Adenylosuccinate Lyase Deficiency

 Adenylosuccinate Lyase Deficiency

Overview

Adenylosuccinate lyase deficiency (ADSL deficiency) is a rare inherited metabolic disorder characterized by developmental delay, seizures, learning/intellectual disability and autism related behaviors.

Based on the age of onset and the severity of the symptoms it can be classified in three forms:

Fatal neonatal form, a very severe form that is present before or at birth

Childhood form or severe form (type I) which begins in infancy or early childhood

Slowly progressive form or mild form (type II), a milder form that worsens more gradually over time

Signs and symptoms across these forms vary greatly from person to person and may include slowing of thought and physical movement (psychomotor impairment), autism related traits such as repetitive behaviors and failure to make eye contact, seizures, progressive loss of muscle tissue (muscle wasting), difficulty eating and drinking due to the psychomotor problems (secondary feeding problems) and in the most severe cases, weakness in the trunk of the body (axial hypotonia) with increased strength and muscle mass in the limbs (peripheral hypertonia).

Differences in body structure that are specifically related to this disorder (dysmorphic features) are not common. However, when they do occur, they are usually subtle and may include slowed growth, skull differences such as a small head circumference (microcephaly) or flattened back of the head (flat occiput), occasional deviation of the eye (intermittent divergent strabismus), small nose with anteverted nostrils, long and smooth philtrum, thin upper lip and low set ears.

ADSL deficiency is caused by changes (pathogenic variants) in the ADSL gene. These variants reduce the activity of the enzyme adenylosuccinate lyase (ADSL enzyme). Inheritance is autosomal recessive.

There is no FDA‑approved, disease‑modifying therapy for ADSL deficiency. Management is supportive and multidisciplinary.

ADSL deficiency is categorized as a purine biosynthesis disorder. Purines are nucleotides that play vital roles in the cells, particularly in the process of building up or breaking down complex chemicals (intermediary metabolism) and in providing energy for cellular activity (energy-transforming reactions). Purines also serve as building blocks for nucleic acids and are involved in molecular mechanisms by which genetic information is stored. Biosynthesis is how an organism makes different molecules and is often used to describe the synthesis of molecules that are particularly important for the organism to survive. In ADSL deficiency, the body’s ability to make these important purines changes. Researchers are still debating how these genetic and molecular mechanisms cause the symptoms seen in people with ADSL deficiency.

Symptoms

According to the onset, the signs and symptoms and the severity of the disease ADSL deficiency can be classified in three forms:

Babies with the fatal neonatal form have encephalopathy with lack of spontaneous movement, respiratory failure and intractable seizures, marked autistic features, axial hypotonia with limb hypertonia (floppy trunk with stiff limbs), involuntary muscle contractions (dystonia) and poor coordination (ataxia). There may be some prenatal indications such as the fetus being small in size (IUGR), having a small head (microcephaly), a low level of fetal movement (hypokinesia) and a loss of fetal heart rate variability (which means the normally fluctuating fetal heart rate pattern becomes unusually smooth and flat, with little to no variation around the baseline heart rate). Most reported cases fall into this category.

The ADSL type l form, or severe childhood form, is only associated with neurological differences. These may include severe slowing of thought and movement (psychomotor impairment), epilepsy, low muscle tone in the trunk of the body (axial hypotonia) with normal tendon reflexes and features associated with autism including absent or poor eye contact, stereotypies, tantrums, agitation and a tendency toward turning aggression onto oneself as well as hyperactivity and inappropriate laughter.

People with the ADSL type ll form, or mild/moderate form, have mild to moderate symptoms compared to the other forms. They may have a slight to moderate psychomotor impairment, show temporary changes in hearing and vision (transient auditory and visual contact disturbance), but less frequency of epilepsy.

The severity of the signs and symptoms seem to be related to the amount of residual ADSL enzyme activity.

Causes

ADSL deficiency is a type of metabolic disorder. Metabolism is the process in which organisms take in various organic materials, use them to build cellular structures and for energy, and expel any waste products. Adenylosuccinate lyase is important in the production of purines (guanine and adenine), which are molecules that are important for the structure of genetic information and in providing sources of energy. ADSL deficiency is caused when the enzyme adenylosuccinate lyase is less functional than normal.

Adenylosuccinate lyase normally converts succinyl aminoimidazole carboxamide ribotide into aminoimidazole carboxamide ribotide in this purine pathway. When adenylosuccinate lyase is not functioning well, succinylaminoimidazole carboxamide ribotide gets converted into succinylaminoimidazole carboxamide riboside. Further down in this pathway, adenylosuccinate lyase also converts adenylosuccinate into adenosine monophosphate. When adenylosuccinate lyase is not functioning well, adenylosuccinate gets converted into succinyladenosine.

