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Mitochondrial Disorders

Mitochondrial disorders consist of a heterogeneous group of conditions arising from inherited mutations to mitochondrial DNA.  These disorders are now known as some of the most common genetic diseases, with a prevalence rate conservatively estimated at 1 in 5,000 (1). Both physical and cognitive symptoms are common, with clinical presentations differing significantly by subtype. These subtypes can be broadly classified into two groups, including primary mitochondrial DNA disorders in which the disease is inherited through the maternal line, or nuclear mitochondrial genetic disorders that result from DNA mutations or rearrangements (2). Because mitochondria are located in cells throughout the body, its associated disorders causes diffuse symptoms affecting multiple organ systems (1).

Cognitive and Psychiatric Symptoms

The central nervous system is affected in an estimated 30-60% of patients with mitochondrial disorders, indicating that cognitive symptoms are common (3). Observed cognitive deficits range from global to focal impairments. Mild cognitive impairment may be the initial presentation of these deficits, which then progress into dementia in certain subtypes of the disorder (classified as mitochondrial dementia) (3). Psychiatric symptoms are also common and may include impaired alertness, concentration, and reasoning; confusion; hallucination; personality changes; and bip olar disorder (3).

The presence of overlapping cognitive and psychiatric symptoms is common (4). While symptom heterogeneity leads to difficulty identifying certain clinical presentations, there are some known cognitive and psychiatric symptoms that are commonly associated with mitochondrial disorder subtypes. These are discussed in more detail below.

 

Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)

Typically diagnosed in childhood, MELAS is an inherited disorder with broad symptomatology which may include stroke-like episodes, epilepsy, lactic acidemia (a build-up of lactate in the body), myopathy (muscular disruption), recurring headaches, hearing difficulties, diabetes, and short height (5). Dementia is a common cognitive manifestation of the disorder, affecting 90% of patients in one study (2). Additionally, broad cognitive deficits and significant cognitive deterioration are commonly observed.  The severity of MELAS deficits is greater compared to other mitochondrial disorders (2). Psychiatric symptoms found in MELAS include psychosis, depression, anxiety and bipolar disorder (5).

 

Kearns-Sayre Syndrome (KSS)

A rare subtype, KSS is typically diagnosed in childhood and has a significant increased mortality rate (2). In one study of 35 patients with KSS, 31% exhibited notable cognitive decline which was also associated with more severe physical disability (6). Another study of six patients specifically identified deficits in visual-spatial and attention/executive function domains (7).

 

Barth Syndrome

Barth syndrome is an X-linked recessive disorder that is diagnosed only in males. As with many other mitochondrial disorders, symptoms emerge in early childhood. Physical symptoms include early congestive heart failure and/or cardiomyopathy (heart disease) and delayed growth through both early and adolescent development. Barth syndrome is associated with a specific cognitive phenotype that consists of specific deficits in mathematics and visual-spatial skills. Language abilities are typically preserved. (8)

 

Treatment

Treatment for mitochondrial disorders is largely supportive, with the goal of managing symptoms. Medications and nutritional supplements are often recommended, including vitamins, hormones, and antioxidants (9). The beneficial effects of co-enzyme Q10 also has growing support (10). These pharmacological agents may be given separately, or administered as a “cocktail” or combination of different drugs (10). Dietary changes (including a ketogenic diet) and exercise therapy also have positive preliminary evidence (9).

 

Treatment options should be considered carefully for individuals experiencing comorbid psychiatric disorders given that certain psychotropic medications may impact mitochondrial function (4). Additionally, side effects of medication may worsen physical symptoms associated with mitochondrial disorders. Thus, non-pharmacologic intervention for psychiatric symptoms is encouraged.  Biofeedback can be helpful in dealing with the balancing of cardiac and autonomic nervous system issues, and neurofeedback might be able to deal with the cognitive issues related to this family of disorders.  Individual tailoring of these techniques would be expected.

— S Jacobs & J. L. Thomas

 

References

  1. DiMauro, S & Davidzon, G (2005). Mitochondrial DNA and disease. Annals of medicine, 37(3), 222-232.
  2. Antshel, K (2010). Neurocognition in mitochondrial disorders. In C. L. Armstrong & L. Morrow (Eds.), Handbook of medical neuropsychology: Applications of cognitive neuroscience(pp. 491-501). New York, NY, US: Springer Science+Business Media.
  3. Finsterer, J (2008). Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). Journal of the Neurological Sciences, 272(1-2), 20-33.  https://www.ncbi.nlm.nih.gov/pubmed/18572195
  4. Anglin, R, Garside, S, Tarnopolsky, M, Mazurek, M & Rosebush, P (2012). The psychiatric manifestations of mitochondrial disorders: a case and review of the literature. The Journal of clinical psychiatry, 73(4), 506-512.
  5. El-Hattab, A, Adesina, A, Jones, J & Scaglia, F (2015). MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Molecular genetics and metabolism, 116(1-2), 4-12.
  6. Khambatta, S, Nguyen, D, Beckman, T & Wittich, C (2014). Kearns–Sayre syndrome: a case series of 35 adults and children. International journal of general medicine, 7, 325.
  7. Bosbach, S, Kornblum, C, Schröder, R & Wagner, M (2003). Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns–Sayre syndrome. Brain, 126(5), 1231-1240.
  8. Mazzocco, M, Henry, A, & Kelly, R (2007). Barth syndrome is associated with a cognitive phenotype. Journal of developmental and behavioral pediatrics: JDBP, 28(1), 22.
  9. Chinnery, P, Majamaa, K, Turnbull, D & Thorburn, D (2006). Treatment for mitochondrial disorders. Cochrane database of systematic reviews, (1). https://www.ncbi.nlm.nih.gov/pubmed/22513923
  10. Parikh, S, Saneto, R, Falk, M, Anselm, I, Cohen, B, & Haas, R (2009). A modern approach to the treatment of mitochondrial disease. Current treatment options iMitochondrial Disordersn neurology, 11(6), 414.
Mitochondrial Disorders

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