What is Alpers Disease: Symptoms and Causes

Alpers Huttenlocher syndrome is a rare mitochondrial disease. Scientists associate it with mutations in mitochondrial DNA gamma polymerase (POLG). A decrease in mitochondrial DNA replication leads to a reduction in enzyme activity. The disease manifests itself when replication levels become critical. There is variability in the onset and progression of Alpers disease. It happens even in normal child development until the onset of clinical manifestations. A triad of symptoms characterizing the disease include: 

• epileptic seizures; 
• liver dystrophy;
• developmental regression. 

Epileptic seizures are usually resistant to treatment and often have a status course. Liver dysfunction is one of the disease manifestations. It is inevitable in the terminal stages. 

A timely diagnosis with a prescription for supportive therapy can increase life expectancy. Also, the exclusion of valproic acid drugs from the therapy works well.

What is Alper’s Huttenlocher Syndrome?

Alpers-Huttenloher syndrome is a progressive encephalopathy with degenerative changes. They occur in the brain’s gray matter combined with liver cirrhosis. We can also say that it is a sporadic mitochondrial disease. Mutations in mitochondrial DNA gamma polymerase (POLG) cause this disease. Nuclear genes encode it.

It is the only eukaryotic DNA polymerase involved in continuous mitochondrial DNA replication. A decrease in mitochondrial activity is associated with a decrease in DNA replication. The disease manifests itself when the replication level reaches a critical level.

Alper’s disease has been extensively studied throughout the 20th century:

• In 1976, Peter Huttenlocher confirmed the disease’s autosomal recessive type of inheritance. Also, he described liver changes in this syndrome. Several symptoms are characteristic of Alpers-Huttenloher syndrome. A decrease in cytochrome С-oxidase activity in liver mitochondria causes them:

1. Progressive hepatomegaly;
2. Fatty dystrophy;
3. Hepatic fibrosis.

• A 1992 article in Bicknes et al. described the catastrophic effects of valproic acid on the liver in children. It was one of the symptoms of Alper’s syndrome. Valproic acid causes apoptosis of liver cells. It leads to fatal toxic hepatitis and rapid death in children. 
• In 1995, Harding analyzed the medical histories of 32 patients. All suffered from liver failure and brain pathology. He confirmed the normal psychomotor development of the child before the disease. But after it, the child gets regression of development combined with metabolic crises. The crises went by bouts of vomiting and pronounced muscle hypotonia. He also specified that epileptic seizures could be with the above symptoms. Or the disease can debut with epileptic seizures. These seizures are resistant to therapy and often have a status course.
• In 2004, scientists identified biochemical and enzymatic changes in Alper’s disease.  The findings clarified the pathophysiology of the clinical phenotype. They confirmed the genetic etiology and the underlying cause of the disease. It is a disorder of DNA gamma polymerase synthesis. Various dominant and recessive mutations of the POLG gene relate to it.

Alper’s Syndrome Symptoms

Seizures manifest Alpers disease in half of the cases. We call “Large epileptic paroxysms”:

• focal seizures;
• myoclonic forms. It is rhythmic muscle twitches without muscle spasms;
• generalized tonic-clonic seizures;
• dementia.

The typical age of onset is 2 to 4 years. Although scientists have described cases of early onset (3 to 4 months) and late-onset (up to 8 years of age). And the second peak is between 17 and 24 years of age. 

Before the appearance of the first clinical symptoms, children have normal psychomotor development. They also have enough intellectual abilities. After the onset of neurological symptoms, there is a sharp decline in before-acquired skills. A bimodal distribution characterizes what we call Alper’s syndrome. 

In children, the first seizures are often triggered by a fever with an infectious disease.

Many neurological disorders can characterize Alper’s disease:

• Patients have gait instability, movement disorder, and impaired fine motor skills.
• Sensory polyneuropathy is manifested by impairment of all types of sensitivity, including paresthesias. 
• As a rule, there are visual disturbances (cortical blindness). Migraines are disturbing, including as part of an explosive aura.

The pronounced toxic effects of valproic acid with the development of toxic fatal hepatitis are independent of:

• a patient;
• the type of mutation;
• the stage of the disease.

It usually occurs within 2-4 months. Blood tests determine the following Alper’s syndrome symptoms:

• hypoglycemia;
• hyperketonemia;
• decreased synthesis of clotting factors;
• increased levels of transaminases. This indicates the initial stage of liver failure. 

