Central nervous system manifestations of mitochondrial disorders

Abstract

The central nervous system (CNS) is, after the peripheral nervous system, the second most frequently affected organ in mitochondrial disorders (MCDs). CNS involvement in MCDs is clinically heterogeneous, manifesting as epilepsy, stroke-like episodes, migraine, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, or hypophysial abnormalities. CNS involvement is found in syndromic and non-syndromic MCDs. Syndromic MCDs with CNS involvement include mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome, myoclonic epilepsy and ragged red fibers syndrome, mitochondrial neuro-gastrointestinal encephalomyopathy syndrome, neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome, mitochondrial depletion syndrome, Kearns-Sayre syndrome, and Leigh syndrome, Leber's hereditary optic neuropathy, Friedreich's ataxia, and multiple systemic lipomatosis. As CNS involvement is often subclinical, the CNS including the spinal cord should be investigated even in the absence of overt clinical CNS manifestations. CNS investigations comprise the history, clinical neurological examination, neuropsychological tests, electroencephalogram, cerebral computed tomography scan, and magnetic resonance imaging. A spinal tap is indicated if there is episodic or permanent impaired consciousness or in case of cognitive decline. More sophisticated methods are required if the CNS is solely affected. Treatment of CNS manifestations in MCDs is symptomatic and focused on epilepsy, headache, lactacidosis, impaired consciousness, confusion, spasticity, extrapyramidal abnormalities, or depression. Valproate, carbamazepine, corticosteroids, acetyl salicylic acid, local and volatile anesthetics should be applied with caution. Avoiding certain drugs is often more beneficial than application of established, apparently indicated drugs.

Central Nervous System Imaging in Mitochondrial Disorders

“…Calcifications are most frequently located within the basal ganglia, uni-or bilaterally, but may occasionally occur in other locations. Basal ganglia calcifications are not restricted to a particular MCD but may occur with most of the known syndromes, most frequently, however, with MELAS or KSS 48,54 . In MELAS the most frequent location of the calcifications is the caudate nucleus, putamen, globus pallidus, or thalamus 51 .…”

“…The CT may show diffuse atrophy or focal atrophy of the supratentorial cortex 22 or the cerebellum 58,59 , focal or diffuse demyelination, uni-or bilateral calcifications of the basal ganglia, frequently observed in MELAS 54,59 , dentate nuclei, or the cerebellum 59 , vasogenic edema 60,61 , bilateral striatal necrosis 59,62 , malformations 63 such as polymicrogyria 52 or tuberous sclerosis 53 , or macro-or microhemorrhages.…”

Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population

“…The resulting multisystem disease presents most commonly with neurological and myopathic features. Mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) is the most common mtDNA disease presenting with phenotypic features including short stature, exercise intolerance, neurosensory hearing loss, migraine-like headaches, seizures, myopathy, ophthalmoplegia, cardiomyopathy, axonal neuropathy, diabetes mellitus, pigmentary retinopathy, and renal tubular acidosis [2]. Approximately 80 % of all MELAS patients carry a single mutation of m.3243A[G in the tRNA leu (UUR) (MTTL1) within the mtDNA [3].…”

“…Mitochondrial diseases are a rare, but well-recognized cause of ischemic stroke (IS)-like episodes at various ages [2,4]. While MELAS is the most common cause, other mitochondrial diseases such as myoclonic epilepsy with ragged red fibers (MERRF), Kearns-Sayre syndrome, Leigh syndrome, mitochondrial recessive ataxia syndrome (MIRAS), and hyperornithinemia-hyperammonemia-homocitrullinuria (triple-H syndrome) have also rarely been reported to be associated with IS-like lesions [4,5].…”

Mitochondrial Encephalomyopathy Associated with Diabetes Mellitus, Cataract, and Corpus Callosum Atrophy

“…Mitochondrial disorders preferentially affect the muscle and nervous systems (2) but they may also affect the endocrine glands, heart, ears, gastrointestinal tract, liver, kidneys, bone marrow, and dermis (3).…”