Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease associated with mutations in the mitochondrial DNA replicate, polymerase gamma. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia). Seizures can rapidly progress to medical intractability with frequent episodes of epilepsia partialis continua or status epilepticus.
Alpers-Huttenlocher syndrome (AHS) is an autosomal recessive disease caused by a mutation in the POLG1 gene, which leads to the reduced functionality of polymerase gamma a key component of mitochondrial DNA (mtDNA) replication and repair. The brain and liver are the classic organs affected by this disease due to their high energy demand and the proportional need for mitochondria.
Alpers’ disease is a progressive, neurodevelopmental, mitochondrial DNA depletion syndrome characterized by three co-occurring clinical symptoms: psychomotor regression (dementia); seizures; and liver disease. It is an autosomal recessive disease caused by a mutation in the gene for the mitochondrial DNA polymerase POLG. The disease occurs in about one in 100,000 persons. Most individuals with Alpers’ disease do not show symptoms at birth and develop normally for weeks to years before the onset of symptoms. Diagnosis is established by testing for the POLG gene. Symptoms typically occur months before tissue samples show the mitochondrial DNA depletion so these depletion studies cannot be used for early diagnosis. About 80 percent of individuals with Alpers’ disease develop symptoms in the first two years of life, and 20 percent develop symptoms between ages 2 and 25. The first symptoms of the disorder are usually nonspecific and may include hypoglycemia secondary to underlying liver disease, failure to thrive, infection-associated encephalopathy, spasticity, and myoclonus (involuntary jerking of a muscle or group of muscles), seizures, or liver failure. An increased protein level is seen in cerebrospinal fluid analysis. Cortical blindness (loss of vision due to damage to the area of the cortex that controls vision) develops in about 25 percent of cases. Gastrointestinal dysfunction and cardiomyopathy may occur. Dementia is typically episodic and often associated with an infection that occurs while another disease is in process. Seizures may be difficult to control and unrelenting seizures can cause developmental regression as well. “Alpers-like” disorders without liver disease are genetically different and have a different clinical course. Fewer than one-third of individuals with the “Alpers-like” phenotype without the liver disease have POLG mutations
Causes
Many researchers believe that Alpers Syndrome, rather than being a distinct disorder, is a clinical entity (i.e., cerebral gray matter degeneration in association with liver disease) that may be due to several different causes. In some cases, it is believed that the syndrome may be inherited as an autosomal recessive genetic trait. In other cases, clinicians attribute the disorder to a prion or prion-like molecule. Some researchers believe that certain individuals may inherit a genetic predisposition for the disorder; in such cases, certain environmental factors in combination with such a genetic predisposition may ultimately result in the expression of the disorder. Research has also indicated that certain metabolic defects or mitochondrial abnormalities may play some role in causing the disorder.
Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers of a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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 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.
Diagnosis
Alpers Syndrome is usually diagnosed during infancy based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include specialized imaging studies of the brain, which may reveal degeneration of the outer portion (cerebral cortex) and, in some cases, other areas of the brain.
Electroencephalography (EEG), which records the brain’s electrical impulses, may reveal an overall slowing of the brain’s electrical activity and/or other electrical discharge abnormalities characteristic of seizure activity. Only post-mortem confirmation is possible using a brain biopsy.
Seizure activity is often an early feature of the disease and should undergo an evaluation with an electroencephalography (EEG). EEG findings in the early stages of the disease have shown a focal slowing of the frequency of epileptiform discharges from the occipital region.[rx] One report showed that a characteristic EEG finding is a unilateral occipital rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS).[rx] Brain magnetic resonance imaging (MRI) may aid in supporting an overall diagnosis of Alpers-Huttenlocher syndrome by showing gray matter involvement in the posterior cortical structures and thalamus, in addition to the involvement of the occipital cortex – the portion of the brain with the highest metabolic activity.[rx]
Treatment
There are no treatments available that will stop the progress of the disease. However, some of the symptoms can be treated to make the patient as comfortable as possible under the circumstances. There are drugs available to treat the frequency of the seizures, cope with muscle spasms and joint pain, and treat the infection.
Clinicians should weigh the benefits of seizure management against the risk of side effects. If prescribing anticonvulsants, the newer generation (lamotrigine, topiramate, oxcarbazepine, primidone) is the recommendation due to a lower hepatic processing burden. Valproic acid and sodium valproate should be avoided to prevent accelerated hepatic damage. Impaired gluconeogenesis may lead to nutritional deficiencies. Small, frequent, low-protein meals are recommended. Eventually, as the patient’s disease progresses, a gastrostomy feeding tube can be offered to supplement nutritional status. Long-term respiratory support is often needed, with the use of tracheostomy and mechanical ventilation. Pain medications and muscle relaxants should be available to keep the patient comfortable.[rx]
Physical therapists may be able to help parents to find more comfortable positions for the child while sitting or standing. Massage often reduces the stress involved. All treatment for Alpers Syndrome is symptomatic and supportive.
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