Josef Finsterer

Mitochondrial toxicity of cardiac drugs and its relevance to mitochondrial disorders

Introduction: One target of toxicity caused by cardiac drugs is the mitochondrion. This review focuses on the mitochondrion-toxic effects of cardiac drugs and the extent to which mitochondrion-mediated side effects influence the treatment of cardiac disease in mitochondrial disorders (MIDs). Areas covered: Areas discussed in this review include the pathogenesis of mitochondrion toxicity and the mechanisms by which cardiac drugs exhibit their mitochondrion-toxic effect. Whenever available, the mitochondrion-toxic effect of cardiac drugs in patients with a MID is highlighted. Expert opinion: Most of the drugs used in cardiology are somewhat mitochondrion-toxic. The degree of toxicity, however, is variable and dependent on the type of drug, tissue, organ, subject, cell system investigated, the co-medication, and the conditions under which the investigations have been carried out. Abnormalities induced by mitochondrion-toxic cardiac drugs include impairment of respiratory chain functions resulting in reduced ATP production, increased production of reactive oxygen species with increased oxidation of proteins or lipids, reduction of the mitochondrial membrane potential and apoptosis. Several other mitochondrial functions may be additionally impaired by culprit compounds. Cardiac drugs that should be applied with particular caution in patients with MIDs include amiodarone, phenytoin, lidocaine, quinidine, isoproterenol, clopidogrel, acetyl-salicylic acid and molsidomine.

Letter to the Editor: Endocrine Compromise in Mitochondrial Disorders

With interest we read the article by Al-Gadi et al. [1] about a retrospective study on endocrinological abnormalities in patients with a mitochondrial disorder (MID) registered in the North American Mitochondrial Disease Consortium Patient Registry. We have the following comments and concerns about the specificity of the information provided. Because endocrinological abnormalities in MIDs may not only be primary but also secondary (e.g., due to drugs, like ketoconazole, sulfnonamides, pentamidine, or infections), it would be of value to learn about the drugs that the included patients were taking regularly and about the prevalence of infectious diseases in the cohort. Likewise, patients with MIDs have an increased risk for development of benign or malign neoplasms [2]. Pituitary adenoma, adenoma of the thyroid gland, and adenoma of the suprarenal gland have been reported in MIDs [2]. Adenoma may or may not go along with endocrinological abnormalities. It would be of great interest to learn how many of the 404 included patients the registry recorded as having a hormone-producing or nonhormoneproducing neoplasm or hyperprolactinemia. Another statistic the authors [1] present relates to polycystic ovary syndrome. This condition is usually associated with menses abnormalities (e.g., amenorrhea, oligomenorrhea) [3], which the authors report separately. This raises the question of whether, in differentiating between PCOS and menses abnormalities, there is overlap of these classes. In the article, Table 1 [1] mentions adrenal insufficiency in three patients, but Al-Gadi et al. did not specify whether it was hypoaldosteronism, hypocorticism, or catecholamine deficiency. All three different types of adrenal insufficiency have been reported in MIDs, and because treatment options are available for adrenal insufficiency, it would be of value to learn which type was found. Al-Gadi et al. [1] provide statistics on the prevalence of hypothyroidism in MIDs. Because hypothyroidism in MIDs is frequently due to Hashimoto thyroiditis, it would be of value to learn how many of the patients with hypothyroidism were thyroperoxidase-antibody or TRAC-antibody positive. In general, because most of the endocrine abnormalities in MIDs are accessible to treatment, it would have been helpful to learn how many received appropriate substitution and how often it was beneficial. There are a number of MIDs associated with endocrinological disorders that are due to depletion of the mitochondrial DNA (mtDNA) [4]. It would be of value to learn how many of

