Sinda Zarrouk-Mahjoub

Considerations about the genetics of left ventricular hypertrabeculation/non-compaction.

Left ventricular hypertrabeculation is a cardiac abnormality increasingly recognised by neurologists as well. According to the American Heart Association/European Heart Association guidelines, left ventricular hypertrabeculation, also known as left ventricular non-compaction or non-compaction, is an unclassified cardiomyopathy characterised by a regionally bi-layered left ventricular myocardium distal to the papillary muscles. The endocardial layer is thicker than the epicardial layer and is characterised by a meshwork of interwoven myocardial strands lined with endocardium. The epicardial layer is thinner than the endocardial layer and is compacted. Spaces between trabeculations are perfused from the ventricular side, but the nonphysiological flow facilitates thrombus formation. Non-compaction may occur in isolation without other cardiac diseases or together with other cardiac abnormalities – such as hypertrophic, dilated, or restrictive cardiomyopathies – or cardiac malformations – such as Ebstein’s anomaly, tetralogy of Fallot, ventricular septal defect, atrial septal defect, hypoplastic right ventricle, non-compaction of the right ventricle, myocardial bridges, absence of the pericardium, mitral valve prolapse, tricuspid atresia, pulmonary atresia, bi-cuspid aortic valve, congenital aortic stenosis, double-orifice mitral valve, aortic interruption, patent ductus arteriosus, congenital atresia of the coronary arteries, or coronary aneurysms. Non-compaction is usually asymptomatic but can be complicated by cardiac embolism, ventricular arrhythmias with sudden cardiac death, or heart failure. The aetiology of non-compaction is unknown, but in the majority of cases it is speculated to result from non-compaction of the myocardium during embryogenesis. This assumption is challenged by patients who are diagnosed with non-compaction in adulthood but do not show non-compaction on previous echocardiographies (acquired non-compaction). In addition, 7% of primigravida develop noncompaction during pregnancy, and 25% develop hypertrabeculation, although the differentiation between non-compaction and hypertrabeculation in the latter study is unclear. Non-compaction has also been observed 2 weeks post-partum. A third argument that supports the hypothesis that noncompaction is not only congenital is the observation that athletes develop hypertrabeculation of the left ventricle when performing extreme exercise training. In pregnant females, the development of non-compaction was attributed to increased pre-load conditions. Several other speculations such as reduced adhesion of cardiomyocytes, frustrate attempt to overcome a metabolic defect, weak myocardium, microinfarction, adaptation to increased stroke volumes, or enlargement of the endocardium to improve oxygenation have been raised to explain acquired non-compaction. In rare cases, non-compaction may disappear over time. Non-compaction is frequently associated with a variety of different neuromuscular disorders (Table 1), but no causal relationship between noncompaction and any neuromuscular disorder has been established so far. A strong argument against a causal relationship is that non-compaction occurs only in a minority of patients with neuromuscular disorders, even when they are systematically screened for noncompaction. A further argument against a causal relationship is the large variability of neuromuscular disorders that are associated with non-compaction, suggesting a compensatory rather than a causal mechanism. An argument in favour of a hereditary cause, however, is the familial occurrence of noncompaction. As up to 80% of the patients with noncompaction are associated with a neuromuscular disorder, it is recommended to screen non-compaction patients systematically for neuromuscular disorders. Correspondence to: J. Finsterer, MD, PhD, Postfach 20, 1180 Vienna, Austria. Tel: + 431 711 659 2085; Fax: + 431 478 1711; E-mail: fifigs1@yahoo.de Cardiology in the Young (2015), 25, 1435–1437

Leber’s hereditary optic neuropathy is multiorgan not mono-organ

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder with bilateral loss of central vision primarily due to mitochondrial DNA (mtDNA) mutations in subunits of complex I in the respiratory chain (primary LHON mutations), while other mtDNA mutations can also be causative. Since the first description, it is known that LHON is not restricted to the eyes but is a multisystem disorder additionally involving the central nervous system, ears, endocrinological organs, heart, bone marrow, arteries, kidneys, or the peripheral nervous system. Multisystem involvement may start before or after the onset of visual impairment. Involvement of organs other than the eyes may be subclinical depending on age, ethnicity, and possibly the heteroplasmy rate of the responsible primary LHON mutation. Primary LHON mutations may rarely manifest without ocular compromise but with arterial hypertension, various neurodegenerative diseases, or Leigh syndrome. Patients with LHON need to be closely followed up to detect at which point organs other than the eyes become affected. Multiorgan disease in LHON often responds more favorably to symptomatic treatment than the ocular compromise.

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.

The Eye on Mitochondrial Disorders.

Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome.

