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Adenylosuccinase deficiency: an unusual cause of early-onset epilepsy associated with acquired microcephaly
Brain & Development 22 (2000) 383±386
www.elsevier.com/locate/braindev
Case report
Adenylosuccinase de®ciency: an unusual cause of early-onset epilepsy associated with acquired microcephaly Marie-CeÂcile Nassogne a, Brigitte Henrot a, GenevieÁve Aubert b, Christine Bonnier a, Sandrine Marie c, Christine Saint-Martin d, Georges Van den Berghe c, Guillaume SeÂbire a, Marie-FrancËoise Vincent c, e,* a
Service de Neurologie PeÂdiatrique, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium b Service d'Electrophysiologie, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium c Groupe de Recherches MeÂtaboliques, Christian de Duve Institute of Cellular Pathology, Avenue Hippocrate 75/7539, B-1200 Bruxelles, Belgium d Service de Radiologie PeÂdiatrique, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium e Laboratoire des Maladies MeÂtaboliques, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium Received 6 August 1999; received in revised form 14 April 2000; accepted 11 May 2000
Abstract Adenylosuccinase de®ciency, an autosomal recessive inborn error of purine synthesis, was ®rst described in 1984 by Jaeken and Van den Berghe (reviewed in J Inher Metab Dis 20;1997:193). The cardinal features are variable psychomotor delay often accompanied by epilepsy and autistic features. Diagnosis is made by detection of abnormal purine metabolites in body ¯uids. We report a girl who presented with early onset epilepsy, associated with acquired microcephaly and severe psychomotor retardation, as the most prominent symptoms. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Adenylosuccinase de®ciency; Metabolic encephalopathy; Acquired microcephaly; Intractable epilepsy; Spasms
1. Case report This girl is the ®rst child of unrelated parents. Pregnancy was uneventful and delivery occurred at 42 weeks of gestation. Birth weight was 3050 g (25 percentile), length 50 cm (50 percentile), and head circumference 33 cm (25 percentile). Physical and neurological examinations were normal. The neonatal period was unremarkable. At three weeks of age, the baby developed partial motor seizures of the upper right limb and valproate was given with disappearance of seizures. At 9 months, there was a resurgence of seizures characterized by sudden ¯exion and extension of four limbs, suggesting spasms occurring sometimes in clusters, but also singly. Sleep recorded-electroencephalograph (EEG) showed a slow background rhythm, but without typical hypsarrythmia. She bene®ted from vigabatrin with partial clinical response, followed by adrenocorticotropic hormone (ACTH). The patient remained seizure-free for 12 months. At 2.5 years, general examination revealed normal growth (weight at the 50 percentile and height at the 75 percentile). Neurological examination showed microce* Corresponding author. Tel.: 132-2-764-7562; fax: 132-2-764-7598. E-mail address: [email protected] (M.-F. Vincent).
phaly (42 cm, more than 4 SD below normal) associated with severe axial hypotonia without any head control, and moderate tetraplegia with limb hypotonia. Tendon re¯exes were present and symmetric. There was severe psychomotor retardation with poor visual contact, and lack of language and motor skills such as voluntary prehension and sitting. In addition, the girl showed repetitive behavior with stereotypic movements of her hands. Epileptic seizures recurred at 21 months and were characterized by sudden tonic spasms with ¯exion and extension of the whole body or generalized tonic-clonic seizures. Treatment included valproic acid associated ®rst with pheneturide, with clinical improvement during 6 months. Lamotrigine was then progressively introduced. Routine blood analyses including glucose, calcium and phosphate, and assessment of liver and kidney function, were normal. TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex type 1 and 2) screening was negative in blood and cerebrospinal ¯uid. Metabolic investigations (amino, organic and very long chain fatty acids, lactate/pyruvate) gave normal results. Cerebrospinal ¯uid analysis showed normal cell count, protein and glucose levels without evidence of local immunoglobulin synthesis. High-resolution chromosome examination was normal. Electrocardio-
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00154-6
384
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
graphy, echocardiography, and abdominal ultrasound were normal. EEG performed at 21 months showed a slow background rhythm with multifocal and asynchronous spikes and sharp waves, with predominance in both temporal regions. Spasms were accompanied by a relative ¯attening of EEG rhythms (4 s), followed by rapid bilateral rhythms and after that slow waves (Fig. 1). Brain magnetic resonance imaging was normal at three weeks of age, but showed slight cerebral atrophy at 1 year. At 2.5 years, it revealed a complete but thin corpus callosum and a small vermis (Fig. 2A). Diffuse white matter abnormalities with extensive ¯uid-attenuated inversion recovery (FLAIR) hyperintensity in the temporal and occipital periventricular areas, as well as in all subcortical territories were noticed (Fig. 2B). Nerve conduction velocities and electromyography were normal. The Braton±Marshall test was positive in urine, suggesting de®ciency of adenylosuccinase. This diagnosis was con®rmed by measurement of urine and cerebrospinal ¯uid succinylaminoimidazolecarboxamide riboside (SAICAriboside, saicar) and succinyladenosine (S-Ado)
by high performance liquid chromatography. SAICAriboside and S-Ado concentrations in urine were 1.72 and 1.58 mmol/mg creatinine, respectively, and 167 and 158 mmol/l in cerebrospinal ¯uid. DNA analysis revealed a point mutation on one allele, resulting in the substitution of arginine by histidine at position 426 (R426H) in the enzyme protein. The second mutation is under investigation.