In rare cases, doctors can stop liver failure by canceling the medication. It is the valproic acid that causes the failure. In the terminal stages of the disease, liver dysfunction is inevitable. 

What Serious Conditions Can Occur in Alper’s Disease?

Hypoglycemia can be one of the early symptoms of the disease. This is especially true in the first two years of life. Hypoglycemia occurs with decreased mitochondrial electrolyte transport system activity. Also, it happens due to a nuclear DNA mutation. In this case, the doctor can identify what Alper’s Huttenlocher syndrome is:

• abnormalities in the hemostasis system;
• a deficiency of vitamin K-dependent clotting factors.

Deep vein thrombosis is common in patients with Alpers Huttenlocher syndrome. These are predominantly subclavian or femoral veins. This is due to a lack of synthesis of anticoagulant proteins.

Associated Alper’s syndrome symptoms are: 

• High body temperature;
• Impaired gait;
• Cramps;
• Tonic-clonic seizures;
• Feverish body temperature.

As the disease progresses, focal clonic seizures join. They can be a Jacksonian march and focal myoclonic seizures. They are resistant to therapy, often with a status course. Treatment-resistant seizures can be caused by hippocampal sclerosis.

What Causes Alper’s Syndrome

Mutation of the POLG1 gene in locus 15q25 causes Alpers disease. This gene is responsible for gamma polymerase function in the mitochondria. The most common gene defects are:

• A467T;
• W748S. 

They differ in the age of onset of diseases and the type of inheritance and clinical manifestations. Alpers-Huttenloher syndrome is a hereditary disease with an autosomal recessive transmission mechanism. The disease predominates among conditions associated with impaired gamma polymerase DNA synthesis.

The disease is inherited through an autosomal recessive agent. So the probability of recurrence of the pathology is 25% in the subsequent pregnancy. The risk of developing the syndrome increases in closely related marriages. Scientists have not yet found thing what we call causes Alper’s syndrome.

Risk Factors of Alper’s Disease

The most dangerous risk factor for Alper’s syndrome is fatal toxic hepatitis. It occurs when drugs from the valproic acid group are taken to relieve seizures. Severe liver failure develops. Changes in biliary tract architectonics and liver fibrosis can indicate lesions of the hepatobiliary system. With the progression of Alper’s disease on the background of muscle, hypotonia develops:

• dysphagia;
• disorders of peristalsis of the gastrointestinal tract. 

There is a need for the introduction of a gastrostomy tube or the use of parenteral nutrition. Pancreatitis can complement a lesion in the digestive system. Cardiomyopathy develops in 10% of patients. It leads to severe heart failure.

Words from Lone Star Neurology

Alpers-Huttenloher syndrome is a rare genetic disease with a severe prognosis and symptoms within several years of clinical symptoms’ onset. Specific changes combined with features of epileptic seizures help to suspect the disease. Complete analysis of the gene allows early confirmation of the disease. Doctors from our Lone Star Neurology clinic do it by direct automated sequencing. You can always turn to our professionals for a complete diagnosis of this and other neurological diseases.

FAQs

• How is Alper’s disease inherited?

This hereditary disease has an autosomal recessive transmission mechanism. A non-hereditary mutation in one of the parents causes this disease. It can also be the development of an accidental abnormality while the child is in the womb.

• When was Alper’s disease discovered?

Bernard Alpers, firstly in 1931, described the case of a four-month-old typically developing girl who suddenly had treatment-resistant epileptic seizures, leading to the rapid death of the child. Alpers was the first to identify the main features of the disease. The age of onset is from 3 months to 7 years, with resistant seizures, developmental regression, and amaurosis. 

• Is Alper’s disease a neurological disease?

Yes, it is a neurological disease. It belongs to a group of diseases associated with defective mitochondrial functioning, leading to impaired body energy functions. It can also cause delays in psychomotor development, epileptic seizures, and liver damage.

• What disorders of the neurological spectrum are similar to Alpers’ Disease?

This is myoclonic epilepsy. It is also a hereditary neurological disorder. Sudden and brief contractions of muscle groups characterize it. This disorder usually manifests itself between the ages of six and sixteen. Loss of consciousness is widespread during seizures. After many years, the frequency and severity of seizures increase.