Journal of Nephrology & Renal Therapy Category: Clinical Type: Case Report
A Case Report of a Novel Variant of X-linked Alport Syndrome
- Robert M Gaeta1*, John M Childs2, Anandita A Datta2, Juvianee Estrada Veras3, Robert Nee4, Christina M Yuan4, John S Thurlow4
- 1 Nephrology Service, Department Of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, United States
- 2 Pathology Service, Walter Reed National Military Medical Center, Bethesda, Maryland, United States
- 3 Pediatrics Medical Genetics And Metabolism, Walter Reed National Military Medical Center, Bethesda, Maryland, United States
- 4 Department Of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, United States
*Corresponding Author:Robert M Gaeta
Nephrology Service, Department Of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, United States
Received Date: Jun 14, 2018 Accepted Date: Jul 20, 2018 Published Date: Aug 09, 2018
Past medical history was notable for compartment syndrome requiring bilateral lower extremity compartment release six years ago. He is an active duty service member and completed two prior deployments. His mother progressed to ESRD due to an unknown etiology at age 35, which prompted a formal pedigree evaluation (Figure 2). His maternal grandfather died at 50, and three maternal great uncles had known kidney disease. No one in the family was previously biopsied. Blood pressure was 146/92 mmHg. Physical examination was unremarkable with no lower extremity edema.
Figure 2: Pedigree structure. Proband is arrowed. Squares represent males, circles represent females. Family history is relevant for ESRD and nephritic syndrome in his mother and three maternal great-uncles. His Maternal grandfather had a history of kidney disease, without ESRD, and passed away at the age of 50 years from an unknown etiology. The proband has a 4-year-old daughter his history of febrile seizures, allergies and asthma. Her carrier status for COL4A5 c.901G>A (p.Gly301Ser) is unknown. She has no history of hematuria.
His first Urinalysis (UA) five years prior to presentation and all subsequent UAs demonstrated 3+ blood and 2-3+ proteinuria. Urine sediment analysis on presentation was remarkable for 60-100 dysmorphic RBCs. His serum creatinine ranged from 1-1.3 mg/dl for all available data points over the last 5 years, with cystatin-C level of 0.63 mg/L on presentation (CKD-EPI Creatinine-Cystatin C eGFR 102ml/min/1.73m2). Serum albumin was 4.1g/dL and he had 7.7gm/24 hour of urine protein. Serum complement was negative and HIV screening negative. A renal ultrasound was unremarkable.
Because of nephrotic-range proteinuria and strong family history of renal disease, renal biopsy and genetic testing were performed. Renal biopsy demonstrated FSGS with non-diagnostic ultrastructural findings (Figure 3). NGS and Sanger Sequencing revealed a COL4A5 missense variant, a substitution of adenine for guanine at nucleotide 901(c.901G>A) of the coding DNA predicting a glycine to serine substitution at amino acid 301 (p.Glyc301Ser). The clinical genetic testing was performed at Prevention Genetics, LLC (Marshfield, WI). This variant has not been reported in the literature or in databases cataloguing natural human genetic variation including dbSNP and the 1000 Genomes project.
The variant genotype has significant implications for individual prognosis. A study of 175 X-linked AS families demonstrated that rate of progression of renal and extra-renal manifestations was associated with the type of mutation, where those with Gly-Xaa-Yaa variants reached ESRD at a median of 33 years compared with 25 years for truncating mutations . In contrast to non-Gly-Xaa-Yaa variants, there was no relationship between mutation position and age of ESRD in those with Gly-Xaa-Yaa variants . This variant also has implications for COL4A3-5 expression (~25% of AS patients)  and we expect expression marks a lower risk for post renal transplant anti-glomerular basement membrane disease.
In conclusion, genetic testing is essential for appropriate management of familial FSGS. We report a case of X-linked AS due to a novel COL4A5 variant detected by NGS. Correct diagnosis allowed for appropriate genetic counseling and treatment, including ACE inhibitor therapy and the avoidance of immunosuppression. Diagnosis also facilitated appropriate disposition to a medical evaluation board given his expected progression to ESRD and high risk for later hearing loss .
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Citation:Gaeta RM, Childs M, Datta AA, Veras JE, Nee R, et al. (2018) A Case Report of a Novel Variant of X-linked Alport Syndrome. J Nephrol Renal Ther 4: 017.
Copyright: © 2018 Robert M Gaeta, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.