What is Alpers-Huttenlocher Syndrome?
Alpers-Huttenlocher syndrome (AHS) is a disease that you can inherit from your parents (an autosomal recessive disease). It’s caused by a change or ‘mutation’ in a specific gene called POLG1. This mutation causes a reduction in the functionality of Polymerase Gamma, an essential part of the process of creating and repairing mitochondrial DNA – the DNA that provides the blueprint for our cells’ powerhouses, the mitochondria.
Because the brain and liver require a lot of energy and therefore have a high demand for mitochondria, they are typically the organs most impacted by this disease. With fewer functional mitochondria in these organs, various symptoms may develop. The most common symptoms are seizures and liver failure.
This disease typically appears early in a person’s life and progresses rapidly. It is a very serious condition that, sadly, usually leads to death.
What Causes Alpers-Huttenlocher Syndrome?
Alpers-Huttenlocher syndrome is a condition that happens due to an issue with a person’s mitochondria, the energy-producing parts of our cells. This condition is caused by a change or mutation in a specific gene known as POLG1, which normally helps regulate a protein called polymerase gamma.
This condition is inherited in an autosomal recessive manner, which means a child needs to inherit a faulty copy of the gene from both parents to have the disease. If a child inherits just one faulty gene, they usually show signs of the illness between 2 to 4 years old. This is considered the typical or classic presentation of the disease.
However, if someone inherits two faulty copies of the gene, one from each parent, the situation might be a bit different. This is referred to as having a homozygous mutation. In these cases, the symptoms of the disease might not appear until later in life, typically between the ages of 17 and 24, and they also tend to be not as severe.
Risk Factors and Frequency for Alpers-Huttenlocher Syndrome
Alpers-Huttenlocher syndrome is a rare condition that affects around 1 in 100,000 children, with no difference between boys and girls. While it seems to occur a bit more in people of Northern European heritage, it’s been found in various ethnic groups across the globe.
Signs and Symptoms of Alpers-Huttenlocher Syndrome
Alpers-Huttenlocher syndrome is typically diagnosed by noticing three main symptoms: hard-to-treat seizures, loss of physical coordination and mental skills, and liver disease. People with this syndrome may also experience blindness, sometimes temporary but often permanent. Other possible symptoms include severe headaches that may come with hallucinations, lack of coordination, stiffness and weakness in the legs, cognitive issues, and feelings of anxiety and depression. The diagnosis can be confirmed through testing the polymerase gamma gene, examining a sample of liver tissue, or ultimately, through an autopsy.
- Hard-to-treat seizures
- Loss of physical coordination and mental skills
- Liver disease
- Blindness, sometimes temporary but often permanent
- Severe headaches that may come with hallucinations
- Lack of coordination
- Stiffness and weakness in the legs
- Cognitive issues
- Feelings of anxiety and depression
Testing for Alpers-Huttenlocher Syndrome
Seizures are often one of the first signs of Alpers-Huttenlocher syndrome, a rare disease. An evaluation with a test called an electroencephalogram (EEG) is generally recommended for patients who experience these seizures. The EEG can help doctors see what’s happening in different parts of the brain. In the early stages of the disease, the EEG often shows slower activity and unusual electrical patterns, more often in the back part of the brain.
In one study, a unique EEG pattern was observed, characterized by a steady, high-amplitude delta wave (a type of slow brain wave) with overlaid spike patterns coming from the back part of the brain. This is often referred to as RHADS.
In addition to EEG, another procedure called magnetic resonance imaging (MRI) can be highly useful in diagnosing Alpers-Huttenlocher syndrome. MRI uses strong magnetic fields and radio waves to produce detailed images of the brain. In the case of Alpers-Huttenlocher syndrome, MRI scans usually show changes in the gray matter, which is involved in many brain functions, and the thalamus, which relays sensory and motor signals. These changes are often seen in the posterior cortical structures (the outer layer of the brain) and the occipital cortex, an area at the back of the brain that has the highest metabolic activity, indicating the most energy use.
