Alpers syndrome

December 31, 2014

Synonyms

Overview

Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. It is a progressive degenerative disease of the central nervous system that occurs mostly in infants and children. It often leads to death from hepatic failure or status epilepticus before age 3 years.

Alpers-Huttenlocher syndrome: It 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.

Symptoms

Infantile onset of symptoms
Intractable seizures
Developmental delay
Missed developmental milestones
Progressive mental retardation
Hypotonia (low muscle tone)
Spasticity (stiffness of the limbs)
Dementia
Seizures
Myoclonus
Epilepsia partialis continua - a form of seizure
Optic atrophy
Convulsions
Progressive spasticity
Involuntary muscle contraction
Impaired ability to control voluntary movements
Visual disturbance
Dementia
Growth retardation
Increasingly small head
Gliosis
Degeneration of cerebral gray matter middle layers
Degeneration of cerebellar gray matter middle layers
Diffuse encephalopathy
Mental retardation
Partial paralysis
Blindness
Seizures
Ataxia
Incoordination
Increased muscle tone
Spasticity
Rigidity
Paraparesis
Quadriparesis
Seizures
Vision problems
Liver disease
Failure to thrive
Fasting hypoglycemia
Liver failure
Cortical blindness
Gastrointestinal dysmotility
Cardiomyopathy
Episodic psychomotor regression
Reduced muscle tone
Mental retardation
Small head
Movement disorder

Causes

It is an autosomal recessive disorder meaning two copies of the defective gene is required for active disease, a single copy conveys carrier status. Alpers' disease is caused by certain genetic mutations in the POLG gene.

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.

Naviaux and Nguyen (2004) reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. The clinical features of the family had been described by Naviaux et al. (1999).

In 4 patients with Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene. Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes.

Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers 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 by means of a brain biopsy.

Prognosis

The prognosis for individuals with Alpers' disease is poor. Those with the disease usually are normal at birth and learn to walk and talk but progressively get worse within their first decade of life. Death shortly occurs after and is usually due to liver failure, although cardiorespiratory failure may also occur. Depletion studies cannot be used for early diagnosis because symptoms usually occur months before tissues show the mitochondrial DNA depletion. The first symptoms are usually ones that can relate to several other diseases and disorders so it is difficult to identify Alpers' syndrome until symptoms are worse and the person is dying.

Treatment

Treatment for Alpers syndrome is limited to managment of symptoms and supportive care. There is currently no cure. However, some of the symptoms can be treated in order to make the patient as comfortable as possible under the circumstances.

Anticonvulsants may be used to treat the seizures. However, caution should be used when selecting valproate as therapy since it may increase the risk of liver failure. Physical therapy may help to relieve spasticity and maintain or increase muscle tone.

A multi-disciplinary medical team of a gastroenterologist, neurologist, occupational, physical and/or speech therapist can assist with management of symptoms to maintain function as long as possible, insure comfort and promote the best possible quality-of-life.