Rare Disease Database

MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is a disorder that begins in childhood and affects mostly the nervous system and muscle. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. Diabetes mellitus and paralysis of eye muscle (chronic progressive external ophthalmoplegia) are often present in isolation or in association with other symptoms. MELAS is caused by mutations in mitochondrial DNA (mtDNA). Some mutations that cause MELAS are found in mtDNA genes that are also associated with MERRF syndrome. In one patient, this syndrome has been associated with mutations in a nuclear gene, POLG1. (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)

Kearns-Sayre syndrome (KSS) is a rare multisystemic disorder. An important clinical symptomatic feature is the presence of droopy eyelids (ptosis) in one or both eyes. This disease is mostly characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), or pigmentary retinopathy, leading to poor night vision and progressive vision loss; and heart disease such as cardiomyopathy and/or progressive arrhythmia leading to complete heart block. Other findings may include muscle weakness, short stature, sensorineural hearing loss, endocrine issues such as diabetes mellitus and hypoparathyroidism (which can cause hypocalcemia) and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some patients, KSS may be associated with other disorders and/or conditions. KSS belongs (in part) to a group of rare disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material (DNA) arises from a part of the cell structure (mitochondria), that produces energy (in the form of adenosine triphosphate, or ATP) causing the brain and muscles to function improperly due to lack of energy (encephalomyopathies). In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of affected individuals with KSS, tests will reveal missing genetic material (deletion) involving the unique DNA in mitochondria (mtDNA).(For more information on this disorder, choose “Kearns Sayre” as your search term in the Rare Disease Database.)

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years, but some patients do not exhibit signs and symptoms until several years later. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most patients, Leigh syndrome is inherited in an autosomal recessive pattern. However, X-linked recessive and maternal inheritance, due to a mitochondrial DNA mutation, are seen in some families. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)

Combined oxidative phosphorylation deficiency is a disease that affects many parts of the body. Onset occurs at or soon after birth in most patients, and features can include growth delay, small head (microcephaly), increased muscle tone, floppiness of the trunk and head, brain disease (encephalopathy), enlarged heart muscle (cardiomyopathy) and liver dysfunction. There are many subtypes, caused by many different gene mutations. Combined oxidative phosphorylation deficiency 27 is characterized by juvenile-onset MERRF-like severe myoclonus epilepsy with ataxia, spastic weakness that affects all four limbs (spastic tetraparesis), vision loss, hearing loss and cognitive decline. It is inherited in an autosomal recessive pattern and is caused by mutations in the CARS2 gene. (For more information on combined oxidative phosphorylation deficiencies, choose “Combined oxidative phosphorylation” as your search term in the Rare Disease Database).

POLG-related disorders are a series of conditions with overlapping symptoms. The disorders include: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), autosomal recessive progressive external ophthalmoplegia (arPEO) and autosomal dominant progressive external ophthalmoplegia (adPEO). Symptoms and severity of these conditions vary but common features include: movement disorder including muscle spasms (myoclonus), seizures (epilepsy), impaired ability to coordinate movements (ataxia), abnormal sensation from nerve damage (peripheral neuropathy), developmental delay, decreased muscle tone (hypotonia) and muscle weakness (myopathy). These disorders are primarily inherited in an autosomal recessive pattern though some do follow an autosomal dominant pattern of inheritance. All are caused by mutations in the POLG gene.