Treatment Options for Alpers-Huttenlocher Syndrome
Alpers-Huttenlocher syndrome is treated with supportive and eventually comfort-based (palliative) care. Doctors carefully consider the risks and benefits of managing seizures, to avoid side effects. If seizure medicines (anticonvulsants) are needed, newer ones like lamotrigine, topiramate, oxcarbazepine, and primidone are recommended because they’re less likely to harm the liver.
Valproic acid and sodium divalproate, two other anticonvulsants, should be avoided as they can cause faster liver damage. Alpers-Huttenlocher syndrome can interfere with how the body breaks down food (gluconeogenesis), leading to nutritional deficiencies. To help manage this, small, frequent, and low-protein meals are suggested.
As the disease gets worse, a feeding tube inserted into the stomach (gastrostomy feeding tube) might be needed to help maintain nutrition. Long-term help to assist breathing often becomes necessary, using a tube inserted into the windpipe (tracheostomy) and a machine to assist with breathing (mechanical ventilation).
Medicines to relieve pain and relax muscles should be readily available to ensure the patient’s comfort as the disease progresses.
What else can Alpers-Huttenlocher Syndrome be?
Doctors need to distinguish Alpers-Huttenlocher syndrome from other related disorders that are also associated with mutations in the POLG gene.
Here are some of these disorders:
- Childhood myocerebro-hepatopathy: Although this condition shares some features with Alpers-Huttenlocher syndrome, it has unique signs that can help differentiate it. These include liver failure, brain dysfunction (encephalopathy), elevated lactic acid levels in the blood (lactic acidosis), hearing loss, repeated vomiting in cycles, and the absence of noticeable seizures. Most children with this disease start showing symptoms before they are six months old, which is earlier than the usual age at which Alpers-Huttenlocher syndrome symptoms appear, which is between two and four years old.
- Ataxia-neuropathy syndrome
- Myoclonus epilepsy myopathy sensory ataxia
- Autosomal recessive progressive external ophthalmoplegia plus
- Autosomal dominant progressive external ophthalmoplegia plus
Understanding the unique features of these conditions can help doctors make a proper diagnosis.
What to expect with Alpers-Huttenlocher Syndrome
Alpers-Huttenlocher syndrome is a severe condition with a generally poor outlook. Typically, patients live less than 4 years after first showing symptoms. Most commonly, death is caused by fatal encephalopathy, which is a form of brain disease, and liver failure.
Possible Complications When Diagnosed with Alpers-Huttenlocher Syndrome
People with Alpers-Huttenlocher syndrome progress through various complications. These complications relate to specific brain structures that the syndrome affects.
Firstly, blindness occurs due to damage to the brain section related to vision, known as the occipital cortex. Secondly, problems with balance, known as ataxia, happen due to cell loss in the cerebellum, a brain area controlling balance and coordination.
This syndrome can also lead to central respiratory drive loss, leading to the low level of oxygen in the body or even requiring a breathing tube.
Damage to the cerebral cortex, the brain’s outermost layer, can result in spastic paraparesis, a condition where your legs feel stiff and hard to move, making walking difficult. In the worst cases, patients may ultimately lose their ability to walk.
Finally, decreased bulbar reflexes, combined with muscle weakness, can lead to swallowing difficulties. This can risk choking or malnutrition. For severe cases, families may consider a gastrostomy tube, a feeding tube inserted directly into the stomach.
These complications include:
- Blindness due to damage to the occipital cortex
- Balance issues from cell loss in the cerebellum
- Respiratory problems, potentially needing a breathing tube
- Stiffness and difficulty moving the legs, possibly causing walking impairment
- Difficulty swallowing leading to risk of choking or malnutrition, necessitating a feeding tube in severe cases
Preventing Alpers-Huttenlocher Syndrome
Alpers-Huttenlocher syndrome is a condition that gradually worsens over time. As such, patients and their families will need ongoing advice and support throughout the course of the disease. It’s important for families to learn about how the disease typically progresses and to gain specific skills needed for the patient’s care as issues come up.
As the disease progresses, patients may lose their ability to move and think clearly. This means that their care needs can increase in the later stages of the disease. It’s very important to make sure that families have the resources they need at home to provide the necessary care and treatment for the patient.
If the family is considering having more children in the future, it could be helpful to have genetic counseling. This involves talking to a healthcare professional about the risk of passing the condition on to future children.