Frequency of Primary LHON Mutations in Northern India

In a recent study by Mishra et al. the genetic background of 40 patients with Leber’s Hereditary Optic Neuropathy (LHON) from Northern India was investigated [1]. Eleven of the 40 patients (27.5%) were found to carry the primary LHON mutation m.11778G>A [1]. In one family, two primary LHON mutations, m.11778G>A and m.14484T>C, were found in the proband and his mother respectively [1]. The authors concluded that the m.11778G>A variant is more frequent among the Indian population than other primary LHON mutations [1]. We have the following comments and concerns. During recent years it turned out that Mitochondrial Disorders (MIDs) including LHON are not necessarily mono-organ diseases but rather progressive multisystem disorders [2]. Affected organs / tissues other than the retinal ganglion-cells and optic nerve include the Central Nervous System (CNS) (psychomotor delay, dementia, epilepsy, leukoencephalopathy, Posterior Reversible Encephalopathy Syndrome (PRES), migraine, chorea, ataxia), the ears (hypoacusis), endocrine organs (diabetes, thyroid dysfunction, parathyroid dysfunction, pituitary adenoma), the heart (left ventricular hypertrabeculation / noncompaction, dilated cardiomyopathy, supraventricular and ventricular arrhythmias, syncope, angina, Sudden Cardiac Death (SCD)), the bone-marrow (anemia), arteries (aortic stiffness), the kidneys (renal insufficiency), or the peripheral nerves (neuropathy) [2]. Thus, we recommend prospectively investigating the 40 patients for subclinical or mild manifestations of a multisystem disease (Mitochondrial Multiorgan Disorder Syndrome (MIMODS)). Usually, a single, primary, homozygous LHON mutation is sufficient for phenotypic expression [3]. Interestingly, in one family two primary LHON mutations (m.11778G>A, m.14484T>C) were found. Were both variants present in the homozygous form, was there compound heterozygosity, and were both variants pathogenic? Was the phenotype more severe than in the other patients who carried only a single mutation? Which were the heteroplasmy rates of the mtDNA variants found in the 40 included patients? We recommend to investigate the cohort in a future study for the following points: how often were the mutations detected in the 40 patients de-novo and how often inherited; how many of the parents of those with a genetic diagnosis also carried a mutation; did any of the parents of the 40 included patients manifest with LHON or other clinical manifestations of a MID; were the parents systematically investigated for clinical or subclinical MID? There are indications that visual impairment spontaneously resolves in some LHON patients, particularly in those carrying the m. 11778G>A variant [4]. In a future study the authors could address the question in how many of the patients carrying the m.11778G>A variant resolution of visual impairment was observed over time. Recently, treatment with idebenone (Raxone®, 900 mg/d) has been approved by the European Medicine Agency (EMEA) for treating LHON patients with acute visual loss due to one of the three primary LHON mutations [5]. In a future study the authors could address the questions how many of the included patients were regularly taking idebenone, in which dosage they were taking idebenone, and if they profited from the treatment? This interesting study could be more meaningful if the included patients would be investigated in a future study for involvement of organs other than the eyes and the optic nerve, for heteroplasmy rates, for haplogroups, and for clinical and genetic manifestations in first-degree relatives. A more widespread discussion about the phenotype and the genetics may stimulate further research to answer at least some of the open questions.

Are NO Precursors Truly Effective in MELAS

We read with interest the review article by El-Hattab et al about the effect of nitric oxide (NO) precursors in the treatment of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome and of strokelike episodes (SLEs) in particular. We have the following comments and concerns. NO deficiency in mitochondrial disorders (MIDs) is most likely a secondary phenomenon and not the primary causative mechanism that leads to clinical manifestations in MIDs. Whether supplementation with NO precursors truly increases the intracellular and serum levels of NO is questionable. However, there are a number of reports, pretending a beneficial effect of NO precursors for MIDs in general and for SLEs in particular. On the other hand, no systematic studies with an appropriate design (double-blind, placebo-controlled crossover) had been carried out that proved or disproved effectiveness of NO precursors in MELAS or SLEs. Furthermore, it has been reported that headache as a manifestation of a SLE may be resistant to L-arginine. The authors mention a number of therapeutic options available for patients with MID. However, many options are not addressed, particularly those which may significantly prolong life in these patients. These include oral anticoagulation, heart failure therapy, antiarrhythmic therapy with drugs or implantation of a pacemaker, a cardiac resychronisation therapy (CRT) system, or an implantable cardioverter defibrillator, and invasive or noninvasive mechanical ventilation. In this respect, it is necessary to mention idebenone as an approved drug for the treatment of patients with Leber hereditary optic neuropathy, which has been shown to improve color vision, increase cellspecific ATP production, and decrease oxidative stress. We do not agree with the statement that SLEs represent ischemic strokes. Stroke-like episodes are the clinical manifestation of a stroke-like lesion (SLL) on MRI, which is clearly distinguishable from an ischemic lesion. The main difference between the 2 is that SLLs are not confined to a vascular territory, whereas ischemic stroke is restricted to the vascular territory of the occluded artery. A second difference is that SLLs manifest as vasogenic edema (hyperintensity on diffusion weighted imaging [DWI], hyperintensity on apparent diffusion coefficient [ADC]) and that ischemic lesions manifest as cytotoxic edema (hyperintensity on DWI, hypointensity on ADC). A third difference is that SLLs show a dynamic course over days, weeks, or even months, whereas ischemic lesions usually reach its final stage within a few days after onset. Fourth, residual imaging findings may also differ between the 2 entities (laminar cortical necrosis, toe-nail sign, white matter lesions, normal brain in SLLs and lacunas, cysts, or white matter lesions in ischemic stroke). Since SLEs are frequently associated with seizures, it is essential that EEGs are recorded in all patients with a MID experiencing a SLE. As soon as seizure activity is recorded, patients with an SLE require treatment with an antiepileptic drug (AED). However, only nonmitochondrion-toxic AEDs and AEDs that are applicable intravenously should be given. Particularly avoided should be valproic acid, carbamazepine, phenytoin, and barbituric acid. In summary, there is currently no proof from appropriately designed studies that NO precursors are effective in MIDs or SLEs. Stroke-like episodes need to be differentiated from ischemic stroke, since treatment options vary considerably between these 2 conditions. There is also a need to record EEGs during SLEs since AEDs may be indicated. In general, patients with MID profit significantly from symptomatic treatment, particularly in case of cerebral or cardiac involvement.