Therefore, in individuals in whom adenylosuccinate lyase is not functioning well, doctors can detect two compounds in body fluids (such as cerebrospinal fluid, plasma and urine) that are normally undetectable in healthy people: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S‑Ado).  When these are measured in the fluid surrounding the brain and spinal cord (cerebrospinal fluid), the S Ado/SAICAr ratio helps doctors estimate disease severity as lower ratios are linked with more severe disease.

Early research suggests that when SAICAr increases, it may over‑activate part of the body’s innate immune system known as the alternative complement pathway. When this pathway is overly active, it produces small signaling fragments called C3a and C5a (pieces of complement proteins). These signals attract leukocytes (white blood cells) and trigger the release of cytokines, natural chemical messengers that drive inflammation. Together, these changes may make the blood–brain barrier (protective lining that helps shield the brain) more permeable which can set off inflammation within the brain and spinal cord and, over time, lead to neurodegeneration (injury and loss of nerve cells). These findings are emerging and help guide future research, but they have not yet changed standard of care.

Inheritance

Inheritance is autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected populations

Only around 100 cases of ADSL deficiency have been reported in the medical literature. Prevalence is estimated at ~0.00125 cases per 100,000 individuals. All forms of ADSL deficiency affect males and females in equal numbers. The age of onset and frequency is different between the different types. People with the fatal neonatal form and type I begin showing symptoms within the first few months of life. In type II, people begin showing symptoms within the first few years of life.

ASLD has been diagnosed in people from many countries (Australia, Belgium, Czech Republic, Colombia, Italy, France, Germany, Malaysia, Morocco, the Netherlands, Norway, Poland, Portugal, Spain, Turkey, the United Kingdom and the United States). Most individuals with this condition are in Belgium and the Netherlands.

Disorders with Similar Symptoms

When evaluating adenylosuccinate lyase (ADSL) deficiency, it is important to consider other conditions that can present with similar symptoms. These mainly include:

Neurological disorders associated with difficult-to-control seizures and encephalopathy

Other inherited disorders of purine and pyrimidine (P/P) metabolism that affect the nervous system

Because ADSL deficiency has a wide range of possible clinical features, distinguishing it from other neurological disorders—especially those marked by seizures that do not respond well to treatment, can be challenging.

In newborns, the first step is to consider five treatable conditions that can primarily present with seizures resistant to standard therapies:

Pyridoxine-dependent seizures

Folinic acid-responsive seizures

3-phosphoglycerate dehydrogenase deficiency

Hyperinsulinemic hypoglycemia

In addition, holocarboxylase synthetase deficiency (biotin-responsive) can occasionally appear with neonatal seizures.

During early infancy, other treatable conditions may also present with intractable seizures, such as:

Biotinidase deficiency (biotin-responsive)

GLUT1 deficiency which may improve with a ketogenic diet

On the other hand, several untreatable inborn errors of metabolism can also manifest in the neonatal period with severe epilepsy. These include nonketotic hyperglycinemia, D-2-hydroxyglutaric aciduria, mitochondrial glutamate transporter defect, peroxisomal biogenesis defects, respiratory chain disorders, sulfite oxidase deficiency and Menkes disease.

Later in infancy, the combination of seizures with features suggestive of autism should raise the possibility of Angelman syndrome in the differential diagnosis.

Additional inborn errors of purine and pyrimidine metabolism can appear early in life with symptoms that overlap with ADSL deficiency. In children with nonspecific neurological symptoms, targeted screening for purine and pyrimidine abnormalities is especially valuable in reaching an accurate diagnosis.

Diagnosis

A diagnosis of ADSL deficiency should be considered in infants with seizures, delayed milestones, muscle weakness and/or autistic features. The diagnosis is based on elevated levels of two compounds in body fluids such as plasma, urine and cerebrospinal fluid (the fluid that surrounds the spinal nerves). These two compounds are called succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, and they are not usually detectable in these fluids. Sequencing of the ADSL gene can identify disease-causing genetic changes (pathogenic variants) that cause ADSL deficiency.

The cerebrospinal‑fluid S‑Ado/SAICAr ratio can support phenotypic stratification (lower ratios correspond to more severe disease).

Imaging can be helpful in supporting a suspicion of ADSL deficiency, as certain brain abnormalities appear with varying severity across different types. In the more severe form (type I), cerebral and cerebellar atrophy as well as white matter abnormalities are typically more pronounced than in children with the milder ADSL type II.

For families where both parents are known to be carriers of an ADSL gene variant, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These tests can be done during pregnancy where a doctor uses an ultrasound to guide a needle and extract cells from either the placenta or from the fluid surrounding the fetus. These cells can be analyzed using molecular analysis of the ADSL gene.

Standard Therapies

Treatment

Current treatments are available to control seizures, although drug resistance can occur. The ketogenic diet has been used in a few people with refractory epilepsy and showed some seizure control improvement.

Patients typically require a multidisciplinary approach involving neurologists, metabolic specialists and other healthcare professionals to manage their symptoms and provide comprehensive care.

Type of Doctor Department : A Pediatric Neurologist or Epileptologist