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- ADSL, adenylosuccinate lyase deficiency
- SAICAR, succinylaminoimidazole carboxamide ribotide
- AICAR, aminoimidazole carboxamide ribotide
- S-AMP, adenylosuccinate
- AMP, adenosine monophosphate
- S-Ado, succinyladenosine
- SAICAr, succinylaminoimidazole carboxamide riboside
- HPLC, high performance liquid chromatography
Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described.
ADSL is a homotetramer involved in two distinct steps of purine synthesis, namely (1) the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR), and (2) the conversion of adenylosuccinate (S-AMP) into adenosine monophosphate (AMP) in the inosine monophosphate transformation pathway (fig 1). The diagnosis of ADSL deficiency is based on the detection of dephosphorylated SAICAR and S-AMP products, that is, S-Ado (succinyladenosine) and SAICAr (succinylaminoimidazole carboxamide riboside). The modified Bratton-Marshall test is the most convenient urinary screening test,8,9 but conclusive diagnosis requires the identification of S-Ado and SAICAr in urine or cerebrospinal fluid by high performance liquid chromatography (HPLC). The gene for adenylosuccinate lyase has been mapped to chromosome 22q13.1-q13.210 and around 20 different missense mutations and one deletion have been identified so far.11–14 Most patients are compound heterozygotes.15
Here, we report on a novel case of adenylosuccinate lyase deficiency, sharing a number of clinical features with previously reported cases, and emphasise the facial dysmorphic features hitherto unreported in this condition.
The proband, a girl, was the first child of unrelated parents, born after an uneventful term pregnancy. Her birth weight was 3800 g, length was 49 cm, and head circumference was 35 cm. Hypotonia was noted at 6 months of age. She presented with seizures at 20 months, which were not controlled by valproate and clonazepam but by lamotrigine only. She was first referred to our genetic clinic at 27 months of age for mental retardation and facial dysmorphism. She could not sit unaided, she was hypotonic, and she had no speech. Dysmorphic features included small head circumference (−2 SD), brachycephaly, flat occiput, prominent metopic suture, intermittent divergent strabismus, small nose with anteverted nostrils, long and smooth philtrum, a thin upper lip, and low set ears (fig 2). Her weight was 11.2 kg (M) and length 88 cm (−1 SD). All standard laboratory investigations were normal and brain MRI showed non-specific asymmetrical ventricles with hypodensity of the white matter. The EEG showed bifrontal seizures. Blood chromosome analyses were normal. The association of severe developmental delay with seizures was suggestive of a metabolic disorder. The modified Bratton-Marshall urinary test was positive, suggesting ADLS deficiency. This diagnosis was confirmed by measurement of urine and cerebrospinal fluid (CSF) SAICAr and S-Ado by HPLC. Urinary SAICAr and S-Ado concentrations were 4.18 and 3.86 μmol/mg creatinine, respectively, and CSF SAICAr and S-Ado concentrations were 376 and 367 μmol/l, respectively. The SAICAr/S-Ado ratio was 0.92 in urine and 0.97 in CSF. Finally, molecular analyses of the ASDL gene showed compound heterozygosity for ADSL mutations (M1L and R374W). The mother was found to be heterozygous for the M1L and the father for the R374W mutations.
Dysmorphic features have not previously been mentioned in ADSL deficiency. We have had the opportunity to analyse pictures of another case of an ADSL deficient child previously reported by Nassogne et al16 (fig 3). This girl had similar dysmorphic features to our patient, namely brachycephaly, prominent metopic sutures, small nose with anteverted nostrils, long, smooth philtrum, and thin upper lip. All of these features, characteristic of metabolic disorders, have been described in mitochondrial disorders (respiratory chain17 and pyruvate dehydrogenase18 deficiencies), peroxysomal disorders,19, and fetal alcohol syndrome,20 and could be the result of either toxicity of the abnormal metabolite accumulation or the direct effect of the primary enzyme deficiency. The simplicity of the urinary screening test should allow consideration of this diagnosis when dealing with the association of developmental delay, dysmorphic features, and seizures.
Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing mental retardation, seizures, and autistic features. The diagnosis is based on the detection of the dephosphorylated SAICAR and S-AMP products and the modified Bratton-Marshall test is a simple urinary screening test.
Here, we report on a new case of adenylosuccinate lyase deficiency presenting with mental retardation, seizures, and facial dysmorphism and having brachycephaly, prominent metopic suture, a small nose with anteverted nostrils, long and smooth philtrum, thin upper lip, and low set ears.
The analysis of another previously reported child with ADSL shows the same dysmorphic features, which could be the result of toxicity of the abnormal metabolite accumulation.
We conclude therefore that the diagnosis of ADSL should be considered when dealing with the association of developmental delay, dysmorphic features, and seizures.