2. Discussion Adenylosuccinase (adenylosuccinate lyase, ADSL, E.C.4.3.2.2) de®ciency (McKusick 10.30.50) is an autosomal recessive inborn error of the synthesis of purines. Adenylosuccinase catalyses two steps in this pathway: the conversion of succinylaminoimidazolecarboxamide ribotide (SAICAR) into aminoimidazolecarboxamide ribotide (AICAR), and the conversion of adenylosuccinate (SAMP) into AMP. The defect results in the accumulation in body ¯uids of two normally undetectable compounds: SAICAriboside and S-Ado, produced by dephosphorylation of SAICAR and S-AMP by cytosolic 5 0 -nucleotidase. This
Fig. 1. EEG performed at the age of 21 months and recorded during one spasm.
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
385
Fig. 2. (A) A midline sagittal T1-weighted image shows microcephaly with posterior plagiocephaly, a thin corpus callosum and a small vermis atrophy. (B) An axial FLAIR-weighted image demonstrates a generalized atrophy with diffuse white matter abnormalities with extensive hyperintensity in temporal and occipital periventricular areas and in all subcortical territories.
disorder was ®rst described in 1984 [2], and to our knowledge, 50 cases have been recognized so far. The ADSL gene is localized on chromosome 22. About 20 mutations have
been identi®ed: most were found in single families with the exception of R426H which was diagnosed in 12 families, six of them from the Netherlands [3,4].
386
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
Clinical presentation is quite variable but a marked psychomotor retardation is nearly always present [1,2,5± 9]. Hypotonia also appears a relevant clinical point. Often, the affected children have a severe encephalopathy without pyramidal syndrome. Epilepsy occurs in approximately two thirds of the patients. Seizures can begin at every age, from 2 days to 7 years of age, and are often intractable. Neonatal myoclonic seizures, tonic±clonic seizures appearing during the ®rst months of life or absences have been reported [1,2,5±9]. Autistic features are common. Cranial growth is usually within normal limits, with sometimes head circumference at percentile 97. In this respect, our case is particular, owing to severe acquired microcephaly. Routine biochemical analyses are usually all normal. In some cases, brain magnetic resonance imaging shows cerebellar hypotrophy, a common, non-speci®c ®nding in metabolic brain diseases [10], associated with variable proportions of cortical and/or sub-cortical atrophy. Diagnosis relies upon the detection of SAICAriboside and S-Ado. Urinary screening tests are available. A modi®ed Braton±Marshall test appears the most practical [11]. Final diagnosis requires identi®cation of SAICAriboside and S-Ado in urine or cerebrospinal ¯uid by high performance liquid chromatography. Mutation analysis can be performed and is essential for prenatal diagnosis [12]. There is no effective treatment. Oral supplements of adenine (10 mg/kg per day) and allopurinol (5±10 mg/kg per day) were given for several months to four patients without any signi®cant clinical or biochemical improvement, with the exception of some acceleration in growth [5]. Neurological diseases with simultaneous occurrence of early-onset epilepsy and acquired microcephaly are rare. They include Rett, Angelman and Alpers syndromes and a few metabolic diseases such as biopterin de®ciency. Adenylosuccinase de®ciency should be looked for in patients with encephalopathy associated with seizures
and/or severe mental retardation, or with hypotonia and acquired microcephaly. References [1] Van den Berghe G, Vincent MF, Jaeken J. Inborn errors of the purine nucleotide cycle: adenylosuccinase de®ciency. J Inherit Metab Dis 1997;20:193±202. [2] Jaeken J, Van den Berghe G. An infantile autistic syndrome characterized by the presence of succinylpurines in body ¯uids. Lancet 1984;2:1058±1061. [3] Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H, et al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat Genet 1992;1:59±63. [4] Marie S, Cuppens H, Heuterspreute M, Jaspers M, Tola EZ, Gu XX, et al. Mutation analysis in adenylosuccinate lyase de®ciency: eight novel mutations in the re-evaluated full ADSL coding sequence. Hum Mutat 1999;13:197±202. [5] Jaeken J, Wadman SK, Duran M, van Sprang