Alpers Disease

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 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 that 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, 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 liver disease have POLG mutations.

Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia)

Synonyms of Alpers Disease

Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis

• Alpers Progressive Infantile Poliodystrophy
• Diffuse Cerebral Degeneration in Infancy
• Poliodystrophia Cerebri Progressiva
• Progressive Cerebral Poliodystrophy

Signs & Symptoms

Alpers disease usually begins during early childhood, usually indicated by seizures at any age between 3 months and 5 years. It is characterized by lack of coordination of motor movement, partial paralysis, seizures, and muscle twitching. The child is unable to achieve normal muscle tone (hypotonia), yet the limbs appear to be stiff. 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 damage.

Mental retardation may be severe and is progressive. The loss of intellectual functions such as thinking, remembering, and reasoning may also interfere with a person’s daily functioning (dementia). In later stages, patients may lose control of the movement of their arms and legs (spastic quadriplegia). The 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.

About 80% of the individuals with Alpers’ Disease develop symptoms within the first two years of life. The other 20% may develop symptoms any period between the ages of 2 and 25 years.

Common signs and symptoms of Alpers’ Disease include:

• Memory loss, dementia
• Liver disease: Jaundice and cirrhosis (liver failure)
• Seizures
• Balance and coordination issues, involuntary twitches
• Reflex-related problems
• Hypotonia (weak muscle tone)
• Headaches
• Irritability
• Speech abnormalities

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 a number of 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 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 for 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 for 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’ Disease is caused by mutations in the POLG polymerase gene. This polymerase aids in the production of mitochondrial DNA, which codes for the production of mitochondria

Mitochondria are important for energy production in the body cells; they are the primary source of energy for the body’s cells. In particular, they are important in maintaining healthy brain tissue. When mutations are present in the POLG polymerase, there is a decrease of mitochondrial DNA

This causes a progressive degeneration of grey matter in the brain. Seizures and liver disease are thought to be a result of the decrease in cellular energy, which is present due to the loss of mitochondria

Affected Populations

It is thought that Alpers disease affects males and females in equal numbers usually during early childhood. However, some clinicians are convinced that the difficulty of diagnosis makes estimating the frequency of this disorder less accurate. It is probable that Alpers disease affects fewer, than one (1) person per 200,000 of population.

Related Disorders

Symptoms of the following disorders can be similar to those of Alpers disease. Comparisons may be useful for a differential diagnosis:

Myoclonic epilepsy is a hereditary neurologic disorder inherited through recessive genes. It is characterized by sudden brief contractions of groups of muscles. Onset is usually between the ages of six and sixteen. During the initial period of seizures there is loss of consciousness. After years of attacks of increasing frequency and severity, spasms involving the muscles of the face, trunk, arms, and legs intensify. Untreated, this type of epilepsy can lead to progressive dementia.

Leigh’s disease is a genetic metabolic disorder characterized by lesions of the brain, spinal cord, optic nerve and in some cases, an enlarged heart. The disorder is usually first diagnosed during infancy but may begin later. Symptoms during infancy may include low body weight, slow growth, tremors, skin changes and interrupted breathing patterns. Progressive neurological disturbances, mental retardation, slurred speech and loss of motor coordination (ataxia) may occur. Abnormalities of eye movement and other vision problems may develop in cases with later onset.

Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early.

Batten disease is a hereditary lipid storage disorder transmitted as a recessive trait. It is characterized by rapidly progressive vision failure (optic atrophy), deterioration of intellect, seizures, loss of muscular coordination (ataxia) and a backward lateral curvature of the spinal column (kyphoscoliosis). Occurring mostly in white families of Northern European Scandinavian ancestry, Batten Disease usually begins between five and seven years of age.

Tay-Sachs disease is a genetic disorder in children that causes the progressive destruction of the central nervous system. It is generally found among children of eastern European Jewish heritage. Infants with Tay-Sachs disease appear normal at birth and seem to develop normally until the age of about six months.

The first signs of the disease vary and become evident at different ages. These signs may include slowed development, loss of peripheral vision, abnormal startle response, progression of feeding difficulties, weakness, restlessness and cherry red spots on the retina. At the age of one year, recurrent convulsions, loss of previously learned skills and muscle coordination, blindness, mental retardation, flaccidity and/or paralysis may occur. This disorder is inherited as a recessive trait.

