Mitochondrial Disorders Affecting the Nervous System

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


Semin Neurol. 2014;34(3):321-340. 

In This Article


The diagnosis of mitochondrial disease requires biochemical, genetic, and clinical evaluation (Fig. 6). Suggested diagnostic criteria vary somewhat, but all classify patients as definite, probably, possible, or unlikely to have mitochondrial disease based on the aggregate findings (Table 1).[188,189] The clinical phenotype may rarely manifest as CNS symptomatology alone, but most patients have multiorgan system involvement. Guidelines for diagnosis are readily available.[11,79,190,191] The availability of next-generation gene sequencing, whether targeted to mtDNA, known nuclear mitochondrial genes, or the whole exome, is rapidly increasing discovery in mitochondrial medicine. Mutations in new genes are increasingly recognized as causes of mitochondrial phenotypes and the phenotypes of known gene defects are expanding. New classes of mitochondrial defect are also being recognized at an accelerated pace; there are many examples: FBXL4 encoding a mitochondrial folding protein can cause an early-onset mitochondrial encephalopathy,[192] and acyl CoA dehydrogenase 9 (ACAD9), a fatty acid oxidation enzyme, was found to function also as an assembly factor for Complex I with mutations causing mitochondrial encephalopathy, which may respond to riboflavin.[193]

Figure 6.

Elements in the diagnosis of mitochondrial disease. CSF, cerebrospinal fluid; EKG, electrocardiogram; Echo, echocardiogram; ETC, electron transport chain; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy.