Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency

https://doi.org/10.1016/j.ymgme.2008.04.013Get rights and content

Abstract

Adenylosuccinate lyase (ADSL) catalyzes two steps in purine nucleotide metabolism—the 8th step in the de novo pathway: conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR), and conversion of adenylosuccinate (S-AMP) to adenylate (AMP) in the purine nucleotide cycle. To date, over 50 patients have been reported suffering from ADSL deficiency. We report all seven so far diagnosed Polish patients with this defect. Most of our patients shared intractable seizures and psychomotor retardation since the neonatal period and had biochemical evidence of severe (type I) deficiency. Two patients with type II suffered only from mild/moderate psychomotor retardation and showed a transientvisual contact disturbance. One patient had a fatal neonatal form of ADSL deficiency with lack of spontaneous movement, respiratory failure, severe encephalopathy and intractable seizures. Analysis of the ADSL gene showed that four apparently unrelated patients carried a R426H mutation (two homozygous and two compound heterozygous). With the exception of the latter mutation, a Y114H mutation that had been reported previously, and a novel mutation T242I, all other mutations (including D268H and three novel S23R, D215H and I351T mutations) were found only in single families in single alleles. A search for this disorder should be included in the screening program of all infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy, developmental delay, hypotonia, and/or autistic features.

Section snippets

Materials and methods

In the period 1999–2007 we examined almost 3000 widely selective urine specimens from children (ca. 60% boys and 40% girls) with various neurological signs and symptoms (at least one of the following: neonatal seizures, infantile epileptic encephalopathy, hypotonia, developmental delay, behavior abnormalities) in whom a diagnosis had not been achieved by the usual laboratory investigations. All the patients ranged between newborn babies and young children. When patients were admitted to the

Results

During the last 8 years, 4 girls and 1 boy were found by means of selective screening using TLC method. Only patient 1 was initially recognized based on clinical picture of psychomotor retardation with surprising, autistic behavior, which drew attention to the possibility of ADSL deficiency. Diagnosis of patient 5 was made post mortem using the neonatal screening card after recognizing ADSL deficiency in her sibling.

Family 1

Patient 1 is the second child of unrelated parents. Pregnancy, delivery and neonatal period were uneventful. At the age of 5 months, psychomotor delay with limited eye contact, stereotypic features and myoclonic movement were noted. MRI at the age of 14 months showed slight cerebral atrophy pronounced mostly in the frontal lobes. Because of strange contact disturbances and psychomotor retardation, she was suspected of having ADSL deficiency and TLC screening for SAICAr detection was performed.

Family 2

Patient 2 is the second child of unrelated parents. The neonatal period was unremarkable. At 6 months of life, delay in psychomotor development, poor eye contact and absence of interest were noted. MRI at the age of 9 months showed slight cerebral atrophy mainly in the frontal lobe area. ADSL deficiency was confirmed at the age of 1.5 years. She could sit and produce two syllables at 18 months. At the age of 4 years she did not walk alone but could stand up with help and was able to say a few

Family 3

Patient 3 is the first child of unrelated parents. From the first month of life she presented axial hypotonia and poor eye contact. There was a psychomotor retardation with a lack of language and poor motor skills. She never learnt to walk and could sit independently at the age of 3 years. In addition, the girl showed repetitive behavior with stereotypic movements of her hands (hand washing movements, repetitive manipulation of toys, repetitive handling of an object). Seizures occurred at 2

Family 4

Patient 4 is the third child of unrelated parents. The eldest sister is healthy, the second one had died at the age of 10 weeks with progressive encephalopathy and seizures, but without established diagnosis. The proposita was born at term after an uneventful pregnancy with Apgar score 10. The neonatal period was unremarkable. At 3 weeks of age, the baby presented hypotonia, seizures, nystagmus and opistotonus. With antiepileptic drugs sufficient control of seizures was achieved. MRI showed

Family 5

Patient 6 is the first child of unrelated parents and was born at term after and uneventful pregnancy. At the age of 3 weeks he developed tonic–clonic seizures, tremor and myoclonic movements. Therapeutic attempt with antiepileptic drugs were unsuccessful, the frequency of convulsions seems to decrease independently of the treatment. MRI at the age of 7 months showed cerebral atrophy with moderately reduced myelinisation.

Currently, at the age of 2.5 years he presents severe generalized

Family 6

Patient 7 is the first child of unrelated parents. Pregnancy was uneventful and delivery occurred at 42 weeks of gestation—with deceleration in II part. She was born at term with 9 Apgar score. Early postnatal adaptation was complicated by respiratory distress, muscle hypotonia and poor ineffective sucking. Refractory seizures developed soon thereafter (4th day), she presented tonic–clonic seizures, opistotonus, tremor and myoclonus. The seizures were refractory on various combinations of

Discussion

In this study, we describe the clinical, biochemical and genetic findings of seven Polish patients with ADSL deficiency, an inborn error of purine metabolism. Four of our patients (3, 4, 6, 7), as the majority of patients described so far, presented type I of ADSL deficiency, with a purely neurological clinical picture characterized by severe psychomotor retardation, epilepsy and impressive autistic features including absent or poor eye contact and stereotypies [3]. Two patients with type II (1, 2)

Acknowledgments

The authors acknowledge the contribution of the patients and their families. We thank Ryszard T. Smolenski and Ewa Slominska (Gdansk, Poland) for expert technical support.

Collaboration with other laboratories was made possible by the grant supported by Polish Scientific Research Committee PB 1121/P01/2007/32. The biochemical measurements, DNA analysis and molecular studies were supported by grant by 301/07/0600 grant from the Czech Science Foundation Institutional support was provided by

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