Pro- and anti-inflammatory cytokines in post-infarction left ventricular remodeling

OBJECTIVES Acute myocardial infarction (MI) leads to molecular, structural, geometric and functional changes in the heart during a process known as ventricular remodeling. Myocardial infarction is followed by an inflammatory response in which pro- and anti-inflammatory cytokines play a crucial role, particularly in left ventricular remodeling. This study aimed at evaluating serum concentrations of interleukin-8 (IL8), tumor-necrosis-factor-alpha (TNFα) and interleukin-10 (IL10), pro- and anti-inflammatory cytokines, and at correlating them with left ventricular remodeling as assessed by echocardiographic parameters. METHODS In a case-control study 30 MI patients were compared with 30 healthy controls. Serum concentrations of IL8, TNFα and IL10 were measured on day 2 and day 30 post-MI by chemiluminescence immunoassay and correlated with echocardiographic parameters. RESULTS There was an increase of IL8, and TNFα together with a decrease of IL10 at both time points. IL8 was negatively correlated with the left ventricular end-diastolic diameter (LVEDD) and positively with left ventricular systolic volume. IL10 was negatively correlated with LVEDD and left atrial volume 30days post-MI. CONCLUSION The increase of pro-inflammatory cytokines TNFα and IL8 was accompanied by decreased anti-inflammatory IL10. This imbalance between pro- and anti-inflammatory cytokines might contribute to the progression of left ventricular remodeling and may lead to heart failure.

Mitochondrial multiorgan disorder syndrome score generated from definite mitochondrial disorders

Objectives Mitochondrial disorders (MIDs) frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) at onset or evolve into MIMODS during the course. This study aimed to find which organs and/or tissues are most frequently affected by MIMODS, which are the most frequent abnormalities within an affected organ, whether there are typical MIMODS patterns, and to generate an MIMODS score to assess the diagnostic probability for an MID. Methods This is a retrospective evaluation of clinical, biochemical, and genetic investigations of adult patients with definite MIDs. A total of 36 definite MID patients, 19 men and 17 women, aged 29–82 years were included in this study. The diagnosis was based on genetic testing (n=21), on biochemical investigations (n=17), or on both (n=2). Results The number of organs most frequently affected was 4 ranging from 1 to 9. MIMODS was diagnosed in 97% of patients. The organs most frequently affected were the muscle (97%), central nervous system (CNS; 72%), endocrine glands (69%), heart (58%), intestines (55%), and peripheral nerves (50%). The most frequent CNS abnormalities were leukoencephalopathy, prolonged visually evoked potentials, and atrophy. The most frequent endocrine abnormalities included thyroid dysfunction, short stature, and diabetes. The most frequent cardiac abnormalities included arrhythmias, systolic dysfunction, and hypertrophic cardiomyopathy. The most frequent MIMODS patterns were encephalomyopathy, encephalo-myo-endocrinopathy, and encepalo-myo-endocrino-cardiopathy. The mean ± 2SD MIMODS score was 35.97±27.6 (range =11–71). An MIMODS score >10 was regarded as indicative of an MID. Conclusion Adult MIDs manifest as MIMODS in the vast majority of the cases. The organs most frequently affected in MIMODS are muscles, CNS, endocrine glands, and heart. An MIMODS score >10 suggests an MID.

Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset

Similarities between a mitochondrial disorder (MID) and amyotrophic lateral sclerosis (ALS) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (MIMODS). However, with mild MIMODS, a MID may still be misinterpreted as ALS. We report a 48-year-old male who presented to the Neurological Hospital Rosenhügel, Vienna, Austria, in February 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. Additionally, he developed tetraspasticity and bulbar involvement. He had been diagnosed with ALS a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. However, a muscle biopsy revealed morphological features of a MID and a combined complex-II/III defect. Nerve conduction studies were performed over subsequent years until February 2011. This case demonstrates that MIDs may mimic ALS at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. A combined complex II/III defect may manifest with bulbar involvement.

Biomarkers for Detecting Mitochondrial Disorders

(1) Objectives: Mitochondrial disorders (MIDs) are a genetically and phenotypically heterogeneous group of slowly or rapidly progressive disorders with onset from birth to senescence. Because of their variegated clinical presentation, MIDs are difficult to diagnose and are frequently missed in their early and late stages. This is why there is a need to provide biomarkers, which can be easily obtained in the case of suspecting a MID to initiate the further diagnostic work-up. (2) Methods: Literature review. (3) Results: Biomarkers for diagnostic purposes are used to confirm a suspected diagnosis and to facilitate and speed up the diagnostic work-up. For diagnosing MIDs, a number of dry and wet biomarkers have been proposed. Dry biomarkers for MIDs include the history and clinical neurological exam and structural and functional imaging studies of the brain, muscle, or myocardium by ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), MR-spectroscopy (MRS), positron emission tomography (PET), or functional MRI. Wet biomarkers from blood, urine, saliva, or cerebrospinal fluid (CSF) for diagnosing MIDs include lactate, creatine-kinase, pyruvate, organic acids, amino acids, carnitines, oxidative stress markers, and circulating cytokines. The role of microRNAs, cutaneous respirometry, biopsy, exercise tests, and small molecule reporters as possible biomarkers is unsolved. (4) Conclusions: The disadvantages of most putative biomarkers for MIDs are that they hardly meet the criteria for being acceptable as a biomarker (missing longitudinal studies, not validated, not easily feasible, not cheap, not ubiquitously available) and that not all MIDs manifest in the brain, muscle, or myocardium. There is currently a lack of validated biomarkers for diagnosing MIDs.