FJ, Beemer FA, Holl RA, et al. Adenylosuccinase de®ciency: an inborn error of purine nucleotide synthesis. Eur J Pediatr 1988;148:126±131. [6] Valik D, Miner PT, Jones JD. First US case of adenylosuccinate lyase de®ciency with severe hypotonia. Pediatr Neurol 1997;16:252±255. [7] Van den Bergh FA, Bosschaart AN, Hageman G, Duran M, Poll-The B. Adenylosuccinase de®ciency with neonatal onset severe epileptic seizures and sudden death. Neuropediatrics 1998;29:51±53. [8] Maaswinkel-Mooij PD, Laan LAEM, Onkenhout W, Brouwer OF, Jaeken J, Poorthuis BJ. Adenylosuccinase de®ciency presenting with epilepsy in early infancy. J Inherit Metab Dis 1997;20:606±607. [9] Sebesta I, Krijt J, Kmoch S, Hartmannova H, Wojda M, Zeman J. Adenylosuccinase de®ciency: clinical and biochemical ®ndings in 5 Czech patients. J Inherit Metab Dis 1997;20:343±344. [10] Ramaekers VT, Heimann G, Reul J, Thron A, Jaeken J. Genetic disorders and cerebellar structural abnormalities in childhood. Brain 1997;120:1739±1750. [11] Laikind PK, Seegmiller JE, Gruber HE. Detection of 5 0 -phosphoribosyl-4-(N-succinylcarboxamide)-5-aminoimidazole in urine by use of the Bratton±Marshall reaction: identi®cation of patients de®cient in adenylosuccinate lyase activity. Anal Biochem 1986;156:81±90. [12] Marie S, Flipsen JW, Duran M, Poll-The B, Beemer FA, Bosschaart AN, et al. Prenatal diagnosis in adenylosuccinate lyase de®ciency. Prenat Diagn 2000;1:33±36.
www.elsevier.com/locate/braindev
Case report
Adenylosuccinase de®ciency: an unusual cause of early-onset epilepsy associated with acquired microcephaly Marie-CeÂcile Nassogne a, Brigitte Henrot a, GenevieÁve Aubert b, Christine Bonnier a, Sandrine Marie c, Christine Saint-Martin d, Georges Van den Berghe c, Guillaume SeÂbire a, Marie-FrancËoise Vincent c, e,* a
Service de Neurologie PeÂdiatrique, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium b Service d'Electrophysiologie, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium c Groupe de Recherches MeÂtaboliques, Christian de Duve Institute of Cellular Pathology, Avenue Hippocrate 75/7539, B-1200 Bruxelles, Belgium d Service de Radiologie PeÂdiatrique, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium e Laboratoire des Maladies MeÂtaboliques, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium Received 6 August 1999; received in revised form 14 April 2000; accepted 11 May 2000
Abstract Adenylosuccinase de®ciency, an autosomal recessive inborn error of purine synthesis, was ®rst described in 1984 by Jaeken and Van den Berghe (reviewed in J Inher Metab Dis 20;1997:193). The cardinal features are variable psychomotor delay often accompanied by epilepsy and autistic features. Diagnosis is made by detection of abnormal purine metabolites in body ¯uids. We report a girl who presented with early onset epilepsy, associated with acquired microcephaly and severe psychomotor retardation, as the most prominent symptoms. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Adenylosuccinase de®ciency; Metabolic encephalopathy; Acquired microcephaly; Intractable epilepsy; Spasms
1. Case report This girl is the ®rst child of unrelated parents. Pregnancy was uneventful and delivery occurred at 42 weeks of gestation. Birth weight was 3050 g (25 percentile), length 50 cm (50 percentile), and head circumference 33 cm (25 percentile). Physical and neurological examinations were normal. The neonatal period was unremarkable. At three weeks of age, the baby developed partial motor seizures of the upper right limb and valproate was given with disappearance of seizures. At 9 months, there was a resurgence of seizures characterized by sudden ¯exion and extension of four limbs, suggesting spasms occurring sometimes in clusters, but also singly. Sleep recorded-electroencephalograph (EEG) showed a slow background rhythm, but without typical hypsarrythmia. She bene®ted from vigabatrin with partial clinical response, followed by adrenocorticotropic hormone (ACTH). The patient remained seizure-free for 12 months. At 2.5 years, general examination revealed normal growth (weight at the 50 percentile and height at the 75 percentile). Neurological examination showed microce* Corresponding author. Tel.: 132-2-764-7562; fax: 132-2-764-7598. E-mail address: [email protected] (M.-F. Vincent).
phaly (42 cm, more than 4 SD below normal) associated with severe axial hypotonia without any head control, and moderate tetraplegia with limb hypotonia. Tendon re¯exes were present and symmetric. There was severe psychomotor retardation with poor visual contact, and lack of language and motor skills such as voluntary prehension and sitting. In addition, the girl showed repetitive behavior with stereotypic movements of her hands. Epileptic seizures recurred at 21 months and were characterized by sudden tonic spasms with ¯exion and extension of the whole body or generalized tonic-clonic seizures. Treatment included valproic acid associated ®rst with pheneturide, with clinical improvement during 6 months. Lamotrigine was then progressively introduced. Routine blood analyses including glucose, calcium and phosphate, and assessment of liver and kidney function, were normal. TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex type 1 and 2) screening was negative in blood and cerebrospinal ¯uid. Metabolic investigations (amino, organic and very long chain fatty acids, lactate/pyruvate) gave normal results. Cerebrospinal ¯uid analysis showed normal cell count, protein and glucose levels without evidence of local immunoglobulin synthesis. High-resolution chromosome examination was normal. Electrocardio-
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00154-6
384
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
graphy, echocardiography, and abdominal ultrasound were normal. EEG performed at 21 months showed a slow background rhythm with multifocal and asynchronous spikes and sharp waves, with predominance in both temporal regions. Spasms were accompanied by a relative ¯attening of EEG rhythms (4 s), followed by rapid bilateral rhythms and after that slow waves (Fig. 1). Brain magnetic resonance imaging was normal at three weeks of age, but showed slight cerebral atrophy at 1 year. At 2.5 years, it revealed a complete but thin corpus callosum and a small vermis (Fig. 2A). Diffuse white matter abnormalities with extensive ¯uid-attenuated inversion recovery (FLAIR) hyperintensity in the temporal and occipital periventricular areas, as well as in all subcortical territories were noticed (Fig. 2B). Nerve conduction velocities and electromyography were normal. The Braton±Marshall test was positive in urine, suggesting de®ciency of adenylosuccinase. This diagnosis was con®rmed by measurement of urine and cerebrospinal ¯uid succinylaminoimidazolecarboxamide riboside (SAICAriboside, saicar) and succinyladenosine (S-Ado)
by high performance liquid chromatography. SAICAriboside and S-Ado concentrations in urine were 1.72 and 1.58 mmol/mg creatinine, respectively, and 167 and 158 mmol/l in cerebrospinal ¯uid. DNA analysis revealed a point mutation on one allele, resulting in the substitution of arginine by histidine at position 426 (R426H) in the enzyme protein. The second mutation is under investigation.
2. Discussion Adenylosuccinase (adenylosuccinate lyase, ADSL, E.C.4.3.2.2) de®ciency (McKusick 10.30.50) is an autosomal recessive inborn error of the synthesis of purines. Adenylosuccinase catalyses two steps in this pathway: the conversion of succinylaminoimidazolecarboxamide ribotide (SAICAR) into aminoimidazolecarboxamide ribotide (AICAR), and the conversion of adenylosuccinate (SAMP) into AMP. The defect results in the accumulation in body ¯uids of two normally undetectable compounds: SAICAriboside and S-Ado, produced by dephosphorylation of SAICAR and S-AMP by cytosolic 5 0 -nucleotidase. This
Fig. 1. EEG performed at the age of 21 months and recorded during one spasm.
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
385
Fig. 2. (A) A midline sagittal T1-weighted image shows microcephaly with posterior plagiocephaly, a thin corpus callosum and a small vermis atrophy. (B) An axial FLAIR-weighted image demonstrates a generalized atrophy with diffuse white matter abnormalities with extensive hyperintensity in temporal and occipital periventricular areas and in all subcortical territories.
disorder was ®rst described in 1984 [2], and to our knowledge, 50 cases have been recognized so far. The ADSL gene is localized on chromosome 22. About 20 mutations have
been identi®ed: most were found in single families with the exception of R426H which was diagnosed in 12 families, six of them from the Netherlands [3,4].
386
M.-C. Nassogne et al. / Brain & Development 22 (2000) 383±386
Clinical presentation is quite variable but a marked psychomotor retardation is nearly always present [1,2,5± 9]. Hypotonia also appears a relevant clinical point. Often, the affected children have a severe encephalopathy without pyramidal syndrome. Epilepsy occurs in approximately two thirds of the patients. Seizures can begin at every age, from 2 days to 7 years of age, and are often intractable. Neonatal myoclonic seizures, tonic±clonic seizures appearing during the ®rst months of life or absences have been reported [1,2,5±9]. Autistic features are common. Cranial growth is usually within normal limits, with sometimes head circumference at percentile 97. In this respect, our case is particular, owing to severe acquired microcephaly. Routine biochemical analyses are usually all normal. In some cases, brain magnetic resonance imaging shows cerebellar hypotrophy, a common, non-speci®c ®nding in metabolic brain diseases [10], associated with variable proportions of cortical and/or sub-cortical atrophy. Diagnosis relies upon the detection of SAICAriboside and S-Ado. Urinary screening tests are available. A modi®ed Braton±Marshall test appears the most practical [11]. Final diagnosis requires identi®cation of SAICAriboside and S-Ado in urine or cerebrospinal ¯uid by high performance liquid chromatography. Mutation analysis can be performed and is essential for prenatal diagnosis [12]. There is no effective treatment. Oral supplements of adenine (10 mg/kg per day) and allopurinol (5±10 mg/kg per day) were given for several months to four patients without any signi®cant clinical or biochemical improvement, with the exception of some acceleration in growth [5]. Neurological diseases with simultaneous occurrence of early-onset epilepsy and acquired microcephaly are rare. They include Rett, Angelman and Alpers syndromes and a few metabolic diseases such as biopterin de®ciency. Adenylosuccinase de®ciency should be looked for in patients with encephalopathy associated with seizures
and/or severe mental retardation, or with hypotonia and acquired microcephaly. References [1] Van den Berghe G, Vincent MF, Jaeken J. Inborn errors of the purine nucleotide cycle: adenylosuccinase de®ciency. J Inherit Metab Dis 1997;20:193±202. [2] Jaeken J, Van den Berghe G. An infantile autistic syndrome characterized by the presence of succinylpurines in body ¯uids. Lancet 1984;2:1058±1061. [3] Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H, et al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat Genet 1992;1:59±63. [4] Marie S, Cuppens H, Heuterspreute M, Jaspers M, Tola EZ, Gu XX, et al. Mutation analysis in adenylosuccinate lyase de®ciency: eight novel mutations in the re-evaluated full ADSL coding sequence. Hum Mutat 1999;13:197±202. [5] Jaeken J, Wadman SK, Duran M, van Sprang FJ, Beemer FA, Holl RA, et al. Adenylosuccinase de®ciency: an inborn error of purine nucleotide synthesis. Eur J Pediatr 1988;148:126±131. [6] Valik D, Miner PT, Jones JD. First US case of adenylosuccinate lyase de®ciency with severe hypotonia. Pediatr Neurol 1997;16:252±255. [7] Van den Bergh FA, Bosschaart AN, Hageman G, Duran M, Poll-The B. Adenylosuccinase de®ciency with neonatal onset severe epileptic seizures and sudden death. Neuropediatrics 1998;29:51±53. [8] Maaswinkel-Mooij PD, Laan LAEM, Onkenhout W, Brouwer OF, Jaeken J, Poorthuis BJ. Adenylosuccinase de®ciency presenting with epilepsy in early infancy. J Inherit Metab Dis 1997;20:606±607. [9] Sebesta I, Krijt J, Kmoch S, Hartmannova H, Wojda M, Zeman J. Adenylosuccinase de®ciency: clinical and biochemical ®ndings in 5 Czech patients. J Inherit Metab Dis 1997;20:343±344. [10] Ramaekers VT, Heimann G, Reul J, Thron A, Jaeken J. Genetic disorders and cerebellar structural abnormalities in childhood. Brain 1997;120:1739±1750. [11] Laikind PK, Seegmiller JE, Gruber HE. Detection of 5 0 -phosphoribosyl-4-(N-succinylcarboxamide)-5-aminoimidazole in urine by use of the Bratton±Marshall reaction: identi®cation of patients de®cient in adenylosuccinate lyase activity. Anal Biochem 1986;156:81±90. [12] Marie S, Flipsen JW, Duran M, Poll-The B, Beemer FA, Bosschaart AN, et al. Prenatal diagnosis in adenylosuccinate lyase de®ciency. Prenat Diagn 2000;1:33±36.