Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report

Lemoine, Sandrine; Panaye, Marine; Rabeyrin, Maud; Errazuriz-Cerda, Elisabeth; Camaret, Bénédicte Mousson de; Petiot, P.; Juillard, Laurent; Guebre-Egziabher, Fitsum

doi:10.1053/j.ajkd.2017.09.020

Cited by 18 publications

(9 citation statements)

References 11 publications

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“…Yet, they all share a common element—decreased energy supply as a consequence of mitochondrial dysfunction. Within this group of disorders, commonly observed mitochondrial abnormalities include mitochondrial network fragmentation [5, 6], decreased OXPHOS capacity [7], increased reactive oxygen species (ROS) [8–10], and Ca 2+ deregulation and alterations in mitochondrial ultrastructure [11–15]. All of these features are consistent with impaired regulation of the mitochondrial permeability transition pore (PTP), a conserved physiological process in mitochondria of all eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

The Mitochondrial Permeability Transition in Mitochondrial Disorders

Šileikytė

Forte

2019

Oxidative Medicine and Cellular Longevity

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Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death—a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.

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Section: Introductionmentioning

confidence: 99%

The Mitochondrial Permeability Transition in Mitochondrial Disorders

Šileikytė

Forte

2019

Oxidative Medicine and Cellular Longevity

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“…[7][8][9]16 White matter abnormalities are not uncommon in Leigh syndrome 17 ; however, ATP synthase dysfunction has been reported with this clinic-radiologic association infrequently 17,18 while chronic kidney disease with isolated proteinuria, which did not require renal replacement therapy, has been reported in a single case of NARP. 19 P2 presented with myoclonic epilepsy with RRF (MERRF)-like phenotype, typically associated with the m.8344A>G in MT-TK. Of interest the previously reported truncating MT-ATP6 mutation m.9127-9128delAT; p.(Ile201Profs*2) was associated with myoclonic epilepsy, ataxia, and cerebellar atrophy, although the muscle biopsy did not reveal RRF.…”

Section: Discussionmentioning

confidence: 99%

Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations

et al. 2020

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ObjectiveTo describe the clinical and functional consequences of 1 novel and 1 previously reported truncating MT-ATP6 mutation.MethodsThree unrelated probands with mitochondrial encephalomyopathy harboring truncating MT-ATP6 mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on ATPase 6 and complex V structure and function were investigated.ResultsPatient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86*) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs*32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86*) mutation.ConclusionsWe expand the clinical and molecular spectrum of MT-ATP6-related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating MT-ATP6 mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling.

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“…Mutations in mitochondrial gene MTTL1 causes mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (known as MELAS); diabetes; deafness; and steroid-resistant nephrotic syndrome. Steroid-resistant nephrotic syndrome has also been reported in association with a case of neuropathy, ataxia, retinitis pigmentosa syndrome (known as NARP) caused by mutation in mitochondrial gene MT-ATP6 (32). Variants in enzymes involved in the coenzyme Q10 (CoQ 10 ) biosynthesis pathway in the mitochondria result in CoQ 10 deficiency and may present with abnormalities in multiple systems including encephalopathy, neuromuscular involvement, and nephrotic syndrome.…”

Section: Transcription Factors and Nuclear And Mitochondrial Genesmentioning

confidence: 99%

Genetic Disorders of the Glomerular Filtration Barrier

Ingham

Lennon

2020

CJASN

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The glomerular filtration barrier is a highly specialized capillary wall comprising fenestrated endothelial cells, podocytes, and an intervening basement membrane. In glomerular disease, this barrier loses functional integrity, allowing the passage of macromolecules and cells, and there are associated changes in both cell morphology and the extracellular matrix. Over the past three decades there has been a transformation in our understanding about glomerular disease, fueled by genetic discovery, and this is leading to exciting advances in our knowledge about glomerular biology and pathophysiology. In current clinical practice, a genetic diagnosis already has important implications for management ranging from estimating the risk of disease recurrence post-transplant to the lifechanging advances in the treatment of atypical hemolytic uremic syndrome. Improving our understanding about the mechanistic basis of glomerular disease is required for more effective and personalized therapy options. In this review we describe genotype and phenotype correlations for genetic disorders of the glomerular filtration barrier, with a particular emphasis on how these gene defects cluster by both their ontology and patterns of glomerular pathology.CJASN 15: ccc-ccc, 2020.

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Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report

Cited by 18 publications

References 11 publications

The Mitochondrial Permeability Transition in Mitochondrial Disorders

The Mitochondrial Permeability Transition in Mitochondrial Disorders

Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations

Genetic Disorders of the Glomerular Filtration Barrier

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