Mitochondrial Myopathies (MM)

Types of Mitochondrial Myopathies

Kearns-Sayre syndrome (KSS)

Onset: Before age 20

Symptoms: This disorder is defined by chronic progressive external ophthalmoplegia (CPEO), which consists in slowly progressive weakness (paresis) of the muscles that control the eye movement (extraocular muscles) along bilateral ptosis (dropping eyelid), plus pigmentary retinopathy, a “salt-and-pepper” pigmentation in the retina that can affect vision but often leaves it intact. Other common symptoms include conduction block (in the heart), deafness, diabetes, anemia, and ataxia (impaired coordination). Less typical symptoms are cognitive disability or deterioration, delayed sexual maturation, and short stature.

Patients with only CPEO typically begin to notice symptoms in the fourth decade of life.¹ KSS refers to a combination of both CPEO and onset before age 20. KSS is usually more severe than isolated CPEO, progressing to complete ophthalmoparesis (weakness of the eye muscles) and often death by the fourth decade of life. Both patients with isolated CPEO and KSS can develop a proximal myopathy (weakness of the muscles closest to the body’s midline).

Leigh syndrome (subacute necrotizing encephalomyopathy) and maternally inherited Leigh syndrome (MILS)

Onset: Typically in infancy or early childhood

Symptoms: Leigh syndrome causes brain abnormalities that can result in ataxia (impaired coordination), dystonia (involuntary muscle movement), external ophthalmoplegia (paralysis of the eye muscles), progressive neurodegeneration seizures, lactic acidosis (buildup of lactate in the body), vomiting, weakness, hypotonia (decreased muscle tone), developmental delays, and altered control over breathing. Together, Leigh syndrome and MELAS are the most common mitochondrial myopathies. The prognosis of Leigh syndrome is generally poor, with survival generally being a matter of months after disease onset.^2,3

Mitochondrial DNA depletion syndrome (MDS)

Onset: Infancy

Symptoms: MDS is actually a group of autosomal recessive conditions (genetic diseases caused by a mutation inherited from both parents) characterized by a significant decrease in mitochondrial DNA affecting multiple tissues. There are four major types of MDS: myopathic (caused by mutations in the TK2 gene), encephalomyopathic (caused by mutations in the SUCLA2, SUCLG1, or RRM2B genes), hepatocerebral (caused by mutations in the DGUOK, MPV17, POLG, or TWNK genes), and neurogastrointestinal (caused by mutations in the ECGF1 gene).⁴ These disorders typically cause muscle weakness and/or liver failure, as well as, more rarely, brain abnormalities. “Floppiness,” eating difficulties, and developmental delays are common symptoms; progressive external ophthalmoplegia (PEO) and seizures are less common.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

Onset: Usually in childhood

Symptoms: MELAS causes lactic acidosis (buildup of lactate in the body) and recurrent stroke-like episodes in the brain, migraine-type headaches, vomiting, and seizures, and can lead to permanent brain damage. Other common symptoms include PEO, general muscle weakness, exercise intolerance, hearing loss, diabetes, and short stature.^5–7

Maternally inherited deafness and diabetes (MIDD)

Onset: Typically between age 30-40

Symptoms: MIDD is characterized by both a defect in insulin secretion, which progresses to insulin dependence, and sensorineural hearing loss. Other abnormalities associated with MIDD are macular retinal dystrophy, myopathy, cardiac disorders, gestational diabetes, renal disease, short stature, and gastrointestinal disease.^8,9

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Onset: Usually between the first and fifth decades of life but occurs before the age of 20 in 73% of patients

Symptoms: This disorder causes ptosis (droopy eyelids), severe gastrointestinal dysmotility, cachexia (extreme weight loss and muscle wasting), ophthalmoplegia (paralysis of the extraocular muscle), ophthalmoparesis (weakness of the extraocular muscle) without diplopia (double vision), gastrointestinal reflux, episodic abdominal pain, and diarrhea.^10–12,13

Myoclonus epilepsy with ragged red fibers (MERRF)

Onset:  Childhood, usually after a normal development

Symptoms: The most prominent symptoms are myoclonus (muscle jerks), seizures, ataxia (impaired coordination), and myopathy (muscle weakness). The disease might also cause hearing impairment, spasticity, cardiomyopathy, and optic atrophy (death of retinal cells).

