What is Alpers disease?
Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. Alpers-Huttenlocher syndrome typically becomes apparent in children between ages 2 and 4, hence called Neuronal degeneration of childhood with liver disease.
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. It is one of the most severe of a group of conditions called the POLG-related disorders. The condition in this group majorly affects muscle-, nerve-, and brain-related functions.
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.
On MRI examination an increased density of the grey matter in the brain is noted. Usually, but not always, Alpers disease is associated with liver damageThe liver may become cirrhotic and fail completely, or may not progress beyond signs of jaundice. Affected individuals may also become blind as a result of optic atrophy as the optic nerve degenerates.
Several assumptions are made regarding this syndrome across the world.
i) 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 a number of different causes.
ii) In some cases, it is believed that the syndrome may be inherited as an autosomal recessive genetic trait. Also, Research has also indicated that certain metabolic defects or mitochondrial abnormalities may play some role in causing the disorder — accepted universally later
iii) In other cases, clinicians attribute the disorder to a prion or prion-like molecule.
iv) 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 expression of the disorder.
Finally it was accepted that 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.
But 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.
The diagnosis of Alpers’ disease can be done when the symptoms are observable. Post the appearance of the symptoms, the diagnostic procedures followed are:
· Medical History Assessment: A clinical analysis is conducted to obtain a detailed patient history as well as physical fitness is evaluated.
· Brain Scan to Diagnose Alpers’ Disease: The specialized imaging of brain using MRI, CT scan are utilized to study the extent of degeneration occurring in the cerebral cortex as well as other parts of the brain.
· Diagnosing Alpers’ Disease with Electroencephalography: EEG is used to study the electrical impulses within the brain. In case of Alpers’ disease, the electrical activity of the brain is abnormal due to presence of seizures.
· Liver Function Tests: These tests include the checking for coagulation, alanine aminotransferase, bilirubin as well as ammonia and glucose levels to check for the extent of liver damage. Ultrasound is also done to check for abnormalities in liver for patients with Alpers’ disease.
· Electrocardiogram: The ECG is conducted to rule out the possibility of cardiomyopathy.
· Audiogram: An audiogram is conducted to check for impairment of hearing ability in patients with alpers’ disease.
Currently, there is no treatment for Alpers’ Disease. However, medications are used to control the symptoms of the disease.
1) Treatment of manifestations: Clinical management is largely supportive and involves conventional approaches for associated complications including physiotherapy, speech therapy, nutritional interventions, respiratory support, and management of seizures and movement disorders.
2) Prevention of secondary complications: Dose reductions of medications metabolized by hepatic enzymes to avoid toxicity.
3) Surveillance: Evaluations by a multidisciplinary team of healthcare providers based on clinical findings; monitoring of liver enzymes every two to four weeks after introduction of any new anticonvulsant.
4) Agents/circumstances to avoid: Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) because of the risk of precipitating and/or accelerating liver disease.
Medications can be prescribed to relieve pain, muscle spasms, treat infections and check the seizures. These medicines include:
· Sedative Medications: Sedative medications for Alpers’ disease are prescribed to treat anxiety and discomfort.
· Anticonvulsants: These are prescribed to treat the seizures, when sedative medication fails to provide the required relief. Valporate should not be taken to reduce the risk of liver failure.
Alpers’ disease is known to have an incidence rate of one in a 100000 to 250000 of population with the development of symptoms within two years for over eighty percent of the population whereas the remaining twenty percent of the population develop symptoms over years up to twenty five years of age.
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A 17-year-old adolescent girl of New Zealand, European, and Pacific Island ethnicity was initially seen with clusters of occipital seizures characterized by a brief visual disturbance followed by head extension, clonic jerking of the right arm, and secondary generalization. An initial electroencephalogram demonstrated diffuse slowing. Handwriting had always been difficult, to the extent that she needed a stenographer to write some final examinations. Nerve conduction studies showed peripheral neuropathy. Developmental milestones were otherwise normal, and she had normal intelligence. Her vision and hearing were also normal. At age 5 years, she had viral meningitis. The cerebrospinal fluid at this stage had a low glucose level. She began experiencing migraines at age 12 years, with visual aura and vomiting.
Family history showed that a maternal aunt, currently aged 48 years, had an undiagnosed neurologic condition, with delayed early milestones and ataxia beginning at age 3 years. She regressed neurologically between ages 5 and 7 years, with subsequent severe intellectual disability. A maternal uncle died at age 3 months of “cot death.”
The patient was treated early with midazolam hydrochloride followed by maintenance therapy with phenytoin sodium. She had a cluster of seizures after 1 month, remained seizure-free for 4 months, and then developed status epilepticus. During the next 2 months, she had repeated admissions to the intensive care unit with status epilepticus or encephalopathy. Although she had lucid periods between episodes, overall she developed stepwise deterioration, with memory impairment, slurred speech, and left-sided hemiparesis. A variety of anticonvulsant agents, including carbamazepine, valproate sodium, lamotrigine, intravenous benzodiazepines, topiramate, gabapentin, and intermittent doses of phenobarbital sodium, were tried without sustained benefit.
Liver function test results became abnormal while the patient was taking carbamazepine .Liver dysfunction persisted when valproate therapy was commenced but deteriorated when the patient received multiple drugs, including antituberculous therapy. Subsequent electroencephalograms showed frequent epileptiform discharges in the left posterior quadrant and continued diffuse slowing. Biopsies of the skin, muscle, and liver were nondiagnostic. Brain biopsy showed slight perivascular lymphocytic cuffing, perhaps representing cerebral angiitis.
A variety of infectious, inflammatory, and neoplastic processes were considered. The patient received empirical therapy for these conditions (immunosuppression, antibiotics, and therapy for tuberculosis), without any improvement. Consultation with a pediatric neurologist suggested the possibility of a mitochondrial disorder. She commenced a high-fat, low-carbohydrate diet and multivitamin therapy, with no improvement. Her neurologic decline continued, and she died at age 17 years 9 months of respiratory failure secondary to her neurologic condition.
At autopsy, the brain showed extensive neuronal loss and gliosis, most prominent in the occipital lobes as typically seen in Alpers disease, but also in the basal ganglia and brainstem. The liver showed extensive steatosis and fresh necrosis
Sequencing of the entire mitochondrial genome in the liver DNA did not reveal any pathogenic mutations. Quantitative polymerase chain reaction showed that the ratio of mtDNA to nuclear DNA in the liver was deficient
In conclusion, Alpers disease should be considered in adults with encephalopathy and intractable epilepsy, particularly when the liver or other organs are involved. Mutation screening of POLG1 should be considered in such patients and is vital for identifying the underlying cause and for genetic counseling.
v Genetic Home Reference- https://ghr.nlm.nih.gov/condition/alpers-huttenlocher-syndrome#statistics
v National Organization for Rare Disorders NORD — https://rarediseases.org/rare-diseases/alpers-disease/
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