Affection of immune cells by a C10orf2 mutation manifesting as mitochondrial myopathy and transient sensory transverse syndrome

We read with interest the article by Gelassi et al. about a 55-year-old female with chronic progressive external ophthalmoplegia (CPEO) and proximal quadruparesis and sudden onset, transient sensory transverse syndrome being attributed to a C10orf2 mutation and a clinical isolated syndrome (CIS), respectively [1]. We have the following comments and concerns. We strongly doubt that the patient had indeed a CIS. Though an association between multiple sclerosis (MS) and mitochondrial disorders (MIDs) has been occasionally reported [2], these cases are most likely misinterpretations of imaging, cerebrospinal fluid (CSF) investigations, and visually evoked potentials (VEPs). There are several arguments against CIS in the presented patient. The Lhermitte sign is non-specific. No enhancement was ever described on imaging investigations. The white matter lesions and the lesion at C7–Th1 presented in figure 1 are non-specific. Differential diagnosis to explain these lesions was not discussed. Lesions of the spinal cord in MIDs are not unusual and have been reported in Leigh syndrome [3]. They may manifest as myelopathy secondary to severe scoliosis, transverse myelitis, or as stroke-like episode (SLE) in the spinal cord. SLEs result from a metabolic break-down and are a hallmark of MELAS, but occur more rarely also in other specific or non-specific mitochondrial multiorgan disorder syndromes (MIMODS) [4]. Though SLEs most frequently occur in the brain, it cannot be excluded that they also occur in the myelon. Sudden onset of the sensory disturbances is no argument against a spinal SLE. Unilateral or bilateral prolongation of the P100 latency is not only due to optic neuritis or neuromyelitis optica (NMO), but may be a non-specific finding due to a number of different causes, including optic atrophy often not detectable on ophthalmologic investigations. Oligoclonal bands are not pathognomonic for MS. Positive oligoclonal bands are a non-specific finding and may occur in a number of other conditions, including genetic disorders. Positive oligoclonal bands in the presently described patient could be interpreted as a local immunological response to the product of a mutated gene [5]. Intrathecal IgG production may have resulted from a similar mechanism. It is also conceivable that lymphocytes are involved in the MID and become dysfunctional resulting in an impaired immune response to external or internal stimuli. An important investigation not reported in the description of the present case is nerve-conduction studies. The patient had developed sensory abnormalities and MIDs frequently go along with either primary or secondary neuropathy. Frequently, neuropathy and myopathy coexist in MIDs. Sensory abnormalities can be attributed to a spinal pathology affecting the centrifugal or centripetal sensory projections only if slowing of nerve conduction along sensory fibers or reduction of the compound muscle action potential had been excluded before unless a pathology is present in the spinal cord plus the sensory nerves. Overall, this interesting case could be more meaningful if the family history would be taken more extensively, Josef Finsterer and Sinda Zarrouk-Mahjoub have contributed equally.

Involvement of the spinal cord in mitochondrial disorders

This review aims at summarising and discussing the current status concerning the clinical presentation, pathogenesis, diagnosis, and treatment of spinal cord affection in mitochondrial disorders (MIDs). A literature search using the database Pubmed was carried out by application of appropriate search terms and their combinations. Involvement of the spinal cord in MIDs is more frequent than anticipated. It occurs in specific and non-specific MIDs. Among the specific MIDs it has been most frequently described in LBSL, LS, MERRF, KSS, IOSCA, MIRAS, and PCH and only rarely in MELAS, CPEO, and LHON. Clinically, spinal cord involvement manifests as monoparesis, paraparesis, quadruparesis, sensory disturbances, hypotonia, spasticity, urinary or defecation dysfunction, spinal column deformities, or as transverse syndrome. Diagnosing spinal cord involvement in MIDs requires a thoroughly taken history, clinical exam, and imaging studies. Additionally, transcranial magnetic stimulation, somato-sensory-evoked potentials, and cerebro-spinal fluid can be supportive. Treatment is generally not at variance compared to the underlying MID but occasionally surgical stabilisation of the spinal column may be necessary. It is concluded that spinal cord involvement in MIDs is more frequent than anticipated but may be missed if cerebral manifestations prevail. Spinal cord involvement in MIDs may strongly determine the mobility of these patients.