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Adenylosuccinate lyase deficiency is an inherited metabolic disorder that is characterized by three categories (fatal neonatal form, type I, and type II), each of which has a specific age of onset and severity of symptoms. Individuals with this disorder may have symptoms such as slowing of thought and physical movement, seizures, and muscle weakness, and may exhibit behaviors associated with autism. This syndrome has been diagnosed in individuals around the world and its incidence is not yet known.
Adenylosuccinate lyase deficiency (ASLD) is a rare, inherited metabolic disorder caused by a genetic change that lowers the effectiveness of the enzyme adenylosuccinate lyase (ASL). The disorder causes the buildup of two chemicals in body fluids (such as cerebrospinal fluid, plasma, and urine) that aren’t normally seen in healthy individuals. These two chemicals are succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine. The symptoms and the physical findings associated with ASLD vary greatly from person to person.
Adenylosuccinate lyase deficiency is a neurological disorder that causes brain dysfunction (encephalopathy) leading to delayed development of mental and movement abilities (psychomotor delay), autistic behaviors that affect communication and social interaction, and seizures.
Types
ASLD is divided into three categories based on the severity of symptoms: the fatal neonatal form, type I, and type II. However, as symptoms occur along a spectrum there are no set criteria to determine which category a patient should be ascribed to.
Fatal neonatal form
Patients with this form of ASLD present with fatal neonatal encephalopathy, respiratory failure, a lack of spontaneous movement, and intractable seizures. Possible prenatal symptoms such as microcephaly, intrauterine growth restriction, loss of fetal heart rate variability and hypokinesia have been reported. Death occurs within the first few weeks of life.
Type I
This is the most common form of ASLD. Symptoms become apparent in the first months of life and include seizures, microcephaly, and severe psychomotor retardation are purely neurological. Some patients display axial hypotonia, peripheral hypertonia, and normal tendon reflexes. Autistic-like behavior including poor eye contact, stereotypies, agitation, tantrums, and self-injurious behavior may occur.
Type II
This is considered to be a mild to moderate form of ASLD. They may demonstrate a milder degree of psychomotor retardation and transient visual and auditory contact disturbances[rx] Seizures, if they occur, begin later than in Type I, typically between 2 and 4 years old but sometimes as late as 9 years old. Speech is impaired with receptive language skills and nonverbal communication skills being better than expressive language skills. Ataxia may occur and cause increasingly severe gait disturbances.[rx]
Causes
Adenylosuccinate lyase deficiency (ASLD) 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. ASLD is caused when the enzyme adenylosuccinate lyase is less functional than normal.
In particular, adenylosuccinate lyase normally converts succinylaminoimidazole 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 adenine 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 that are normally undetectable: aminoimidazole carboxamide riboside and succinyladenosine. These compounds can be found in different fluids in the body including in plasma (a component of blood) and in the cerebral spinal fluid (the fluid that surrounds the nerves in our spine).
ASLD is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All forms of adenylosuccinate lyase deficiency are caused by mutations in the ADSL gene. This gene provides instructions for making an enzyme called adenylosuccinate lyase, which performs two steps in the process that produces purine nucleotides. These nucleotides are building blocks of DNA, its chemical cousin RNA, and molecules such as ATP that serve as energy sources in 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).
Most of the mutations involved in adenylosuccinate lyase deficiency change single protein building blocks (amino acids) in the adenylosuccinate lyase enzyme, which impairs its function. Reduced function of this enzyme leads to buildup of SAICAR and SAMP, which are converted through a different reaction to succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). Researchers believe that SAICAr and S-Ado are toxic; damage to brain tissue caused by one or both of these substances likely underlies the neurological problems that occur in adenylosuccinate lyase deficiency.
Symptoms
Three categories of adenylosuccinate lyase deficiency have been recognized. The first is the fatal neonatal form, where babies have encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures. 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.
Adenylosuccinate lyase deficiency type I (ASLD-I), the 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.
Patients with type II adenylosuccinate lyase deficiency (ASLD-II) have mild to moderate clinical features in comparison. They may have slight to moderate psychomotor impairment and show temporary changes in hearing and vision (transient auditory and visual contact disturbance), but do not have epilepsy.
The prognosis for ASLD is generally poor. Several patients, particularly those referred to as type I or with early onset of epilepsy, have died in early infancy. Others have died at around 10 years of age. In most patients, there is an absent or minimal progression of psychomotor development and persistence of autistic behavior (if present), except for occasional improvement of eye contact. Nevertheless, some patients, particularly those referred to as type II, fare relatively well, and the oldest of these patients is over thirty.
People with ASLD can have a mix of neurological symptoms such as:
- Slowing of thought and physical movement (psychomotor impairment)
- Features commonly associated with autism, such as repetitive behaviors and failure to make eye contact
- Epilepsy
- Progressive loss of muscle tissue (muscle wasting)
- Difficulty eating and drinking due to the issues described above (secondary feeding problems)
- Weakness in the trunk of the body (axial hypotonia) with increased strength and muscle mass in the limbs (peripheral hypertonia). This only occurs in severe ADSL deficiency.
Differences in body structure that is 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.
Diagnosis
A diagnosis of adenylosuccinate lyase 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 the disease-causing genetic change (pathogenic variant).
For families where both parents are known to be carriers of adenylosuccinate lyase deficiency, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These two tests occur during pregnancy when 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.
Treatment
Current treatments are available to control seizures, although drug resistance can occur. Studies have been done to identify treatments specific for ASLD (such as D-ribose, uridine, and S-adenosyl-1-methionine), but these experimental treatments have not been proven to be beneficial. Treatment of adenylosuccinate lyase deficiency can be done via epilepsy management with anticonvulsive drugs. Additionally the following options include:[rx]
- D-ribose and uridine administration
- Ketogenic diet
- S-adenosyl-l-methionine
D-ribose and uridine administration
D-ribose administration, which increases the provision of phosphoribosyl pyrophosphate (PRPP) and stimulates de novo purine synthesis, has been applied in a few ADSL patients. Salerno et al published promising results in motor coordination and seizure control in a 13-year-old female after several months of D-ribose therapy
S-adenosyl-l-methionine
Recently Werkhoven et al evaluated S-adenosyl-l-methionine (SAMe) as a potential treatment for ADSL deficiency (van Werkhoven et al 2013). After 9 months of SAMe treatment, there was no clear response evidenced in urine metabolite levels or clinical parameters
Epilepsy treatment
The aim of treating epilepsy is to control or at least decrease seizure frequency with minimal side effects. Treatment with anticonvulsive drugs (e.g., valproic acid, phenobarbital, carbamazepine, topiramate, levetiracetam, phenitoin, clobazam) depends on the type of seizures. Patients with ADSL deficiency often require polypharmacy with the use of two or more anticonvulsants. Drug resistance is common.
Ketogenic diet
Recently there have been reports about the positive use of a ketogenic diet for the treatment of refractory epilepsy and glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent.
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