A family case of X-linked Alport syndrome patients with a novel variant in COL4A5

Abstract

We herein report 2 Japanese patients with X-linked Alport syndrome (XLAS), with a novel variant in COL4A5 . Patient 1 was a 16-year-old Japanese girl with a history of microscopic hematuria, without proteinuria, renal dysfunction, deafness, or ocular abnormalities. At 13 years of age, renal biopsy was performed; however, a diagnosis of AS was not considered. When her mother (patient 2) was 40 years of age (3 years after patient 1 underwent a renal biopsy), patient 2 was found to have asymptomatic hematuria, proteinuria, and an increased serum creatinine level, without deafness and ocular abnormalities. Subsequently, immunofluorescence staining for alpha 5 chains of type IV collagen was performed in patient 1. Pathological findings were consistent with AS, and genetic analysis demonstrated that both patients had a heterozygous mutation in COL4A5 (NM_000495.4: exon41:c.C3769T: p.Q1257X). To date, more than 900 different COL4A5 mutations have been identified; however, this variant has not been previously described. Physicians have to consider AS when they perform a renal biopsy in all patients with hematuria despite absent/present of family history, hearing loss, and ocular abnormality. Especially, when findings of light microscopy and immunofluorescence microscope are unclear, it should be considered carefully. Electron microscopy findings are very important.

Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

“…Male patients with XLAS mutations are affected more severely than females [20], with about 70% of male patients developing ESRD before the age of 30 years [21]. In women with XLAS, the severity of the phenotype varies because of the 2 X chromosomes [22]. The initial manifestations that result in ESRD can occur at any time between the first and seventh decade of life in affected women [23].…”

Síndrome de Alport: una genómica para tener presente

“…El colágeno de tipo IV es crucial en la estabilidad de la membrana basal y comprende aproximadamente el 50 % de la masa proteica total (14,17) . La presencia de inflamación crónica es uno de los mecanismos que genera alteraciones renales (17,18) . La inflamación crónica en los compartimientos tubulointersticial y glomerular, acompañado de disfunción metabólica son las vías finales comunes en la patogenia de la progresión de la enfermedad renal crónica asociadas a la disminución de la tasa de filtración glomerular (18,19) .…”

“…La presencia de inflamación crónica es uno de los mecanismos que genera alteraciones renales (17,18) . La inflamación crónica en los compartimientos tubulointersticial y glomerular, acompañado de disfunción metabólica son las vías finales comunes en la patogenia de la progresión de la enfermedad renal crónica asociadas a la disminución de la tasa de filtración glomerular (18,19) . La inflamación aguda es una respuesta inmune natural a la lesión renal y desempeña un papel fundamental en la reparación de las células renales después del daño.…”

“…En niños se debe realizar valoración audiológica y visual cada uno o dos años a partir de los 6-7 años. En individuos masculinos con mutación XLAS se realizará un control periódico por riesgo de alteraciones vasculares (aneurismas aórticos) (18) .…”

Genome-Wide Study Updates in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN)

“…It is well established that genetic factors contribute to the development and progression of specific types of chronic kidney disease (CKD), yet many previous studies have been limited in scope due to small sample sizes and genotyping strategies (Azarpira et al, 2014; Misra et al, 2014; Phelan et al 2014; Parsa et al, 2017; Stapleton et al, 2018). Studies of families with severe phenotypes of diseases, such as Alport’s Syndrome and Fabry Disease, have significantly contributed to the understanding of the genetic characteristics of these conditions (Gillion et al, 2018; Kashiwagi et al, 2018; McCloskey et al, 2018). However, milder forms of these diseases and their role in the development of ESRD have yet to be explored in great depth.…”