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 by means of a brain biopsy.

A diagnosis of Alper’s Disease may involve:

• A complete evaluation of medical history along with a thorough physical exam
• A family history of the disorder is very important

Some of the diagnostic tests may include:

• Evaluation of liver function will show elevation of transaminase enzymes
• Cerebrospinal fluid examination will show elevated levels of proteins and lactate
• POLG DNA testing is the gold-standard for confirming a diagnosis of Alper’s Disease

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

Standard Therapies

Treatment

There is no treatments available that will stop the progress of the disease. However, some of the symptoms can be treated in order to make the patient as comfortable as possible under the circumstances. There are drugs available to treat the frequency of the seizures, to cope with muscle spasms and joint pain, and to treat infection.

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.

Who gets Alpers’ Disease? (Age and Sex Distribution)

Alpers’ Disease is a congenital (inherited) condition that is present from birth. Nevertheless, the symptoms of the condition may arise any period from birth to the age of 25 years

Males and females are equally affected by Alpers’ Disease

What are the Risk Factors for Alpers’ Disease? (Predisposing Factors)

Alpers’ Disease is a genetic disorder inherited in an autosomal recessive pattern. This means that the mutation must be inherited from both parents in order to inherit the disorder and manifest signs and symptoms of Alpers’ Disease

If the individual only inherits one copy of the mutated gene, then they will be a carrier of the disorder, not showing any signs or symptoms of the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the possible Complications of Alpers’ Disease?

Along with the three primary symptoms of Alpers’ Disease, such as dementia, seizures, and liver disease, other complications may also arise.

Many individuals suffer from coordination and balance problems due to nerve damage in the brain

A complete loss of movement may also occur

Cortical blindness: Loss of vision due to damage of the brain area that controls vision

How is Alpers’ Disease Treated?

Currently, there is no treatment for Alpers’ Disease. However, medications are used to control the symptoms of the disease.

Anticonvulsants are often used to manage seizures

Physical therapy is also recommended to help maintain muscle tone and relieve spasticity

How can Alpers’ Disease be Prevented?

Currently, there are no specific methods or guidelines to prevent Alpers’ Disease, since it is a genetic condition

Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy

If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child

Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Alpers’ Disease? (Outcomes/Resolutions)

Individuals with Alpers’ Disease may survive anywhere from a few months to more than 10 years after the first symptoms are noted

Medication and therapy are beneficial in keeping the symptoms in check; however, these do not improve the survival rate

Additional and Relevant Useful Information for Alpers’ Disease:

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children.

If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

Clinical description

Development is usually normal until disease onset and presentations are highly variable. The most common age of onset is between 2-4 years (ranges from 3 months to 36 years). Seizures (mainly partial, secondary generalized tonic-clonic, or myoclonic) are often the presenting feature, evolving into focal status epilepticus, epilepsia partialis continua, and/or multifocal myoclonic epilepsy.

Seizures may respond to treatment initially but usually become intractable. Headaches, visual disturbances and movement disorders (e.g. myoclonus and choreoathetosis) are also common. Cerebellar ataxia develops in most patients. Peripheral neuropathy develops in many and becomes increasingly common in older children and young adults. Loss of cognitive function progresses with varying rates (rapid regression seen during infectious diseases) with manifestations including somnolence, irritability, loss of concentration, loss of language skills and memory deficits, ending in dementia and visual loss.

Gastrointestinal involvement (i.e. swallowing dysfunction, intestinal dysmotility) is also noted. Liver disease may be indolent for years before the first acute exacerbation, but may be the first presenting symptom in some children. The clinical course of both brain and liver abnormalities is often episodic with acute exacerbations followed by periods of partial recovery.

Etiology

AHS is due to mutations in the polymerase gamma (POLG) gene (15q24). This gene encodes DNA polymerase subunit gamma-1, which is involved in the replication and repair of mtDNA. Ecogenetic and epigenetic stressors, including incidental infections and drugs like valproic acid, can accelerate the onset of symptoms and modify how the phenotype unfolds.

Prognosis

The prognosis is severe with life-expectancy in patients ranging from 3 months to 12 years, after disease onset.

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