Pathogenicity of AIFM1 Variants and Beneficial Effect of Riboflavin Need to Be Appropriately Confirmed

We read with interest the article by Heimer et al. about two pediatric patients with X-linked cerebellar ataxia due to two different mutations in the AIFM1 gene. We have the following comments and concerns. nWe do not agree that the mutation c.422C>T is truly pathogenic. Pathognicity was claimed after in-silico prediction and after protein modelling. No other family member carried the mutation, thus there was no segregation, and no biochemical or functional investigations were carried out. Location of the variant in a region where pathogenic mutation cluster not necessarily implies that the variant c.422T>C is also pathogenic. nPatient 2 was initially diagnosed with epilepsia partialis continua and three antiepileptic drugs (AEDs), benzodiazepines, valproic acid, and levetirazetam, were tried, but without effect. Why were only 3 AEDs given and no further AEDs tried? Were they given in monotherapy or in combination? Why was valproic acid chosen from which it is well known that it is mitochondrion-toxic and can even cause fatalities in some mitochondrial disorders (MIDs). Did the authors try pirazetam or was the patient ever put on a ketogenic diet?

Comment to: Focal segmental glomerulosclerosis associated with mitochondrial disease by Lim et al. in Clin Nephrol Case Stud. 2017; 5: 20-25.

Not available.

Phenotypic Heterogeneity of the m.14459G>A Mutation

The authors read with interest the article by Kurt et al about 2 unrelated, pediatric patients carrying the mutation m.14459G>A in the ND6 gene, which manifested clinically as Leigh-like syndrome with generalized dystonia. The authors have the following comments and concerns. The authors do not agree with the statement in the Introduction that most of the mutations affecting subunits of complex I of the respiratory chain are maternally inherited. Only 7 of the 44 subunits of complex I are mtDNA-encoded. Thus, it is much more likely that genes located on the nDNA are mutated in case of complex I defects. Were reduced tendon reflexes in patient 2 attributable to myopathy or neuropathy? Since myopathy is more frequent than neuropathy in mitochondrial disorders and since bilateral ptosis was present, myopathy is much more likely. Were there other indications for myopathy, such as myalgia, cramps, fasciculations, easy fatigability, exercise intolerance, or creatine kinase elevation? The readers should be informed about the results of nerve conduction studies and electromyography in this patient. Mitochondrial disorders frequently present with elevated cerebral lactate. Did the 2 patients undergo magnetic resonance spectroscopy or lumbar puncture to see whether lactate in the cerebrospinal fluid was elevated or not? Was lactate elevated in the serum or was the lactate stress test abnormal? The authors mention “stroke” as clinical manifestation of a m.14458G>A mutation. Do they mean ischemic stroke or a stroke-like episode, frequently found in mitochondrial disorders? Were cardiovascular risk factors, such diabetes, arterial hypertension, hyperlipidemia, smoking, or atrial fibrillation, positive in this particular patient? Were imaging findings indicative of an ischemic stroke or a stroke-like lesion? Which therapy did this patient receive for the “stroke”? Leber’s hereditary optic neuropathy is more frequently due to homoplasmic than heteroplasmic mtDNA mutations. The authors describe 3 patients with Leber’s hereditary optic neuropathy in Table 1 in whom the mutation was heteroplasmic. How to explain heteroplasmy in these 3 Leber’s hereditary optic neuropathy patients? Did visual impairment recover in these 3 patients? Due to marked phenotypic heterogeneity of heteroplasmic mtDNA mutations and high intrafamilial heterogeneity, family members of both index cases should be extensively investigated for subclinical involvement of organs frequently affected in mitochondrial disorders, such as the brain, endocrine, organs, muscle, nerve, heart, intestines, or the kidney. Heteroplasmy rate in the mothers may go undetected if very low. Overall, this interesting case study could be more meaningful by providing more clinical data, by providing explanations for some unusual findings, and by a more extensive investigation of first-degree family members.