Adenylosuccinate Lyase Deficiency - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Adenylosuccinate lyase deficiency, also known as succinylpurinemic autism or ASLD deficiency, is a rare metabolic disorder borne out of suboptimal functioning of the enzyme adenylosuccinate lyase (ADL) enzyme resulting in critical neurological dysfunction. The enzyme plays an important role in the production of purines (guanine and adenine) which are the functional units of the genetic material (DNA and RNA). ADL insufficiency results in three distinctive subtypes with varying characteristics and severity of the signs and symptoms.

What Are the Types of Adenylosuccinate Lyase Deficiency?

1. Fatal neonatal type.

2. Type I ADSL deficiency (severe form).

3. Type II ADSL deficiency (moderate or mild form).

Who Is Susceptible to Adenylosuccinate Lyase Deficiency?

Adenylosuccinate lyase deficiency has been recorded in less than 100 cases globally, with a majority of cases diagnosed in the Netherlands and Belgium. Other reported cases were in the Czech Republic, Poland, Germany, the United Kingdom, Spain, Italy, Portugal, France, Norway, Turkey, Morocco, Australia, Colombia, and the United States. About 70 to 80% of the patients present with type I, 12 to 20 % with type II variant of the condition, and five to 10% of the cases present with the neonatal form.

The condition shows equal gender predilection with varying ages of onset across the variants.

What Causes Adenylosuccinate Lyase Deficiency?

All three forms of adenylosuccinate lyase deficiency are caused due to mutations in the ADSL gene. The ADL enzyme catalyzes the process of purine nucleotide production. Purines; guanine and adenine; are one of the four nucleotides (guanine, adenine, cytosine, and thymine: ATGC) that make up the structural and functional unit of genetic material-DNA and RNA, and also the energy molecule ATP. The mutation of the ADSL gene leads to the production of inefficient ADL-enzyme that create ulterior neurological dysfunctions.

What Is the Pathophysiology of Adenylosuccinate Lyase Deficiency?

ADL-enzyme converts a molecule succinylaminoimidazole carboxamide ribotide to aminoimidazole carboxamide ribotide and succinyl adenosine monophosphate (SAMP) to adenosine monophosphate. Most of the results of such ADSL gene mutations lead to mutated amino acids in the ADL enzyme which impairs its efficiency. Diminished amounts of ADL-enzyme build up succinylaminoimidazole carboxamide riboside and succinyladenosine which are toxic and damaging to the rural tissue. These substances are believed to be pathognomic in causing neurological dysfunctions.

Some studies portray that the amounts of succinylaminoimidazole carboxamide riboside are proportional to the severity of adenylosuccinate lyase deficiency-related symptoms. Succinylaminoimidazole carboxamide riboside has reportedly been more tainted than succinyladenosine in causing severe encephalopathies and psychomotor delays.

What Are the Signs and Symptoms of Adenylosuccinate Lyase Deficiency?

The symptoms of adenylosuccinate lyase deficiency vary with the types of ASDL.

Fatal Neonatal Type:

• Encephalopathy (affected functioning of the brain).

• Lack of spontaneous movement.

• Respiratory failure.

• Intractable seizures.

• Intrauterine growth restriction.

• Microcephaly (small head of the baby) .

• Loss of fetal heart rate variability.

Adenylosuccinate Lyase Deficiency Type I:

• Severe slowing of thoughts.

• Psychomotor impairment.

• Epilepsy.

• Axial hypotonia (low muscle tone in the trunk).

• Autism-associated features.

• Failure to make eye contact.

• Hypersensitivity to noise.

• Hypersensitivity to light.

• Poor eye contact.

• Stereotypies (purposeless repetitive movements in children).

• Tantrums.

• Agitation.

• Tendency to aggressive behavior.

• Hyperactivity.

• Speech impairment.

• Muscle wasting.

• Spasticity (abnormal increase in muscle tone).

Adenylosuccinate Lyase Deficiency Type II:

• Slight to moderate psychomotor impairment.

• Transient auditory disturbances.

• Transient visual contact disturbances.

How to Diagnose Adenylosuccinate Lyase Deficiency?

A diagnosis of ASDL deficiency may be considered in infants presenting with seizures, delayed milestones, and muscle weakness along with autistic features. The diagnosis is based on serological analysis.

Laboratory Studies:

The presence of two compounds (succinylaminoimidazole carboxamide riboside and succinyladenosine) of the succinylpurines family may be found in body fluids like plasma, urine, and cerebrospinal fluid which are not usually the mediums where such substances are found naturally.

ADSL enzyme activity in cultures of skin fibroblasts demonstrates a significant decrease in ADSL activity, up to 80 to 98% decrease in enzyme activity.

Magnetic Resonance Imaging (MRI):

Imaging studies include MRI (magnetic resonance imaging) scans which report white matter anomalies, atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed or lack of myelination, and lissencephaly (absence of normal folds in the cerebral cortex).

Genetic Studies:

Genomic cDNA sequencing of the ADSL gene can detect the etiologic mutation concerned with the developing condition and characterization of mutant proteins.

How to Treat Adenylosuccinate Lyase Deficiency?

The therapeutic approach to treating ASDL deficiency involves using D-ribose and uridine administration which increases the provision of phosphoribosyl pyrophosphate and stimulates purine synthesis. S-adenosyl-l-methionine has been reported as a potential treatment for ADSL deficiency with limited success.

Epileptic symptoms may be managed as individual symptoms with a larger foothold in overall condition management by the use of anticonvulsants like Valproic acid, Phenobarbital, Carbamazepine, Topiramate, Levetiracetam, Phenytoin, or Clobazam depending on the type of seizures with potential drug resistance.

A ketogenic diet can be regarded as therapeutic treatment option against intractable seizures but must be implemented with caution as such a diet imparts a heavy toll on the kidneys and digestive tract. The patients require regular blood examinations to monitor systemic misgivings.

What Is the Prognosis of Adenylosuccinate Lyase Deficiency?

The prognosis of ASDL deficiency is variable according to the affecting type. Neonatal fatal type presents a poor prognosis with a high fatality whereas early diagnosis may lead to favorable evolution of prognosis.

What Is the Differential Diagnosis of Adenylosuccinate Lyase Deficiency?

• Neurological disorders with intractable seizures.

• Neurological disorders with encephalopathy.

• Inborn errors of ATGC metabolism.

• Autism.

• Biotin-responsive biotinidase deficiency.

• GLUT1 deficiency.

• Nonketotic hyperglycinemia.

• D-2-hydroxyglutaric aciduria.

• Mitochondrial glutamate transporter defect.

• Peroxisomal biogenesis defects.

• Respiratory chain disorders.

• Sulfite oxidase deficiency.

• Menkes disease.

• Angelman syndrome.

What Are the Complications of Adenylosuccinate Lyase Deficiency?

• Mental retardation.

• Impairment of energy metabolism.

• Death.

Conclusion

Adenylosuccinate lyase deficiency, although fatal in childhood, early detection can result in a better management protocol. Antenatal diagnosis is a diagnostic path where the peripheral blood of the mother or a sample of amniotic fluid can be studied to determine the presence of any such mutations in the gene, not just pertaining to ASDL deficiency but also any other genetic disorder. Since the condition is of autosomal recessive inheritance, it requires two copies of mutant genes (one from each parent) to be phenotypically significant. Hence, parents must undergo genetic counseling before family planning to prevent any complications in the offspring.