Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome.

BACKGROUND: Platelet α-granule biogenesis in precursor megakaryocytes is critically dependent on VPS33B and VPS16B, as demonstrated by the platelet α-granule deficiency seen in the rare multisystem disorder arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome associated with biallelic pathogenic variants in VPS33B and VIPAS39 (encoding VPS16B). VPS33B and VPS16B are ubiquitously expressed proteins that are known to interact and play key roles in protein sorting and trafficking between subcellular locations. However, there remain significant gaps in our knowledge of the nature of these interactions in primary cells from patients with ARC syndrome. OBJECTIVES: To use primary cells from patients with ARC syndrome to better understand the interactions and roles of VPS33B and VPS16B in platelets and precursor megakaryocytes. PATIENTS/METHODS: The proband and his male sibling were clinically suspected to have ARC syndrome. Confirmatory genetic testing and platelet phenotyping, including electron microscopy and protein expression analysis, was performed with consent in a research setting. RESULTS: We describe the first case of ARC syndrome identified in Costa Rica, associated with a novel homozygous nonsense VPS33B variant that is linked with loss of expression of both VPS33B and VPS16B in platelets. CONCLUSION: These results indicate that stable expression of VPS16B in platelets, their precursor megakaryocytes, and other cells is dependent on VPS33B. We suggest that systematic evaluation of primary cells from patients with a range of VPS33B and VIPAS39 variants would help to elucidate the interactions and functions of these proteins.

Current Practices and Challenges in the Diagnosis and Management of PKU in Latin America: A Multicenter Survey.

This study aimed to describe the current practices in the diagnosis and dietary management of phenylketonuria (PKU) in Latin America, as well as the main barriers to treatment. We developed a 44-item online survey aimed at health professionals. After a pilot test, the final version was sent to 25 practitioners working with inborn errors of metabolism (IEM) in 14 countries. Our results include 22 centers in 13 countries. Most countries (12/13) screened newborns for PKU. Phenylalanine (Phe) targets at different ages were very heterogeneous among centers, with greater consistency at the 0-1 year age group (14/22 sought 120-240 µmol/L) and the lowest at >12 years (10 targets reported). Most countries had only unflavored powdered amino acid substitutes (10/13) and did not have low-protein foods (8/13). Only 3/13 countries had regional databases of the Phe content of foods, and only 4/22 centers had nutrient analysis software. The perceived obstacles to treatment were: low purchasing power (62%), limited/insufficient availability of low-protein foods (60%), poor adherence, and lack of technical resources to manage the diet (50% each). We observed a heterogeneous scenario in the dietary management of PKU, and most countries experienced a lack of dietary resources for both patients and health professionals.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Wilson disease in Costa Rica: Pediatric phenotype and genotype characterization.

INTRODUCTION: The prevalence of Wilson disease (WD) in Costa Rica is among the highest reported in the world, 4.9:100 000. Previous investigators have also described a burden of autosomal recessive conditions in this country. Genetic testing for WD began in 2010 as a strategy for earlier detection due to the country's high prevalence. Here we describe what we have learned about the genotype and phenotype of the Costa Rican pediatric population with WD. METHODS: We completed a retrospective review of medical records from pediatric individuals (<18 years of age) with molecular testing for ATP7B between 2010 and 2015. We documented phenotype and genotype for cases with WD as defined by the international scoring system. RESULTS: Thirty-four WD cases from 28 families were included, 15 female and 19 male patients. The most frequent pathogenic variant in ATP7B was NM_000053:c.3809A>G, p.Asn1270Ser, with 58.8% of affected individuals homozygous for this variant. Age of diagnosis ranged from 1 to 17 years, with an average of 8.8 ± 3.6 years. All individuals who presented with acute liver failure (n = 6) were homozygous for the p.Asn1270Ser variant (Chi-squared, P < .05). DISCUSSION: Molecular testing has facilitated the detection of presymptomatic patients with WD in Costa Rica. We hope that ongoing efforts in the delivery of clinical services lead to optimized molecular screening for WD and other genetic conditions in Costa Rica.

