hematopoietic stem cell transplantation and enzyme replacement. Mexican case reports were analyzed to estimate the prevalence of the associated genetic variants. CONCLUSION: Despite the challenges of managing this rare disease in Mexico, our patient benefited from the combined therapy. The discrete clinical manifestations and prompt evaluation by a geneticist were crucial in establishing a diagnosis, enabling an early intervention by a multidisciplinary team. The combination of ERT before and after HSCT provided health benefits to our patient.

Critical CHD screening programme: a 3-year multicentre experience in Mexico.

INTRODUCTION: CHDs are the most common type of birth defect. One in four newborns with a heart defect has a critical CHD. In Mexico, there is a lack of data available to determine its prevalence. Pulse oximetry screening programmes have been implemented worldwide, reporting opportunity areas in algorithm interpretation and data management. Our study aims to share preliminary results of a 3-year experience of a multicentre pulse oximetry screening programme that addresses critical challenges. MATERIALS AND METHODS: This retrospective study examined the reports of newborns screened from February 2016 to July 2019 from five hospitals. Two algorithms -the New Jersey and the American Academy of Pediatrics- were implemented over consecutive periods. The algorithms' impact was assessed through the calculation of the false-positive rate in an eligible population. RESULTS: A total of 8960 newborns were eligible for the study; from it, 32.27% were screened under the New Jersey and 67.72% under the American Academy of Pediatrics algorithm - false-positive rate: 1% (CI 95: ± 0.36%) and 0.71% (CI 95: ± 0.21%), respectively. Seventy-nine newborns were referred, six were diagnosed with critical CHD, and six with CHD. The critical CHD estimated prevalence was 6.69:10,000 newborns (CI 95: ± 5.36). Our results showed that the algorithm was not related to the observable false-positive rate reduction. DISCUSSION: Other factors may play a role in decreasing the false-positive rate. Our experience implementing this programme was that a systematic screening process led to more confident results, newborn's report interpretation, and follow-up.

Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case.

The intellectual disability syndrome characterized by seizures and dysmorphic features was initially described in 2017 and was associated with genetic variants in the OTUD6B gene, identified by exome sequencing (ES) in a large cohort. This multisystem disorder primarily affects the central nervous system, the gastrointestinal, and the skeletal systems. In this article, we describe the first Mexican patient diagnosed by ES. The homozygous c.433C>T (p.Arg145*) variant of the OTUD6B gene confirmed this intellectual disability syndrome. In addition to seizures and other more frequently reported manifestations of this condition, this is the third patient with associated hypothyroidism and hypogammaglobulinemia, underscoring the value of screening for these conditions in other patients. The current challenge with this patient is to ensure medical management of his seizures and provide him with a better quality of life. The possibilities of additional therapeutic approaches may increase by understanding the physiopathology of the involved pathways.

Early detection of and intervention for two newborns with critical congenital heart disease using a specialized device as part of a screening system.

Screening for critical congenital heart disease is a clinical method used for their early detection using pulse oximetry technology. This, followed by a diagnostic confirmatory protocol, allows timely therapeutic interventions that improve the newborn's outcome. According to Mexican birth statistics, approximately 18,000-21,000 neonates are born with a form of congenital heart disease each year, of which 25% are estimated to be critical congenital heart disease. We report two cases with an early critical congenital heart disease detection and intervention through an innovative critical congenital heart disease screening program implemented in two Mexican hospitals. They integrated a new automated pulse oximetry data analysis method and a comprehensive follow-up system (Cárdi-k®). Both cases were confirmed by echocardiogram, which served for an intervention in the first week of life, and the patients were discharged in good clinical condition. In addition, to the routine physical assessments, the critical congenital heart disease screening program (which includes echocardiogram for presumptive positive cases) should be implemented in a timely manner.

Clinical Characterization of 2 Siblings with a Homozygous SPAST Variant.

