Among the various central nervous system (CNS) manifestations of mitochondrial disorders (MIDs), cognitive impairment is increasingly recognized and diagnosed (mitochondrial cognitive dysfunction). Aim of the review was to summarize recent findings concerning the aetiology, pathogenesis, diagnosis and treatment of cognitive decline in MIDs. Among syndromic MIDs due to mitochondrial DNA (mtDNA) mutations, cognitive impairment occurs in patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome, myoclonus epilepsy with ragged-red fibres syndrome, mitochondrial chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, neuropathy, ataxia and retinitis pigmentosa syndrome and maternally inherited diabetes and deafness. Among syndromic MIDs due to nuclear DNA (nDNA) mutations, cognitive decline has been reported in myo-neuro-gastro-intestinal encephalopathy, mitochondrial recessive ataxia syndrome, spinocerebellar ataxia with encephalopathy, Mohr-Tranebjaerg syndrome, leuko-encephalopathy; brain and spinal cord involvement and lactic acidosis, CMT2, Wolfram syndrome, Wolf-Hirschhorn syndrome and Leigh syndrome. In addition to syndromic MIDs, a large number of non-syndromic MIDs due to mtDNA as well as nDNA mutations have been reported, which present with cognitive impairment as the sole or one among several other CNS manifestations of a MID. Delineation of mitochondrial cognitive impairment from other types of cognitive impairment is essential to guide the optimal management of these patients. Treatment of mitochondrial cognitive impairment is largely limited to symptomatic and supportive measures. Cognitive impairment may be a CNS manifestation of syndromic as well as non-syndromic MIDs. Correct diagnosis of mitochondrial cognitive impairment is a prerequisite for the optimal management of these patients.

Cognitive dysfunction in 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.

/pdf/mitochondrial-multiorgan-disorder-syndrome-score-generated-2j4zdd37vg.pdf

Mitochondrial multiorgan disorder syndrome score generated from definite mitochondrial disorders.

www.eymj.org To the Editor, Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike episodes (MELAS) syndrome is one of the most frequent syndromic mitochondrial disorders (MIDs). It is diagnosed according to the Japanese criteria if at least two features of category A [headache with vomiting, seizures, hemiplegia, cortical blindness, stroke-like lesion (SLL)] and at least two features of category B (elevated lactate in serum or cerebro-spinal fluid, mitochondrial myopathy on muscle biopsy, MELAS-related mutation) being present. MELAS is diagnosed according to the Hirano criteria if all three of the canonical features [strokelike episode (SLE) before age of 40 years, encephalopathy (seizures or dementia), and mitochondrial myopathy on biopsy] and at least two of the other features (normal early psychomotor development, recurrent headache, or recurrent vomiting) are present. Eighty percent of the MELAS cases are due to the variant m.3243A>G in MT-TL1. Other mutated genes associated with MELAS include MT-ND5, MT-TC, MT-TF, MT-TH, MT-TK, MTTL2, MT-TQ, MT-TV, MT-TW, MT-TS1, MT-TS2, MT-ND1, MTND6, MT-CO2, MT-CO3, and MT-CYB. The most frequent phenotypic manifestations of MELAS include seizures (76% of patients), headache (50% of patients), SLEs (>90%), visual loss (52% of patients), muscle weakness (48% of patients), vomiting (55%), as well as short stature (>25% of cases), impaired consciousness, impaired cognition, hearing loss, or diabetes (10– 24% of patients). Although the phenotypic spectrum of MELAS is broader than anticipated (Table 1), most of these features are rare and often reported only in a single patient or family. This is why it is sometimes questionable if these rare features are truly attributable to the MID or due to a secondary problem. Rare phenotypic manifestations occurring in <10% of the MELAS cases include cerebral manifestations (dystonia, chorea, parkinsonism), psychiatric abnormalities (delirium, confusion, mutism, hallucinations, delusions, dysexecutive syndrome), ophthalmologic manifestations (cataract, retinal detachment, maculopathy, polymegathism), otologic disease (vestibular dysfunction), endocrine abnormalities (hypoaldosteronism, Addison’s disease, hyperthyroidism, hypopituitarism, osteoporosis), cardiac manifestations (noncompaction, arterial hypertension), lungs (pulmonary hypertension, chronic obstructive pulmonary disease), gastrointestinal compromise (pancreatitis, odynophagia), kidneys (Fanconi syndrome), and vascular involvement (artery dissection, aneurysm formation, aortic rupture). Rare non-specific manifestations include developmental delay or fever (<10% of cases). Non-specific manifestations of MELAS may also include dysmorphism (hypertelorism, protruding ears). Knowing the entire spectrum of the phenotype is crucial, as prospective investigations may also be carried out for these rare features and some of them may strongly determine the prognosis and outcome. Although SLLs, the morphological equivalent of SLEs on MRI, develop predominantly in the cortex and subcortical white matter, they can rarely occur ubiquitously in the central nervous system, including the cerebellum, brainstem, the spinal cord, or the optic nerve. Though epilepsy is frequent in MELAS, certain seizures have only been infrequently reported. These include non-convulsive status epilepticus, epilepsia partialis continua, occipital status epilepticus, and myoclonic seizures. Overall, although MELAS is a frequent phenotype, we still do require more comprehensive evaluations of the phenotype to assess which features are truly attributable to a MELAS mutation to encompass the entire phenotypic spectrum of the disease. Rare phenotypic features should be regarded as part of the phenotype only if the diagnostic criteria for MELAS are met, if a MELAS-associated mutation is present, and if there is no other plausible explanation for a particular feature. It is important to describe the pathophysiological relationship between a rare phenotypic feature and the underlying mitochondrial Received: August 19, 2020 Revised: September 1, 2020 Accepted: September 3, 2020 Corresponding author: Josef Finsterer, MD, PhD, Klinik Landstrasse, Messerli Institute, Postfach 20, 1180 Vienna, Austria. Tel: 43-1-71165-72085, Fax: 43-1-71165, E-mail: fifigs1@yahoo.de

/pdf/rare-phenotypic-manifestations-of-melas-oj2bycub6m.pdf

Rare Phenotypic Manifestations of MELAS.

Distinct Neuropsychological Profile and Associated Neurochemical Changes in Individuals with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

Introduction. – MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a rare genetic mitochondrial disease which can cause cerebral

Mutisme et troubles du comportement aigus revelant un

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