Adenylosuccinate Lyase Deficiency

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There are three forms of ADSL deficiency. All forms are caused by mutations (changes) in the ADSL gene. This gene provides instructions for making an enzyme called Adenylosuccinate lyase which is responsible for two steps in the process that produces purine nucleotides. These nucleotides are building blocks of DNA, RNA and molecules such as ATP that provide energy for the cell. Adenylosuccinate lyase converts a molecule called succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and converts succinyladenosine monophosphate (SAMP) to adenosine monophosphate (AMP).

These mutations change single protein building blocks (amino acids) in the Adenylosuccinate lyase enzyme causing its function to be impaired. Problems with the function of this enzyme causes a build-up of SAICAR and SAMP. This build-up is toxic and causes neurological problems and the other symptoms associated with ADSL deficiency.

ADSL deficiency is a rare inherited disorder. Less than 100 cases have been reported to date. The condition is most prevalent (common) in the Netherlands and Belgium. This condition has however also been found to affect people in countries worldwide (Australia, Belgium, Czech Republic, Italy, France, Germany, Malaysia, Morocco, Netherlands, Norway, Poland, Spain, Turkey, United Kingdom and the United States of America).

ADSL deficiency is grouped into three forms based on the severity of the signs and symptoms. The most severe type is the neonatal form. Signs and symptoms of this form can be detected at or before birth and may include:

• Impaired growth during foetal development
• Microcephaly (small head circumference/size)
• Severe encephalopathy (brain disease, damage or malfunction) leading to:
• A lack of movement
• Difficulty feeding
• Life threatening respiratory problem
• Seizures that do not improve with treatment

Due to the severity of the encephalopathy, infants with this form of the condition usually do not survive more than a few weeks after birth.

ADSL deficiency type I (also known as the severe form) is the most common form of this condition. Signs and symptoms for this form usually begin in the first months of life and may include:

• Severe psychomotor delay
• Hypotonia (weak muscle tone)
• Microcephaly (small head circumference/size)
• Recurrent seizures that are difficult to treat
• Autistic behaviour (for example, repetitive behaviour and lack of eye contact)

In patients with ADSL deficiency type II (also known as the moderate or mild form) development is usually normal for the first few years of life but then slows down. Symptoms may include:

• Mild or moderate psychomotor delay
• Seizures
• Autistic behaviours

All infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy (a neurological disorder characterised by seizures), developmental delay, hypotonia (also known as floppy baby syndrome) and/or autistic features should be tested for ADSL deficiency. Tests include specialised urine tests looking for the presence of SAICA riboside and succinyladenosine in the urine.

A diagnosis can be confirmed through molecular genetic testing which will show mutations in the ADSL gene.

Prenatal diagnosis has performed through molecular analysis of the amniotic fluid at 8 weeks of gestation from the pregnant mother with a previous diagnosis of ADSL deficiency

There are currently no effective therapies or treatments for ADSL deficiency. Treatment is support based, providing support for the patient and their families.

ADSL deficiency is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.

The pattern of inheritance of ADSL deficiency is autosomal recessive. This means that carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with ADSL deficiency are carriers.

When both parents are carriers, the risk to the baby in each pregnancy is

• 25% chance (1 in 4) of developing the condition
• 50% chance (1 in 2) for the baby to be a carrier of the condition
• 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier

Genetic counselling can be requested to get a full explanation.

References are available on request. Please contact us by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: APPN05].