Clinical Diagnostic and Therapeutic Approach to the Patient with Suspected Mitochondrial Disease

ABSTRACT

1. This chapter focuses on the clinical approach to diseases with impaired respiratory chain function. Diseases of other mitochondrial pathways, such as disorders of fatty acid oxidation (FAO), the Krebs cycle, the urea cycle, and pyruvate oxidation are addressed in other chapters.

2. Respiratory chain diseases are clinically very heterogeneous. They include multisystem or monosystem disorders, and can have congenital, infantile, or late-onset presentations. They may be familial or sporadic. Familial cases may result from mutations of nuclear DNA (nDNA), which show Mendelian transmission, or of mitochondrial DNA (mtDNA), which show maternal transmission. Mitochondrial diseases are frequently but not invariably associated with characteristic laboratory abnormalities (e.g., elevated blood or CSF lactate, characteristic findings on muscle biopsy and brain MRI, and known pathogenic genetic changes).

3. Syndromology. Certain signs or combinations of signs should alert clinicians to a possible mitochondrial disorder. Many are due either to mtDNA mutations or to nuclear mutations affecting mtDNA maintenance. Progressive external ophthalmoplegia (PEO) is often a telltale sign of mitochondrial dysfunction, present in isolation or associated with multiple symptoms, manifesting as a “PEO-plus” syndrome often with involvement of extramuscular systems excluding the CNS, or as “mitochondrial encephalomyopathy” such as in Kearns–Sayre syndrome (KSS). Two mitochondrial syndromes frequently cause optic atrophy: autosomal dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON). The former is due to mutations in the gene (OPA1) encoding a crucial dynamin-like mitochondrial fusion protein; the latter is predominantly due to mutations in three mtDNA genes encoding complex I subunits (ND1, ND4, and ND6). Stroke-like episodes with mitochondrial encephalomyopathy and lactic acidosis suggest MELAS syndrome, which appears most commonly in older children or adults and can result from a variety of mtDNA mutations. A common infantile mitochondrial disorder is hepatocerebral syndrome (Alpers–Huttenlocher syndrome), a devastating condition with liver failure and intractable seizures, due to POLG mutations causing mtDNA depletion. The absence of a classical mitochondrial syndrome does not exclude a mitochondrial disease, and many mitochondrial disease patients present with a single complaint.

4. Molecular prenatal diagnosis is straightforward for nuclear encoded conditions if the causal mutations are known. For diseases caused by mtDNA mutations, some degree of prenatal prediction of clinical outcome is possible for certain mutations in protein-coding mtDNA genes. An example is m.8993T>G, which causes neuropathy, ataxia, and retinitis pigmentosa (NARP), and maternally inherited Leigh syndrome (MILS). For NARP/MILS, a mutation level below 30% in chorionic villus samples (CVS) or in amniocytes suggests a favorable outcome, but a mutant fraction exceeding 70% is an ominous sign, and intermediate mutation loads leave us uncertain about the outcome. Prenatal diagnosis is considerably less reliable for mutations in mtDNA genes of protein synthesis, such as tRNA genes (e.g., the MELAS m.3243A>G mutation), because the mutation load in prenatal samples may differ considerably from that of fetal tissues and the mutant fraction can shift during gestation and after birth.

5. There are three major therapeutic strategies for mitochondrial diseases. They focus on root causes, ...