Neuropathy, ataxia, and retinitis pigmentosa (NARP)

Onset: Late-childhood or adult onset is common

Symptoms: NARP causes neuropathy (a malfunction of the nerves that can lead to sensory impairment and muscle weakness), muscle weakness, epilepsy, ataxia (impaired coordination), and retinitis pigmentosa (degeneration of the retina in the eye, with resulting loss of vision). It also can cause developmental delay, seizures, and dementia.¹⁴

Pearson syndrome

Onset: Congenital

Symptoms: This syndrome causes severe anemia, neutropenia (low level of immune cells, called neutrophils), thrombocytopenia (low blood platelet count), and malfunction of the pancreas. Pearson syndrome is usually fatal in infancy. Children who survive the disease usually go on to develop Kearns-Sayre syndrome (KSS).¹⁵

References

1. Yu Wai Man, C.Y., Smith, T., Chinnery, P.F., Turnbull, D.M. & Griffiths, P.G. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye (2006) doi:10.1038/sj.eye.6701924.
2. Finsterer, J. Leigh and Leigh-Like Syndrome in Children and Adults. Pediatric Neurology (2008) doi:10.1016/j.pediatrneurol.2008.07.013.
3. Lee, H.F., Tsai, C.R., Chi, C.S., Lee, H.J. & Chen, C.C.C. Leigh Syndrome: Clinical and Neuroimaging Follow-Up. Pediatr. Neurol. (2009) doi:10.1016/j.pediatrneurol.2008.09.020.
4. El-Hattab, A.W. & Scaglia, F. Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options. Neurotherapeutics (2013) doi:10.1007/s13311-013-0177-6.
5. Pavlakis, S.G., Phillips, P.C., DiMauro, S., De Vivo, D.C. & Rowland, L.P. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: A distinctive clinical syndrome. Ann. Neurol. (1984) doi:10.1002/ana.410160409.
6. Montagna, P. et al. MELAS syndrome: Characteristic migrainous and epileptic features and maternal transmission. Neurology (1988) doi:10.1212/wnl.38.5.751.
7. Ohno, K., Isotani, E. & Hirakawa, K. MELAS presenting as migraine complicated by stroke: Case report. Neuroradiology (1997) doi:10.1007/s002340050505.
8. Kadowaki, T. et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. (1994) doi:10.1056/NEJM199404073301403.
9. Donovan, L.E. & Severin, N.E. Maternally inherited diabetes and deafness in a North American kindred: Tips for making the diagnosis and review of unique management issues. in Journal of Clinical Endocrinology and Metabolism (2006). doi:10.1210/jc.2006-1498.
10. Hirano, M. & Díaz, B.G. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE). in Mitochondrial Case Studies: Underlying Mechanisms and Diagnosis (2016). doi:10.1016/B978-0-12-800877-5.00022-X.
11. Giordano, C. et al. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am. J. Pathol. (2008) doi:10.2353/ajpath.2008.080252.
12. Nishino, I. et al. Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations. Ann. Neurol. (2000) doi:10.1002/1531-8249(200006)47:6<792::AID-ANA12>3.0.CO;2-Y.
13. Teitelbaum, J.E. et al. Diagnosis and management of MNGIE syndrome in children: Case report and review of the literature. J. Pediatr. Gastroenterol. Nutr. (2002) doi:10.1097/00005176-200209000-00029.
14. Holt, I.J., Harding, A.E., Petty, R.K.H. & Morgan-Hughes, J.A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. (1990).
15. DiMauro, S. & Hirano, M. Mitochondrial DNA Deletion Syndromes. in Gene Rev. (2011).