Alkaptonuria: Homogentisic acid accumulation in the
Brain

Alkaptonuria (AKU) is a rare metabolic disorder caused by a genetic abnormality that results in a deficiency of the enzyme homogentisate dioxygenase. Usually, this condition does not cause symptoms until adulthood.

 

This enzyme is essential for breaking down homogentisic acid (HGA), an intermediate in the metabolism of certain amino acids.
When this enzyme is missing, homogentisic acid builds up in the body, which can lead to various health problems.

Symptoms may include: dark, almost black discoloration of the urine when exposed to air, and cartilage damage with severe joint pain/arthritis symptoms. AKU patients can also experience kidney stones and kidney problems. The buildup of the enzyme HGA can harden and damage the blood vessels and heart valves, which can lead to a heart complication such as heart failure.

 

As the patient ages, black spots may appear in the whites of the eyes. Some people develop a bluish to blue-black discoloration of the ears. The areas of the skin exposed to the sun and where sweat glands are located may develop a blue-black mottled discoloration.
In rare cases, the buildup of homogentisic acid can also affect the brain. This can lead to neurological complications. Symptoms such as memory problems, cognitive decline or motor disorders. A possible link between AKU and Parkinson's disease has been identified. A study has determined that Parkinson's disease occurs approximately 20 times more often in people with Alkaptonuria than in people who do not suffer from Alkaptonuria.

 

• Brochures in alkaptonurie are available from the international AKU association: https://akusociety.org/download-resources/
• Information about heart complications: https://akusociety.org/what-is-aku/heart-complications/
• In the Netherlands, information can be found on the website of the patient association for metabolic diseases

 

Glutaric aciduria type 1: glutaric acid and 3-hydroxyglutaric acid in the brain

Glutaric aciduria type 1 (GA-1) is a rare inherited metabolic disorder in which a problem in the breakdown of certain amino acids, such as lysine and tryptophan, leads to the accumulation of harmful substances, including glutaric acid and 3-hydroxyglutaric acid, in the body.

This is caused by an error in the genetic material and in Glutaraciduria type I this is on chromosome 19, in the GCDH gene. In parents who are distantly related, there is a greater chance that they are both carriers of the faulty chromosome and that they, although healthy themselves, can still pass on the disease.

 

The accumulations of amino acids can be particularly damaging to the brain, where they can damage nerve cells and brain structures. This can lead to neurological problems such as muscle weakness, muscle weakness, difficulty swallowing,
movement disorders (problems with movement and coordination) particularly chorea, spasticity, arm tremors, epilepsy or
cognitive problems.
Although intelligence is usually spared, development can be somewhat regressed and regressed if there are frequent periods of elevated glutaric acid levels.

 

At birth, there is often a somewhat larger head and problems with drinking are observed in the early period. The first symptoms are usually seen in childhood between 1 and 2 years or later. This metabolic disorder has been included in the heel prick since 2006, which allows an early diagnosis. The complaints often occur during a period of fever, during which normally many proteins are already broken down. In these patients, more lysine and tyrosine are then released. The children are then sleepier and difficult to wake up. An epileptic attack or an absence may occur in which the child only looks absently, stares.

 

Early diagnosis and a strict diet, combined with medical supervision, can help limit the accumulation of these substances and prevent serious complications.

 

Information can be found on this website:

https://www.nhs.uk/conditions/glutaric-aciduria/

 

Walker Warburg syndrome (WWS)

Walker Warburg syndrome is a rare and serious hereditary (genetic) disorder that affects the development of muscles, eyes and the brain. This disease belongs to the group of congenital muscular dystrophies, which are present at birth and are caused by changes (mutations) in certain genes that are important for muscle and brain development.

 

Children with Walker Warburg syndrome often have symptoms such as muscle weakness, eye problems such as severe nearsightedness or glaucoma, where the optic nerve and nerve fibers are damaged by increased eye pressure. Sometimes there are also abnormalities in other organs.

 

The children also have lisencephaly (smooth brain). This means that the brain does not fully develop during pregnancy. This results in a smooth brain structure, without the normal grooves and convolutions in the cerebral cortex. The cerebral cortex is underdeveloped.
The cerebral cortex plays an important role in processing information from the body and in many of the higher cognitive functions, such as thinking, perceiving, reasoning and planning.
The cerebral cortex is divided into different areas, each responsible for specific functions, such as vision, motor skills and speech.

 

Symptoms may therefore vary, but often include developmental delays, seizures, and decreased muscle tone. The condition is usually diagnosed at birth or in the first year of life. Unfortunately, there is currently no cure, and life expectancy is often short.

Supportive care is aimed at relieving symptoms and improving the quality of life for both the child and the family.

 

Rett Syndrome

Rett syndrome is a developmental disorder of the central nervous system (brain and cranial nerves) with metabolic components. Rett syndrome occurs almost exclusively in girls. Girls have a deficiency of hereditary material of the MECP2 gene. A change in the MECP2 gene (gene mutation) occurs on the X chromosome.

 

Children with Rett syndrome develop normally for the first few months, but from about 6 to 18 months, sometimes 24 months, symptoms begin. These include loss of use of hands, typical hand movements such as wringing or clapping, other motor skills (think of dyspraxia, very difficult to control all body movements (ataxia), including eye movements), speech, cognitive skills and difficulty with communication. Epilepsy and breathing problems may also occur.

 

After this decline, a stable phase can follow, which can last a long time. Sometimes some progress can be seen. There are many
variants of Rett syndrome. The children have a smaller brain volume  and a smaller head circumference than healthy people.
There is currently no cure. Treatment focuses on controlling symptoms and improving the quality of life.
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