Solid organ transplantation in primary mitochondrial disease: Proceed with caution

Parikh, Sumit; Karaa, Amel; Goldstein, Amy; Ng, Yi Shiau; Gorman, Gráinne; Feigenbaum, Annette; Christodoulou, John; Haas, Richard; Tarnopolsky, Mark A.; Cohen, B; Dimmock, David; Feyma, Tim; Koenig, Mary Kay; Mundy, Helen; Niyazov, Dmitriy; Saneto, Russell P.; Wainwright, Mark S.; Wusthoff, Courtney J.; McFarland, Robert; Scaglia, Fernando

doi:10.1016/j.ymgme.2016.04.009

Cited by 62 publications

(42 citation statements)

References 24 publications

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“…Although liver transplantation remains the only treatment option for liver failure in this disease, liver transplantation in mitochondrial hepatopathies remains controversial, largely because of the multiorgan involvement in mitochondrial diseases (Parikh et al., ). Liver transplantation has been performed for ∼20% of affected children; however, the outcome has not been satisfactory with ∼60% of the transplanted children died during the post‐transplantation period.…”

Section: Managementmentioning

confidence: 99%

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

et al. 2018

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Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.

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Section: Managementmentioning

confidence: 99%

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

et al. 2018

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“…However, liver transplantation in mitochondrial hepatopathy remains controversial, largely because of the multi-organ involvement [85]. Although, liver transplantation is not recommended in children with Alpers-Huttenlocher syndrome because liver transplantation does not change the rapid progression of the neurological manifestations, liver transplantation in adults with other POLG -related mtDNA depletion syndromes who have an acceptable quality of life may be beneficial [86].…”

Section: Liver and Stem Cell Transplantationmentioning

confidence: 99%

Therapies for mitochondrial diseases and current clinical trials

El‐Hattab

Zarante

Almannai

et al. 2017

Molecular Genetics and Metabolism

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154

113

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Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, ribo-flavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.

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“…Patients with MD are generally at risk for worsening of their disease by the catabolic stress associated with transplantation and associated risks of infection or medication-related toxicity. However, in a recent case series that examined the largest group of post-transplant patients (35 patients) with primary MDs to-date who underwent either liver, kidney, or heart transplantation, the majority of patients did not have worsening of their MD within 90 days of their transplantation [19]. The authors also reported that post-transplant complications, including organ rejection, were not a common occurrence.…”

Section: Discussionmentioning

confidence: 99%

Focal segmental glomerulosclerosis associated with mitochondrial disease

Lim¹,

Steele²,

Fenves³

et al. 2017

CNCS

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Primary mitochondrial diseases (MD) are complex, heterogeneous inherited diseases caused by mutations in either the mitochondrial or nuclear DNA. Glomerular diseases in MD have been reported with tRNA mutation m.3243A>G causing a syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). We describe here a case of focal segmental glomerulosclerosis (FSGS) associated with a new tRNA mutation site. A 34-year-old man with a history of living related kidney transplantation, diabetes, hearing loss, and developmental delay presented to the outpatient clinic with complaints of new behavioral difficulties, worsening symptoms, and brain involvement on imaging. Physical examination was remarkable for difficulty hearing, a pattern of dysarthric speech, and cerebellar gait. Laboratory investigations including lactate levels were unremarkable. Based on this set of clinical circumstances, concern for an underlying genetic abnormality was raised. Multiple metabolic tests were unremarkable. Whole exome sequencing revealed a mitochondrial MT-TW tRNA change at position m.5538G>A. Genotype-phenotype correlations are consistent with this tRNA mutation as a cause of his symptoms. To the best of our knowledge, this is the first case describing FSGS-associated MD caused by an m.5538 G>A mutation. Consideration of an underlying MD should be made in patients presenting with deafness, neurologic changes, diabetes, and renal failure.

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Solid organ transplantation in primary mitochondrial disease: Proceed with caution

Cited by 62 publications

References 24 publications

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

Therapies for mitochondrial diseases and current clinical trials

Focal segmental glomerulosclerosis associated with mitochondrial disease

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