Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the central nervous system, retina, and muscle.
See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism.
Cellular respiration (oxidative phosphorylation) occurs in the mitochondria, where a series of enzymes catalyze the transfer of electrons to molecular oxygen and the generation of energy-storing adenosine triphosphate (ATP). Defects involving enzymes used in this process impair cellular respiration, decreasing the ATP:ADP (adenosine diphosphate) ratio. Mitochondria have their own DNA (mitochondrial DNA [mtDNA]), which is maternally derived. However, mtDNA shares responsibility with nuclear DNA for mitochondrial function. Thus, both mitochondrial and nuclear mutations can cause mitochondrial disorders.
Tissues with a high energy demand (eg, brain, nerves, retina, skeletal and cardiac muscle) are particularly vulnerable to defects in oxidative phosphorylation.
The most common clinical manifestations are
Seizures
Hypotonia
Ophthalmoplegia
Strokelike episodes
Muscle weakness
Severe constipation
Cardiomyopathy
Biochemically, there may be profound lactic acidosis because the NADH:NAD ratio increases, shifting the equilibrium of the lactate dehydrogenase reaction toward lactate. The increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation defects from other genetic causes of lactic acidosis, such as pyruvate carboxylase or pyruvate dehydrogenase deficiency, in which the lactate:pyruvate ratio remains normal. Fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) are additional biomarkers that may suggest mitochondrial dysfunction. A large number of oxidative phosphorylation defects have been described; only the most common ones are outlined here, along with their distinguishing features.
Перли й пастки
|
Mitochondrial mutations and variants have also been implicated in a number of diseases of aging (eg, Parkinson disease, Alzheimer disease, diabetes, deafness, cancer).
The following disorders are conditions with a known phenotype/genotype correlation. Other less well-defined defects in mitochondrial function exist. Additionally, there are a number of conditions in which a genetic defect causes secondary mitochondrial dysfunction.
Спадкова нейропатія зорового нерва Лебера (LHON)
LHON is characterized by acute or subacute bilateral central vision loss caused by retinal degeneration. Onset usually occurs in the patient’s 20s or 30s but can occur from childhood to adulthood. Male:female ratio is 4:1. Many mitochondrial DNA mutations have been defined, but 3 common ones account for 90% of cases. LHON pedigrees usually show a pattern of maternal inheritance typical of mitochondrial disorders that involve mutations of mtDNA.
Intravitreal gene therapy has shown very promising results in early clinical trials.
Мітохондріальна енцефаломіопатія, лактоацидоз та інсультоподібні епізоди (MELAS)
Mutations in the mitochondrial tRNAleu gene cause this progressive neurodegenerative disease characterized by repeated episodes of “chemical (metabolic) strokes,” myopathy, and lactic acidosis. In many cases, cells contain both wild-type and mutant mitochondrial DNA (heteroplasmy); thus, expression is variable.
Міоклонічна епілепсія з рваними червоними волокнами (MERRF)
This progressive disorder is characterized by uncontrolled muscle contractions (myoclonic seizures), dementia, ataxia, and myopathy, which shows ragged-red fibers (indicating mitochondrial proliferation) with specialized stains when biopsied. Mutations are in the mitochondrial tRNAlys gene. Heteroplasmy is common; thus, expression is variable.
Синдром Кернса-Сейра і хронічна прогресуюча зовнішня офтальмоплегія (CPEO)
These disorders are characterized by ophthalmoplegia, ptosis, atypical retinitis pigmentosa, ragged-red fiber myopathy, ataxia, deafness, and cardiomyopathy typically occurring before age 20 years.
Kearns-Sayre syndrome is caused by a large contiguous deletion in mtDNA that results in the loss of genes important for mitochondrial protein formation and oxidative phosphorylation.
CPEO can result from mutations in one of several different nuclear genes that are critical for the production and maintenance of mtDNA and result in the deletion of large segments of mtDNA in muscle cells. Less common causes involve point mutations in mtDNA genes that provide instructions for making molecules called transfer RNAs.
Невропатія, атаксія та пігментний ретиніт (NARP)
NARP is a progressive condition characterized by sensory neuropathy (with numbness, tingling or pain in the extremities), muscle weakness, ataxia, vision loss caused by retinal deterioration (retinitis pigmentosa), cognitive decline, seizures, hearing loss, and cardiac conduction defects. The disorder can begin in childhood or early adulthood.
NARP results from mutations in the ATP6 gene contained in mtDNA. ATP6 mutations alter the structure or function of adenosine triphosphate (ATP) synthase, reducing the ability of mitochondria to make ATP.
Хвороба Лі (підгостра некротична енцефалопатія)
Leigh disease is a severe neurologic disorder that usually manifests in the first year of life. It is characterized by progressive swallowing problems, poor weight gain, hypotonia, weakness, ataxia, ophthalmoplegia, nystagmus, and optic atrophy along with lactic acidosis. Patients typically die within 2 to 3 years, usually due to respiratory failure.
Imaging studies show degenerative lesions in the basal ganglia, cerebellum, and brain stem.
Leigh disease results from mutations in one of more than 75 different nuclear or mtDNA genes involved in energy production in mitochondria.
Мітохондріальна нейрошлунково-кишкова енцефаломіопатія (MNGIE)
MNGIE is a very rare disorder characterized by degeneration of the muscles of the gastrointestinal (GI) tract, leading to poor motility of the GI tract and causing numerous GI symptoms. Additionally, weakness of the eye muscles as well as loss of sensation and weakness of the extremities due to degeneration of the peripheral nerves also occur. Onset is variable but usually before 20 years of age.
MNGIE is caused by mutations in the TYMP gene, which encodes thymidine phosphorylase with secondary changes in mtDNA. Inheritance is autosomal recessive; males and females are equally affected.
Treatment is focused on management of symptoms. Long-term prognosis is poor, with mean age of death in the late 30s.
Більше інформації
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Online Mendelian Inheritance in Man® (OMIM®) database: Complete gene, molecular, and chromosomal location information
