Adenylosuccinase Deficiency

A number sign (#) is used with this entry because adenylosuccinase deficiency (ADLSD) is caused by homozygous or compound heterozygous mutation in the ADSL gene (608222) on chromosome 22q13.

Description

Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (summary by Baresova et al., 2012).

Clinical Features

In 3 children with severe psychomotor delay and autism, Jaeken and Van den Berghe (1984) found succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide (SAICA) ribotide in the body fluids. Concentrations of both compounds were about 100 micromol/l in CSF, between 5 and 10 micromol/l in plasma, and in the millimol/l range in urine. Normally these compounds are not found in blood and CSF but may be detected in trace amounts in urine. The authors noted that the compounds are dephosphorylated derivatives of the intracellular metabolites adenylosuccinate and succinylaminoimidazole carboxamide ribotide, the 2 substrates of adenylosuccinase (adenylosuccinate lyase). Assays of the enzyme in 1 patient showed marked reduction of activity in liver and absence of activity in the kidney. Two of the 3 affected children were brother and sister, offspring of related Moroccan parents. The authors suggested that adenylosuccinase deficiency is a specific autosomal recessive cause of autism.

Jaeken et al. (1988) presented clinical and biochemical data on 8 children with adenylosuccinase deficiency. Seven of the 8 children showed severe psychomotor retardation. Epilepsy was documented in 5, autistic features in 3, and growth retardation associated with muscular wasting in a brother and sister. One female patient was strikingly less retarded mentally and had only mild psychomotor retardation. In this patient, the ratio of the 2 metabolites in body fluids was quite different from that in the severely retarded patients, showing an approximately 5-fold excess of succinyladenosine. In addition, adenylosuccinase activity in fibroblasts was only about 6% of normal, whereas it was about 40% of normal in 6 severely retarded patients. At least 2 of the patients from separate families were the offspring of consanguineous parents.

Jaeken et al. (1992) described a patient with an intermediate phenotypic severity resulting from adenylosuccinase deficiency. Chemical findings in the patient supported the impression that there is an inverse relationship between the degree of clinical involvement and the excess of succinyladenosine over SAICA riboside. Jaeken et al. (1992) concluded that SAICA riboside may be the offending compound that interferes with neurofunction and that succinyladenosine may protect against its effects.

In Prague, Sebesta et al. (1997) screened urine samples from more than 2,000 children with unexplained neurologic disease. Using thin-layer chromatography, they identified 2 boys and 3 girls in 4 kindreds with adenylosuccinase deficiency. Two of the 4 kindreds were of Gypsy origin. Two boys were diagnosed at ages 2 and 5 years, and 3 girls were diagnosed at ages 9 months, 3 years, and 6 years. The onset of the disease ranged from the fourteenth day to 6 months. Two sibs exhibited a less severe clinical picture and identical clinical course. They came to attention in the first year of life when psychomotor retardation developed. Neurologic examination showed hypotonia and hyperactivity. All 3 of the other patients exhibited severe psychomotor retardation in early infancy.

Whereas most cases of adenylosuccinase deficiency had been detected by metabolic screening for severe psychomotor retardation, Maaswinkel-Mooij et al. (1997) described an infant who manifested generalized seizures as a first symptom of the disorder. She was initially diagnosed with West syndrome (308350). The first admission was at 9 weeks of age. The patient was treated with phenobarbital and remained seizure-free for 10 months. At the age of 15 months, she was reinvestigated because of a cluster of tonic seizures, and electroencephalogram showed hypsarrhythmia. Psychomotor retardation became apparent in the second year of life.

Holder-Espinasse et al. (2002) reported 2 patients with adenylosuccinase deficiency who had similar mild facial dysmorphic features, including brachycephaly, prominent metopic sutures, a small nose with anteverted nostrils, long and smooth philtrum, thin upper lip, and low-set ears. The authors noted that a patient previously reported by Nassogne et al. (2000) had similar features.

Clinical Variability

Edery et al. (2003) observed an unusually variable combination of clinical features and striking intrafamilial variability in the phenotype. Among 3 sibs from a family originally from Portugal, the proband had marked psychomotor regression and progressive cerebellar vermis atrophy; the other 2 affected sibs presented mainly autistic features. The sibs were homozygous for the R426H mutation (608222.0002). The authors suggested that adenylosuccinate lyase deficiency should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in all patients with mental retardation of unexplained origin.

