NORD gratefully acknowledges Professor Costantino Salerno, Clinical Biochemistry, University of Roma La Sapienza, for assistance in the preparation of this report.
Adenylosuccinate lyase deficiency (ASLD) is a rare, inherited metabolic disorder due to a lack of the enzyme adenylosuccinate lyase (ASL). The defect is characterized by the appearance of two unusual chemicals, succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, in cerebrospinal fluid, in urine and, to a much smaller extent, in plasma. These compounds, which are never found in healthy individuals, are formed from the two natural compounds acted upon by the enzyme. The symptoms and the physical findings associated with ASLD vary greatly from case to case. As a rule, patients with ASLD present with a mix of neurological symptoms that usually will include some of the following: psychomotor retardation, autistic features, epilepsy, axial hypotonia with peripheral hypertonia, muscle wasting, and secondary feeding problems. Although abnormal physical features (dysmorphism) are not common, when they do occur they may include severe growth failure, small head circumference, brachycephaly, flat occiput, prominent metopic suture, intermittent divergent strabismus, small nose with anteverted nostrils, long and smooth philtrum, thin upper lip, and low set ears.
Adenylosuccinate lyase deficiency is categorized as a disorder of the manufacture of purine nucleotides from scratch (biosynthesis) in the body. Purine nucleotides play vital roles in the cells, particularly in the process of building up or breaking down complex body chemicals (intermediary metabolism) and in energy-transforming reactions. Moreover, they serve as building blocks of nucleic acids and thus participate in molecular mechanisms by which genetic information is stored. Just how the genetic and molecular mechanisms interact to generate the symptoms of ASLD is still debated.
The clinical presentation of adenylosuccinate lyase deficiency varies remarkably. Seizures are observed in 60 percent of the cases, start to manifest themselves within the first month of life in 35 percent of the cases, and represent the first sign of the disease in many patients. In some infants, epileptic seizures accompanied by peculiar electroencephalographic signs are among the very first indicators that something is wrong. Electroencephalograms are abnormal in 85 percent of the cases.
Neurologically, symptoms include marked “floppiness” (axial hypotonia) with severe tension of the hands and feet (peripheral hypertonia), muscle wasting, twitchings (fasciculations) of the tongue or distal extremities, and crossed eyes (strabismus). Delayed motor milestones are evident in all patients ranging from mild to severe. In the first years of life, growth retardation has been observed in 30 percent of the cases, mainly related to feeding problems. Recent findings confirm that autism is present in only one third of patients.
Some children show an unusual behavioral phenotype characterized by inability to fix, several stereotypes (hand washing movements, repetitive manipulation of toys, grimacing, clapping hands, rubbing feet, and inappropriate laughter), aggressive behavior, temper tantrums, marked impulsivity, hyperactivity, short attention span, and hypersensitivity to noise and lights. Many patients show severe mental retardation, language delay, slurred pronunciation and limited vocabulary.
Four variants of adenylosuccinate lyase deficiency have been recognized. Most of the patients have adenylosuccinate lyase deficiency type I (ASLD-I) with a neurologic picture characterized by severe psychomotor retardation, epilepsy, axial hypotonia with normal tendon reflexes, and impressive autistic features including absent or poor eye contact, stereotypes, tantrums, agitation, and a tendency toward turning aggression onto oneself.
Patients with type II adenylosuccinate lyase deficiency (ASLD-II) suffer only from slight to moderate psychomotor retardation, show a transient auditory and visual contact disturbance, but do not manifest epilepsy. Type III is similar to type I from the neurologic point of view. It is remarkable for severe growth failure, with muscle wasting starting between 1 and 2 years of age. Type IV is characterized by symptoms that are intermediate between those of type I and type II: an intermediate degree of psychomotor development, minor epilepsy and stereotypes, aggressive behavior, and normal eye contact.
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 cases, further evolution is characterized by 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.
Adenylosuccinate lyase deficiency is inherited as autosomal recessive trait. The defective gene has been traced to Gene Map Locus 22q13.1.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 22q13.1” refers to band 13.1 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait, which are on the chromosomes received from the father and the mother.
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 for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective 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 individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
All forms of adenylosuccinate lyase deficiency affect males and females in equal numbers. Type I is the most common form, accounting for about 55 percent of cases. Type IV accounts for about 30 percent of cases, while type II and type III, are relatively rare. In general, children are born after uncomplicated pregnancy, and the family history and birth are normal.
The age of onset of symptoms is during early infancy. In about 35 percent of cases, seizures were observed in the first month of life.
The inherited defect has been diagnosed up to now in approximately 90 patients from a number of countries (Australia, Belgium, Czech Republic, Italy, France, Germany, Malaysia, Morocco, Netherlands, Norway, Poland, Spain, Turkey, United Kingdom and the United States of America). A number of patients have been found in Belgium and Netherlands, while the defect seems to be even more rare in other countries, such as in United Kingdom.
A search for adenylosuccinate lyase deficiency should be included in the screening program of metabolic investigations in all infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy, developmental delay, hypotonia, and/or autistic features. The diagnosis is based on the presence of succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine in urine and cerebrospinal fluid. For systematic screening, a colorimetric test (Bratton-Marshall test), performed on fresh urine stored at -20 C and alkaline pH, appears most practical. High performance liquid chromatography of the urine sample is the method of choice for final diagnosis.
Prenatal diagnosis has been performed by molecular analysis of chorion villi and amniotic fluid obtained at 8 weeks of gestation from the mother of a child with previous diagnosis of adenylosuccinate lyase deficiency.
There is no effective therapies for the treatment of adenylosuccinate lyase deficiency.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
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FROM THE INTERNET
OMIM On line Mendelian Inheritance in Man. Last updated: April 17, 2009. 2p.
The Purine Research Society. Last updated: April 15, 2009. 1p. http://www.purineresearchsociety.org/
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