Each column keeps its native condition scope. Initial features are displayed alphabetically, not ranked by clinical importance. Counts remain separate, and an empty cell does not mean a feature cannot occur.
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Researchers have described different forms of this disorder. Approximately 75 percent of affected individuals have the hepatocerebral form, which causes serious problems in the liver (hepato-) and brain (cerebral). Approximately 20 percent of people with deoxyguanosine kinase deficiency have the isolated hepatic form, which causes liver disease without serious neurological problems. The myopathic form is the least common form; it affects approximately 5 percent of people with deoxyguanosine kinase deficiency. The myopathic form causes problems with the skeletal muscles, which are the muscles used for movement. 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This enzyme plays an important role in mitochondria, which are the energy-producing centers inside the cell. Mitochondria each contain their own DNA, known as mitochondrial DNA or mtDNA, that is essential for their normal function. Deoxyguanosine kinase is involved in producing and maintaining the building blocks (nucleosides) that make up mtDNA.
The variants (also called mutations) in the DGUOK gene that cause deoxyguanosine kinase deficiency reduce or eliminate the activity of the deoxyguanosine kinase enzyme. Reduced enzyme activity leads to problems with the production and maintenance of mtDNA. A decrease in the amount of mtDNA (known as mitochondrial DNA depletion) impairs mitochondrial function in many of the body's cells and tissues. These problems lead to the brain, liver, and muscle dysfunction associated with deoxyguanosine kinase deficiency.
","key":"forms","title":"What causes Deoxyguanosine kinase deficiency?"},{"bodyHtml":"Infants with the hepatocerebral form of deoxyguanosine kinase deficiency typically have low blood glucose levels (hypoglycemia) and a buildup of lactic acid in the body (lactic acidosis) soon after birth. Within the first few weeks of life, these infants typically begin to show signs of liver disease and brain dysfunction. Neurological signs and symptoms may include weak muscle tone (hypotonia), abnormal involuntary eye movements (nystagmus), developmental delays, and, rarely, seizures. Early signs of liver disease may include an enlarged liver (hepatomegaly) and yellowing of the skin and the whites of the eyes (jaundice). Liver disease usually progresses to liver failure.
Signs and symptoms of the isolated hepatic form of deoxyguanosine kinase deficiency may appear soon after birth or during childhood. Like those with the hepatocerebral form, people with the hepatic form often have liver disease that worsens over time and may progress to liver failure. Some affected individuals have additional signs and symptoms that indicate the involvement of other body systems, such as the kidneys and the heart.
Signs and symptoms of the myopathic form often appear in adulthood, although they sometimes appear earlier in life. In addition to problems with the skeletal muscles, people with the myopathic form of deoxyguanosine kinase deficiency can have heart problems, brain abnormalities, or weakness of the eye muscles. People with the myopathic form typically do not have liver disease.
Without intervention, most individuals with deoxyguanosine kinase deficiency have a shortened life expectancy. Those with liver disease typically do not survive past early childhood, while those with the myopathic form may survive into middle or late adulthood.
Source: MedlinePlus Genetics
Alpers-Huttenlocher syndrome is one of the most severe of a group of conditions called the POLG-related disorders. The conditions in this group feature a range of similar signs and symptoms involving muscle-, nerve-, and brain-related functions. Alpers-Huttenlocher syndrome typically becomes apparent in children between ages 2 and 4. People with this condition usually have three characteristic features: recurrent seizures that do not improve with treatment (intractable epilepsy), loss of mental and movement abilities (psychomotor regression), and liver disease.
People with Alpers-Huttenlocher syndrome usually have additional signs and symptoms. Most have problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). Neuropathy can lead to abnormal or absent reflexes (areflexia). In addition, affected individuals may develop weak muscle tone (hypotonia) that worsens until they lose the ability to control their muscles and movement. Some people with Alpers-Huttenlocher syndrome lose the ability to walk, sit, or feed themselves. Other movement-related symptoms in affected individuals can include involuntary muscle twitches (myoclonus), uncontrollable movements of the limbs (choreoathetosis), or a pattern of movement abnormalities known as parkinsonism.
Affected individuals may have other brain-related signs and symptoms. Migraine headaches, often with visual sensations or auras, are common. Additionally, people with this condition may have decreased brain function that is demonstrated as sleepiness, inability to concentrate, irritability, or loss of language skills or memory. Some people with the condition may lose their eyesight or hearing. People with Alpers-Huttenlocher syndrome can survive from a few months to more than 10 years after the condition first appears.
Alpers-Huttenlocher syndrome is caused by mutations in the POLG gene. This gene provides instructions for making one part, the alpha subunit, of a protein called polymerase gamma (pol γ). Pol γ functions in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. Pol γ "reads" sequences of mtDNA and uses them as templates to produce new copies of mtDNA in a process called DNA replication.
Most POLG gene mutations change single protein building blocks (amino acids) in the alpha subunit of pol γ. These changes result in a mutated pol γ that has a reduced ability to replicate DNA. Although the mechanism is unknown, mutations in the POLG gene often result in a reduced number of copies of mtDNA (mtDNA depletion), particularly in muscle, brain, and liver cells. MtDNA depletion causes a decrease in cellular energy, which could account for the signs and symptoms of Alpers-Huttenlocher syndrome.