Gitiaux et al. (2009) reported 2 sisters, aged 11 and 12 years, with genetically confirmed adenylosuccinate lyase deficiency (608222.0008). The girls presented with global developmental delay, motor apraxia, severe speech deficits, and seizures. They also had unusual behavioral features, including excessive laughter, very happy disposition, hyperactivity, short attention span, mouthing of objects, tantrums, and stereotyped movements, which were reminiscent of Angelman syndrome (AS; 105830). Both had had an increased succinyladenosine/SAICAr ratio of 1.6.

Biochemical Features

The de novo purine biosynthesis pathway involves 10 steps that lead from 5-phosphoribosylpyrophosphate (PRPP) to inosine monophosphate (IMP), from which the adenine and guanine nucleotides are formed. Marie et al. (2004) noted that deficiency of adenylosuccinate lyase (ADSL) was the first inborn deficiency of purine synthesis to be identified in humans. This disorder is characterized by the presence in urine and cerebrospinal fluid of succinyl-5-amino-4-imidazolecarboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado), the nucleosides corresponding to SAICA-ribotide (SARCAR) and adenylosuccinate (S-AMP), respectively, the 2 substrates of ADSL.

In patients with ADSL deficiency, the lower the S-Ado:SAICAr ratio in CSF, the more severe the phenotype. Patients with neonatal fatal disease have a ratio less than 1, those who present in the first months of life with a severe form of the disorder have a ratio of about 1, whereas those who present later with a relatively milder phenotype have ratios equal to or greater than 2 (Jurecka et al., 2008).

Diagnosis

Maddocks and Reed (1989) described a sensitive and specific test for succinyladenosine in the urine.

Jaeken et al. (1992) suggested that a modified Bratton-Marshall test, originally designed as an assay for sulfonamides, would be a practical screening method for the disorder, provided the patients are not receiving sulfonamides.

Inheritance

Stone et al. (1992) confirmed autosomal recessive inheritance of adenylosuccinase deficiency in the family reported by Jaeken and Van den Berghe (1984).

Molecular Genetics

In 2 affected Moroccan sibs with adenylosuccinase deficiency reported by Jaeken and Van den Berghe (1984), Stone et al. (1992) identified a point mutation in the ADSL gene (608222.0001).

Marie et al. (1999) found reports of 9 missense mutations in the ADSL gene in 6 apparently unrelated sibships. In a study of 10 additional patients with ADSL deficiency, they found 9 point mutations.

Kmoch et al. (2000) identified 8 mutations among 6 ADSL patients. Expression studies of the mutant proteins showed that the level of residual enzyme activity correlated with the severity of the clinical phenotype.

Among 7 unrelated Polish patients with ADSL deficiency, Jurecka et al. (2008) identified 7 biallelic mutations in the ADSL gene, including 5 novel mutations. R426H (608222.0002) was the most common mutation. One patient had a fatal neonatal course, 4 had a severe phenotype with intractable seizures and psychomotor retardation since early infancy, and 2 had a milder phenotype with later-onset, transient visual contact disturbance, and mild to moderate psychomotor retardation. There was no apparent genotype/phenotype correlation.

Pathogenesis

In skin fibroblasts derived from 9 patients with ADSLD, Baresova et al. (2012) found that immunostaining for ADSL was almost undetectable in patients with the most severe neonatal form of the disease, decreased compared to controls in those with the intermediate (type I) form of the disease, and similar to wildtype in those with the mildest (type II) form of the disease. There were no signal overlaps between ADSL and other enzymes of the de novo purine synthesis pathway in a purine-depleted medium in all cells with the neonatal or type I forms and 1 patient with type II compared to controls, suggesting impaired assembly of the purinosome. Signal overlap suggestive of protein compartmentalization was detected in 2 cell lines from patients with type II disease, although this was still lower than controls. Baresova et al. (2012) concluded that the phenotypic severity of ADSLD correlates with the ability to form purinosomes, which is determined by the structural stability and residual catalytic activity of the mutant ADSL protein complex. Mutations that reduce the effectiveness of substrate channeling through the DNPS pathway result in accumulation of toxic S-Ado and SAICAr intermediates in patient tissue.