Mitochondrial disorders (including MELAS, MERRF, Kearns–Sayre syndrome, and POLG-related disorders)

Mitochondrial disorders are a heterogeneous group of genetic neurometabolic disorders caused by impaired mitochondrial energy metabolism, resulting in variable neurologic, psychiatric, and multisystemic manifestations. Important examples include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); myoclonic epilepsy with ragged red fibers (MERRF); Kearns–Sayre syndrome (KSS); and POLG-related disorders (polymerase gamma; pronounced “poll-G”).

They can arise from pathogenic variants or deletions in mitochondrial or nuclear DNA, with inheritance patterns varying substantially among disorders. Although some, including MELAS and MERRF, are typically associated with maternal mitochondrial inheritance, Kearns–Sayre syndrome usually results from de novo mitochondrial DNA deletions, while POLG-related disorders are caused by pathogenic variants in nuclear DNA and may follow autosomal dominant or autosomal recessive inheritance. A relevant family history may therefore be absent in any of these disorders. They affect both males and females.

They can present with psychiatric features, which collectively may include depression, anxiety, irritability, behavioural or personality change, cognitive impairment, and psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood and may precede or accompany other neurologic manifestations. Psychosis has been reported in several mitochondrial encephalopathies, including MELAS, MERRF, Kearns–Sayre syndrome (KSS), and POLG-related disorders, although the frequency and clinical phenotype vary substantially between disorders. MELAS has a particularly well-described psychiatric phenotype, including depression, bipolar-spectrum symptoms, anxiety, personality change, and psychosis; psychiatric manifestations are also recognized in adult-onset POLG-related disease. MERRF and KSS are more commonly associated with cognitive and mood or behavioural manifestations, with psychosis reported less consistently.

Other characteristic features collectively include seizures, cognitive impairment or dementia, muscle weakness and exercise intolerance, peripheral neuropathy, and variable movement disorders.

From a movement lens perspective, the movement phenomenology and other characteristic features of the specific mitochondrial disorders can be distinguished as follows:

• MELAS: characterized by stroke-like episodes, seizures, migraine-like headaches, cortical visual impairment, hearing loss, and myopathy; ataxia and myoclonus may occur, while choreiform movements and parkinsonism are uncommon but reported.

• MERRF: characterized particularly by myoclonus, generalized epilepsy, ataxia, weakness, exercise intolerance, and progressive cognitive impairment; myoclonus and ataxia are the characteristic movement manifestations.

• KSS: characterized by progressive external ophthalmoplegia, pigmentary retinopathy, and often cardiac conduction disease, with cerebellar ataxia, tremor, myoclonus, and cognitive decline also occurring; chorea and parkinsonism are not typical features.

• POLG-related disorders: have a particularly broad movement-disorder phenotype, including cerebellar and sensory ataxia, myoclonus, choreoathetosis or chorea, dystonia, and parkinsonism. Progressive external ophthalmoplegia, ptosis, peripheral neuropathy, and myopathy are also characteristic of several POLG phenotypes.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: cardiomyopathy and cardiac conduction abnormalities or arrhythmias may occur, particularly in MELAS, MERRF, and KSS.

• Renal/electrolytes: renal tubular dysfunction, proteinuria, nephropathy, or other renal abnormalities may occur, particularly in MELAS and less commonly in some other mitochondrial disorders.

• Gastrointestinal: recurrent or cyclic vomiting, diarrhea, constipation, gastric dysmotility, intestinal pseudo-obstruction, and other gastrointestinal manifestations may occur, particularly in MELAS and POLG-related disorders.

• Endocrine: diabetes mellitus and other endocrine abnormalities may occur, particularly in MELAS and KSS; premature ovarian or testicular dysfunction may occur in some mitochondrial and POLG-related disorders.

• Musculoskeletal: myopathy, muscle weakness, exercise intolerance, and other skeletal-muscle manifestations are common across several mitochondrial encephalopathies; short stature may occur particularly in MELAS, MERRF, and KSS.

Early diagnosis is important to recognize a potentially treatable cause of psychiatric and neurologic illness, particularly when psychiatric manifestations precede other neurologic features; identify potentially serious cardiac, renal, endocrine, gastrointestinal, and muscular complications; inform medication selection and help avoid potentially harmful treatments, including valproate, which is particularly concerning in POLG-related disease; guide appropriate genetic and metabolic evaluation and disorder-specific management; and enable appropriate genetic counselling and family assessment.