[ALFA-1 antitrypsin deficiency, a commonly missed cause of chronic liver disease in theadult: presentation of 9 cases with review of current literature]. / Déficit de Alfa-1 antitripsina, una causa de hepatopatía crónica comúnmente insospechada en el adulto: presentación de 9 casos con revisión de literature.

INTRODUCTION: Alfa 1-antitrypsin deficiency is one of the most prevalent genetic diseases in the human being, sadly it is not a commonly suspected clinical entity. With more than 100 known mutations, those associated with hepatic disease are the Z homocygote allele mutations in the gene a1AT which occur in every 2000-3500 births. Opposing to the pulmonary disease, in which de sequelae are caused by the deficit of this protein which in turn fastens the enzymatic destruction of the airway microstructure, the hepatic compromise is secondary to the intracellular accumulation of the aberrant misfolded protein. This accumulation causes cellular damage, hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma through activation of a series of mechanisms which culminate in hepatocitary apoptosis, regeneration and chronic cellular injury. MATERIALS AND METHODS: 9 cases of confirmed a1AT deficiency are presented, from different ages ranging from adolescence through elderly patients. RESULTS: Each of one of them with different clinical presentation going from asymptomatic liver enzyme elevations to transplanted cirrhosis in which the diagnosis was post procedural. CONCLUSION: We comment about the management of the chronic liver disease and the evolution of these patients through time in the liver clinic.

Déficit de Alfa-1 antitripsina, una causa de hepatopatía crónica comúnmente insospechada en el adulto: presentación de 9 casos con revisión de literatura / ALFA-1 antitrypsin deficiency, a commonly missed cause of chronic liver disease in the adult: presentation of 9 cases with review of current literature

Introducción: El déficit de alfa-1 Antitripsina (a1AT) es una de las enfermedades genéticas más prevalentes en el ser humano, lastimosamente como entidad clínica tiende a ser pobremente sospechada. Con más de 100 mutaciones conocidas, las que se encuentran asociadas a enfermedad hepática son los homocigotos Z en el alelo del gen a1AT que ocurre en 1 a 2000- 3500 nacimientos. A diferencia de la enfermedad pulmonar donde las secuelas ocurren primordialmente por el déficit propio de la a1AT con destrucción enzimática de la microestructura de la vía aérea, el compromiso hepático ocurre por acúmulo intracelular de la proteína Z mutante, que se desdobla de forma aberrante, en vez de ser secretada. Esta acumulación produce lesión celular, hepatitis, fibrosis, cirrosis y carcinoma hepatocelular (CHC) por desencadenar una serie de eventos que culminan con la apoptosis hepatocitaria, regeneración e injuria crónica. Materiales y métodos: Se presentan 9 casos de pacientes que se han encontrado bajo nuestro cuidado, con edades variadas desde infantes hasta adultos mayores. Resultados: Cada uno con una presentación clínica distinta que va desde la elevación de enzimas hepáticas y otros como cirrosis que se han trasplantado con diagnóstico confirmatorio postquirúrgico. Conclusión: Se comenta acerca del manejo de la hepatopatía y su progresión a lo largo del tiempo que se han mantenido en la clínica de hígado a nuestro cargo.

Introduction: Alfa 1-antitrypsin deficiency is one of the most prevalent genetic diseases in the human being, sadly it is not a commonly suspected clinical entity. With more than 100 known mutations, those associated with hepatic disease are the Z homocygote allele mutations in the gene a1AT which occur in every 2000-3500 births. Opposing to the pulmonary disease, in which de sequelae are caused by the deficit of this protein which in turn fastens the enzymatic destruction of the airway microstructure, the hepatic compromise is secondary to the intracellular accumulation of the aberrant misfolded protein. This accumulation causes cellular damage, hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma through activation of a series of mechanisms which culminate in hepatocitary apoptosis, regeneration and chronic cellular injury. Materials and methods: 9 cases of confirmed a1AT deficiency are presented, from different ages ranging from adolescence through elderly patients. Results: Each of one of them with different clinical presentation going from asymptomatic liver enzyme elevations to transplanted cirrhosis in which the diagnosis was post procedural. Conclusion: We comment about the management of the chronic liver disease and the evolution of these patients through time in the liver clinic.