Early-onset of ADCK4 glomerulopathy with renal failure: a case report

Abstract

BackgroundWe present a rare early presentation of a ADCK4-related glomerulopathy. This case is of interest as potentially treatable if genetic results are timely obtained.Case presentationWe report the case of a 5-year-old boy who was identified with significant proteinuria by a urinary routine screening program for school children. Physical examination revealed dysplastic ears and abnormal folded pinna. Albumin level was 41 g/L (39–53 g/L), and urine proteins/creatinine ratio was 2.6 g/g. Renal ultrasound showed enlarged kidneys and perimedullary hyperechogenicity. Treatment by angiotensin-converting-enzyme inhibitor was not beneficial. Renal biopsy showed signs of focal segmental glomerulosclerosis. After 4 years of follow-up, he developed a clinical nephrotic syndrome and no response to prednisone and other immunosuppressive agents was obtained. Within 6 months, he was in end-stage-renal-failure (ESRF) and hemodialysis was started. He was transplanted at 10 years with his mother’s kidney. Genes known to be responsible in steroid-resistant nephrotic syndromes were tested. Our patient is compound heterozygous for two mutations in the aarF domain-containing-kinase 4 (ADCK4) gene. ADCK4 gene is one of the genes involved in coenzyme Q10 (CoQ10) biosynthesis, is located in chromosome 19q13.2 and expressed in podocytes. ADCK4 mutations show a largely renal-limited phenotype. The nephropathy usually presents during adolescence, fast evolves towards ESRF, and may be treatable by CoQ10 supplementation if started early in the disease. Our patient presented nephrotic range proteinuria at 5 years, and he reached ESRF at 10 years.ConclusionADCK4-related glomerulopathy is an important novel and potentially treatable cause of isolated nephropathy not only in adolescents, but also in children in their first decade of life. Discovery of important proteinuria in an asymptomatic child should prompt early genetic investigations.

Clinical syndromes associated with Coenzyme Q10 deficiency

“…Also, the 2 COQ7 patients described showed peripheral polyneuropathy, again with SNHL and one of them with visual dysfunction(101,102). SNHL is very frequent, especially in COQ6 patients(16/26) (69,71,(107)(108)(109), /74), which generally progressed to ESRD(50,64,110,(112)(113)(114)(115)(116). Onset of SRNS may be before 10 years of age (29/74).Patients with PDSS1 (1/3) (96) and PDSS2 (7/7) (71,97-100)mutations also showed SRNS.…”

Estimating the occurrence of primary ubiquinone deficiency by analysis of large-scale sequencing data

“…Additionally, our list of known pathogenic variants may not have included variants detected as part of recent large-scale studies 39 – 41 , and the fact that some UQ biosynthesis genes were found to be associated with disease earlier than others (e.g., COQ2 was first found in 2006 42 , vs. COQ8B in 2013 29 and COQ7 in 2015 43 ) could have delayed the introduction of some genes into widely used genetic screening panels 44 , meaning that more patients were screened for some genes compared to others. Finally, after the literature review phase of our analysis was concluded, novel pathogenic variants have continued to be described in the clinical literature (e.g., COQ4 45 , COQ6 46 , COQ7 47 , ADCK4 48 , 49 ), indicating that many remain to be reported.…”

A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes

“…Many signs and symptoms of CoQ10 deficient patients are common among other mitochondrial diseases; these involve multiple organ systems and often show prominent neurologic and myopathic features. However, glomerular dysfunction, such as early-onset FSGS and/or SRNS, is peculiar to CoQ10 deficiencies because of the following mutations: PDSS2 [6,7], COQ2 [8], COQ6 [9,10], and COQ8B [11,12,[19][20][21][22][23][24]. Of four genes, mutation in COQ8B causes selective glomerular phenotype mostly without neurological and myopathic deficits [11,12,[19][20][21][22][23][24].…”

“…However, glomerular dysfunction, such as early-onset FSGS and/or SRNS, is peculiar to CoQ10 deficiencies because of the following mutations: PDSS2 [6,7], COQ2 [8], COQ6 [9,10], and COQ8B [11,12,[19][20][21][22][23][24]. Of four genes, mutation in COQ8B causes selective glomerular phenotype mostly without neurological and myopathic deficits [11,12,[19][20][21][22][23][24]. The age at onset is usually between 5 and 20 years [11,12,[19][20][21][22][23][24][25].…”

“…Of four genes, mutation in COQ8B causes selective glomerular phenotype mostly without neurological and myopathic deficits [11,12,[19][20][21][22][23][24]. The age at onset is usually between 5 and 20 years [11,12,[19][20][21][22][23][24][25].…”