BACKGROUND Hereditary spastic paraplegia (HSP or SPG) consists of a heterogeneous group of disorders, clinically divided into pure and complex forms. The former is characterized by neurological impairment limited to lower-extremity spasticity. The latter presents additional symptoms such as seizures, psychomotor impairment, cataract, deafness, and peripheral neuropathy. The genetic structure of HSP is diverse, with more than 72 loci and 55 genes identified so far. The most common type is SPG4, accounting for 40% of cases. This case report describes 2 siblings presenting SPG4, one presumptive and one confirmed with a homozygous SPAST variant. CASE REPORT Two siblings born to third-degree consanguineous and healthy parents presented a SPG4 complex phenotype characterized by progressive psychomotor deterioration, mixed seizure patterns, corneal opacity, dysostotic bones, limb spasticity with extensor plantar responses, and axial hypotonia. After ruling out most inborn errors of metabolism in one of the patients, the complexity of the case derived from exome sequencing. The identification of a homozygous variant in the SPAST gene established a diagnosis for SPG4. The phenotype-genotype did not correlate to classical manifestations, most likely due to the variant's zygosity. Moreover, 34 patient's relatives were identified with SPG4 clinical manifestations or asymptomatic with the same genetic variant in heterozygous state. CONCLUSIONS We described visual loss and seizures for SPG4 complex phenotype associated with a homozygous variant in the SPAST gene. This diagnosis will lead clinicians to consider it as a differential diagnosis providing adequate genetic counseling.

Hawkinsinuria clinical practice guidelines: a Mexican case report and literature review.

Hawkinsinuria is an autosomal dominant disorder of tyrosine metabolism. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) result in an altered HPD enzyme, causing hawkinsin and tyrosine accumulation. Persistent metabolic acidosis and failure to thrive are common features in patients with hawkinsinuria. We present the first known Latin American patient diagnosed with hawkinsinuria, and the tenth reported patient in the literature. We aim to establish clinical practice guidelines for patients with hawkinsinuria. The patient's plasma tyrosine level was 21.5 mg/dL, which is several times higher than the reference value. Mutation analysis indicated heterozygosity for V212M and A33T variants in HPD. In the case of altered tyrosine levels found during newborn screening, we propose exclusive breastmilk feeding supplemented with ascorbic acid. Amino acid quantification is useful for monitoring treatment response. If tyrosinemia persists, protein intake must be decreased via a low-tyrosine diet. Molecular studies can be used to confirm a patient's disease etiology. Further reports are required to elucidate new pathogenic and phenotypic variations to enable the development of an appropriate therapeutic approach.

Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

OBJECTIVE: To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). STUDY DESIGN: Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. RESULTS: From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. DISCUSSION: NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS.

The Incidence of Transient Neonatal Tyrosinemia Within a Mexican Population

Abstract Transient neonatal tyrosinemia (TNT) is a form of hypertyrosinemia produced by the immaturity of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a high intake of phenylalanine and tyrosine, and a relative ascorbic acid deficiency. Our objectives are to determine the incidence of TNT in Mexican newborns and to correlate it based on their sex, gestational age, and weight for gestational age to determine whether these are risk factors that predict the development of TNT. A cross-sectional descriptive study was conducted from January 2006 to August 2017. We analyzed 175 976 of newborn screening reports and found that the overall incidence of TNT was 1 (0.29%) in 342 newborns. It is more prevalent in preterm infants and in small for gestational age newborns (0.35%).The TNT incidence was determined in this Mexican population, and it was established as the most frequently occurring amino acid defect. We propose that pediatricians intentionally search for this pathology to offer patients access to adequate and timely treatment.

Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital

Abstract Newborn screening for the detection of inborn errors of metabolism (IEM), endocrinopathies, hemoglobinopathies, and other disorders is a public health initiative aimed at identifying specific diseases in a timely manner. Mexico initiated newborn screening in 1973, but the national incidence of this group of diseases is unknown or uncertain due to the lack of large sample sizes of expanded newborn screening (ENS) programs and lack of related publications. The incidence of a specific group of IEM, endocrinopathies, hemoglobinopathies, and other disorders in newborns was obtained from a Mexican hospital. These newborns were part of a comprehensive ENS program at Ginequito (a private hospital in Mexico), from January 2012 to August 2014. The retrospective study included the examination of 10 000 newborns' results obtained from the ENS program (comprising the possible detection of more than 50 screened disorders). The findings were the following: 34 newborns were confirmed with an IEM, endocrinopathies, hemoglobinopathies, or other disorders and 68 were identified as carriers. Consequently, the estimated global incidence for those disorders was 3.4 in 1000 newborns; and the carrier prevalence was 6.8 in 1000. Moreover, a 0.04% false-positive rate was unveiled as soon as diagnostic testing revealed negative results. The most frequent diagnosis was glucose-6-phosphate dehydrogenase deficiency; and in the case of carriers, it was hemoglobinopathies. The benefit of the ENS is clear as it offers prompt treatment on the basis of an early diagnosis including proper genetic counseling. Furthermore, these results provide a good estimation of the frequencies of different forms of newborn IEM, endocrinopathies, hemoglobinopathies, and other disorders at Ginequito.