Mitochondrial Disorders Affecting the Nervous System

R.H. Haas, MB, BChir; Z. Zolkipli, MB, ChB

Semin Neurol. 2014;34(3):321-340.

Abstract and Introduction

Abstract

Mitochondrial diseases are multiorgan system disorders and the brain is the most commonly affected organ. The high-energy requirement of the brain leaves it vulnerable to energy failure. All components of the neuraxis including muscle, the neuromuscular junction, peripheral nerve, spinal cord, and brain can be affected. Genetic mitochondrial disease can be caused by nuclear gene defects and mitochondrial DNA defects. Mitochondrial medicine is rapidly expanding as exome and mtDNA sequencing is identifying new gene defects on a daily basis. This review will focus on primary genetic mitochondrial diseases that impair energy production and affect the nervous system, pathophysiology of disease, classical phenotypes, diagnosis, and treatment.

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Table 1. Probability of a diagnosis of mitochondrial disease (after Bernier et al and North American Mitochondrial Disease Consortium [NAMDC] research criteria)
Criteria	Clinical phenotype	Gene testing	Biochemistry	Muscle histology	Neuroimaging	Metabolic
Major	Well-defined mitochondrial disease phenotype	Proven dominant or recessive nuclear gene mutation or high-level heteroplasmy mtDNA mutation or deletion	Very low mitochondrial enzyme activity (typically < 20%)	> 2% ragged red fibers > 5% COX negative fibers
Minor	Less well-defined mitochondrial phenotype	Likely pathogenic mutation	Reduced mitochondrial enzyme activity (between 20% and 45% of mean control). Elevated citrate synthetase (> 60%)	Mitochondrial accumulation ± structural abnormality Paracrystalline inclusions on electron microscopy	Basal ganglia, brainstem, cerebellar T2/FLAIR hyper-intensities Stroke-like lesions in a nonvascular distribution. High brain or CSF lactate on MRS.	Elevated plasma and/or CSF lactate or pyruvate. Abnormal lactate/pyruvate ratio Organic or amino acid elevation suggestive of mitochondrial dysfunction.

Abbreviations: CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion-recovery; MRS, magnetic resonance spectroscopy. Note: Definite mitochondrial disease: two major criteria (one clinical), one major biochemical or molecular defect with one major or minor clinical criterion, one major and two minor criteria (one clinical); probable mitochondrial disease: one major and one minor criterion (one clinical), three or > minor criteria (one clinical); possible mitochondrial disease: one major, two minor criteria (one clinical); unlikely mitochondrial disease: no major or < two minor criteria.

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Mitochondrial Disorders Affecting the Nervous System

Abstract and Introduction

Abstract

Tables

References

Authors and Disclosures

Authors and Disclosures

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