A mutation in the POLG gene has not been identified in approximately 13 percent of people diagnosed with Alpers-Huttenlocher syndrome. Researchers are working to identify other genes that may be responsible for the condition.
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is an inherited disorder that can cause liver disease and neurological problems. The signs and symptoms of this condition begin in infancy and typically include vomiting, diarrhea, and an inability to grow or gain weight at the expected rate (failure to thrive). Many affected infants have a buildup of a chemical called lactic acid in the body (lactic acidosis) and low blood glucose (hypoglycemia). Within the first weeks of life, infants develop liver disease that quickly progresses to liver failure. The liver is frequently enlarged (hepatomegaly) and liver cells often have a reduced ability to release a digestive fluid called bile (cholestasis). Rarely, affected children develop liver cancer. After the onset of liver disease, many affected infants develop neurological problems, which can include developmental delay, weak muscle tone (hypotonia), and reduced sensation in the limbs (peripheral neuropathy). Individuals with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome typically survive only into infancy or early childhood.
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is most frequently seen in the Navajo population of the southwestern United States. In this population, the condition is known as Navajo neurohepatopathy. People with Navajo neurohepatopathy tend to have a longer life expectancy than those with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. In addition to the signs and symptoms described above, people with Navajo neurohepatopathy may have problems with sensing pain that can lead to painless bone fractures and self-mutilation of the fingers or toes. Individuals with Navajo neurohepatopathy may lack feeling in the clear front covering of the eye (corneal anesthesia), which can lead to open sores and scarring on the cornea, resulting in impaired vision. The cause of these additional features is unknown.
As the condition name suggests, mutations in the MPV17 gene cause MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. The protein produced from the MPV17 gene is located in the inner membrane of cell structures called mitochondria. Mitochondria are involved in a wide variety of cellular activities, including energy production, chemical signaling, and regulation of cell growth, division, and death. Mitochondria contain their own DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. It is likely that the MPV17 protein is involved in the maintenance of mtDNA. Having an adequate amount of mtDNA is essential for normal energy production within cells.
MPV17 gene mutations that cause MPV17-related hepatocerebral mitochondrial DNA depletion syndrome lead to production of a protein with impaired function. One mutation causes all cases of Navajo neurohepatopathy and results in the production of an unstable MPV17 protein that is quickly broken down. A dysfunctional or absent MPV17 protein leads to problems with the maintenance of mtDNA, which can cause a reduction in the amount of mtDNA (known as mitochondrial DNA depletion). Mitochondrial DNA depletion impairs mitochondrial function in many of the body's cells and tissues, particularly the brain, liver, and other tissues that have high energy requirements. Reduced mitochondrial function in the liver and brain lead to the liver failure and neurological dysfunction associated with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Researchers suggest that the less mtDNA that is available in cells, the more severe the features of Navajo neurohepatopathy.
MedlinePlus: MPV17-related hepatocerebral mitochondrial DNA depletion syndrome
Infantile-onset spinocerebellar ataxia (IOSCA) is a progressive disorder that affects the nervous system. Babies with IOSCA develop normally during the first year of life. During early childhood, however, they begin experiencing difficulty coordinating movements (ataxia); very weak muscle tone (hypotonia); involuntary writhing movements of the limbs (athetosis); and decreased reflexes. By their teenage years affected individuals require wheelchair assistance.
People with IOSCA often develop problems with the autonomic nervous system, which controls involuntary body functions. As a result, they may experience excessive sweating, difficulty controlling urination, and severe constipation.
IOSCA also leads to vision and hearing problems that begin by about age 7. Children with this disorder develop weakness in the muscles that control eye movement (ophthalmoplegia). In their teenage years they experience degeneration of the nerves that carry information from the eyes to the brain (optic atrophy), which can result in vision loss. Hearing loss caused by nerve damage (sensorineural hearing loss) typically occurs during childhood and progresses to profound deafness.
Individuals with IOSCA may have recurrent seizures (epilepsy). These seizures can lead to severe brain dysfunction (encephalopathy).
Most people with IOSCA survive into adulthood. However, a few individuals with IOSCA have an especially severe form of the disorder involving liver damage and encephalopathy that develops during early childhood. These children do not generally live past age 5.
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the TWNK gene cause IOSCA. The TWNK gene provides instructions for making a protein called Twinkle. This protein is found in mitochondria, which are structures within cells that convert the energy from food into a form that cells can use.
Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. The Twinkle protein acts as a helicase, which is an enzyme that binds to particular regions of DNA and temporarily unwinds the two spiral strands (double helix) of the DNA molecule. The Twinkle protein unwinds mtDNA so that it can be copied (replicated) when new mitochondria are made.
Pathogenic variants in the TWNK gene result in the production of Twinkle proteins with reduced or impaired function. As a result, mtDNA cannot be replicated efficiently, which reduces the amount of mtDNA (mtDNA depletion). Because of this, IOSCA is sometimes referred to as mitochondrial DNA depletion syndrome 7. Without mtDNA, mitochondria cannot produce as much energy. This affects tissues that require large amounts of energy to function, such as the nervous system and muscles, and leads to the neurological dysfunction and the other problems associated with IOSCA.