Alpers-Huttenlocher syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at January 6, 2017
StartDiseasesAlpers-Huttenlocher syndrome

Alpers-Huttenlocher syndrome (AHS) is a rare but serious genetic disorder. It is characterized by progressive neuromuscular weakness, seizures, and eventual brain damage and liver damage

Contents

Definition & Facts

AHS is defined as a myocerebrohepatopathy resulting from mitochondrial DNA depletion. AHS is disease of the brain (primarily) and liver as a result of the loss of cellular mitochondria. This is a rare syndrome, occurring in only about 1 out of every 100,000 births. The prognosis is very poor; the average life expectancy is four years from the onset of symptoms.

Although the progression of the disease varies, most children develop symptoms very early and succumb before the end of toddlerhood. There is no particular ethnic group or gender that is more likely to develop AHS. It is usually the result of an autosomal recessive disorder, which means that one copy of the gene is needed from each parent for the child to develop the disease. 

Symptoms & Complaints

AHS usually presents in toddlers aged two to four, and is characterized by three key symptoms; seizures that are unresponsive to treatment, progressive loss of muscular and mental abilities (collectively called psychomotor functions), and liver failure.

Recurrent, uncontrollable seizures are almost always the first symptoms that initiate a diagnosis. They prove untreatable and eventually progress to brain damage. Children born with AHS often have developmental delays.

Other neurological signs include muscle weakness and loss of tone (hypotonia), spastic muscle movements, and neuropathy. Older patients can complain of migraines and visual impairments.

Because the disease process is progressively debilitating, the patient will eventually be completely unable to walk or communicate. A feeding tube or ventilator to assist breathing may become necessary in the end stages.

Liver failure can manifest as jaundice (yellowing of the skin and sclera or whites of the eyes) or abdominal pain. In some instances, acute liver failure occurs, resulting in a condition called lactic acidosis. This amplifies the disorientation and mental deterioration the patient may already be experiencing.

Causes

Mitochondria are numerous, small organelles found within the cytoplasm of every cell in the body. They are known as the “powerhouses” of cells because their job is to produce energy in the form of adenosine triphosphate (ATP) for cellular activities. Mitochondria exist in a somewhat independent way from the rest of the cell. They receive some of their genetic input from the cell’s nucleus, but also contain a small amount of their own DNA.

Organs such as the brain and liver that require higher amounts of energy naturally have higher concentrations of mitochondria in their cytoplasm. When something goes wrong in the mitochondrial ability to function, their numbers become depleted. Cessation of mitochondrial activity quickly results in failure of the cell and, ultimately, the major body organs they compose.

Patients with AHS may have inherited two copies of the recessive gene that causes a defect in their mitochondrial DNA (mtDNA), impeding gene replication and repair. The defective genes may be in the cell’s nucleus or may only be located in the mtDNA. As the individual cells housing the defective mitochondria die, the drop in ATP levels quickly begins to affect the body’s ability to compensate. This especially impacts the most ATP-dependent organ, the brain. 

Diagnosis & Tests

AHS can be difficult to distinguish from other epileptic disorders. Since seizures are dominant features, specific electroencephalogram findings have been identified that correlate with Alpers. The back part of the brain, called the occipital lobe, is usually affected. This discovery in combination with the other characteristic features of the disease can help direct doctors down the correct diagnostic path.

Mitochondrial DNA testing, computed tomography (CT) scans of the brain, and cytology tests of the brain and liver can provide clues but are not specific enough to point directly to AHS. Only full gene sequencing to identify the known specific gene mutations (of the POLG gene) affecting mitochondria can give doctors a firm diagnosis. A licensed clinician can order these tests to be done by a specialty laboratory.

Treatment & Therapy

Unfortunately, there is no cure for Alpers-Huttenlocher syndrome. Because it stems from an irreversible genetic defect, once symptoms arise it is 100 percent fatal. Management of the symptoms, however, can delay progression and prolong the patient’s life. The exact onset and order of symptoms varies between people, so early intervention is paramount.

Seizure management is very complicated. The traditional use of the most effective antiepileptic drug, valproic acid is strictly forbidden, since the liver cannot tolerate it. The sudden onset of liver failure after valproate, in fact, is often the first clue that a mitochondrial disease is behind the seizures. The exact reason for this is unknown. Therefore, patients will have to be closely managed by a skilled neurologist to slow seizure progression with alternate medications such as lamotrigine and benzodiazepines.

The use of medically-induced coma therapy during active seizure episodes has shown some benefit. Careful monitoring of the liver is also important. The easiest method is routine blood testing that screens for elevated liver enzymes and for ammonia levels, which rise as the liver loses its ability to remove waste products from the blood.

When the child’s condition has progressed to the end stage, hospice and palliative care may be sought. Hospice offers a range of holistic end-of-life services, including pain management and, equally important, emotional support for the whole family. 

Prevention & Prophylaxis

Once conception has taken place, the disease is inevitable and irreversible. Hopeful parents with any family history of mitochondrial disorders or of neurological infant mortalities may seek genetic counseling. If a physician or genetic counselor determines that there is a significant risk of developing the disorder, prospective parent(s) can make informed decisions about family planning.