The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

Abstract

ABSTRACT. The A3243G mutation of the mitochondrial tRNA(Leu) gene has been recently reported in rare patients with focal and segmental glomerulosclerosis (FSGS). However, the full spectrum of systemic and kidney manifestations in adults presenting with this mutation remains poorly defined. Assessment of renal and nonrenal manifestations was performed in nine patients with A3243G mutation and prominent kidney disease diagnosed in adulthood. At first renal evaluation, median age was 35 years. Renal lesions consisted of FSGS (n = 2), tubulointerstitial nephropathy (n = 3), or bilateral enlarged cystic kidneys (n = 1). All but one patient exhibited extrarenal manifestations: deafness (8 of 9) requiring hearing aid in half the cases, diabetes mellitus (3 of 9), neuromuscular involvement (2 of 9), hypertrophic cardiomyopathy (1 of 9), and macular dystrophy (1 of 9). After a median follow-up of 5 yr, five patients progressed to end-stage renal disease between the ages of 15 and 51 years, four being successfully transplanted. Similarly, extrarenal manifestations progressed since all patients had deafness and diabetes (including three posttransplants), while half had neuromuscular, cardiac, or retinal involvement. In the adult patients with A3243G mutation and renal involvement, preexisting deafness is almost consistently found. While FSGS remains the most typical lesion, tubulointerstitial nephropathy or bilateral, enlarged cystic kidneys may also be encountered. In most cases, diabetes mellitus, macular dystrophy, hypertrophic cardiomyopathy, or neuromuscular features occur later in the course of the disease. The severity of the clinical course is heterogeneous, with end-stage renal failure being reached between the second and sixth decades. Renal transplantation may be offered to these patients, despite a high incidence of steroid-induced diabetes mellitus. E-mail: dominique.chauveau@nck.ap-hop-paris.fr

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case–control study

“…Macular oedema was diagnosed from the presence of hard exudates within one disc diameter of the foveola. Molecular studies As previously described, the m.3243 A>G detection was based on an allele-specific PCR [17].…”

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS

“…1 In the kidney, mitochondriopathies typically cause proximal tubulopathy 2 ; however, glomerular dysfunction has been reported with mitochondrial DNA mutations in the tRNA LEU gene and coenzyme Q biosynthesis defects. [2][3][4][5] Coenzyme Q (ubiquinone; CoQ 10 ) is a component of the mitochondrial respiratory chain, 4 a potent lipophilic antioxidant, and a cofactor for mitochondrial dehydrogenases and in pyrimidine nucleoside biosynthesis. CoQ 10 is synthesized ubiquitously through a multienzyme complex at the inner mitochondrial membrane.…”

“…In patients with mutations in PDSS2, COQ2, and COQ6, the other mitochondriopathy genes associated with SRNS, renal symptoms usually occur as part of a multisystemic disease complex encompassing progressive encephalopathy, ataxia, seizures, mental retardation, deafness, retinopathy, hypertrophic cardiomyopathy, and generalized myopathy. [1][2][3][4][5]10 By contrast, ADCK4 disease typically manifests as an isolated nephropathy with only occasional extrarenal symptomatology. Combining our cohort with five previously published cases with available data on extrarenal involvement, 6 we oversee 30 patients from 17 families with detailed phenotypic information.…”

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

“…1 Mitochondrial dysfunction has been implicated in the pathogenesis of a range of renal diseases, including acute kidney injury after ischemiareperfusion (IR) injury, 2,3 the renal Fanconi syndrome, 4 and some glomerulopathies. 5 Thus, a better understanding of mitochondrial biology in the kidney may help us to develop a more rational approach to therapies.…”