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Novel MRI and clinical findings in a boy with adenylosuccinate lyase deficiency
European Journal of Radiology Extra 71 (2009) e3–e5
Contents lists available at ScienceDirect
European Journal of Radiology Extra journal homepage: intl.elsevierhealth.com/journals/ejrex
Novel MRI and clinical findings in a boy with adenylosuccinate lyase deficiency Monika Bekiesinska-Figatowska a,∗ , Krystyna Szymanska b,1 , Bogna Schmidt-Sidor c,2 , Hanna Mierzewska b,1 , Anna Bogdanska d,3 , Katarzyna Kusmierska d,3 , Anna Romaniuk-Doroszewska a a
Department of Diagnostic Imaging, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland Department of Neurology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland c Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland d Department of Biochemistry and Experimental Medicine, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland b
a r t i c l e
i n f o
Article history: Received 7 December 2008 Accepted 22 January 2009 Keywords: ADSL deficiency Brain MRI Demyelination
a b s t r a c t Adenylosuccinate lyase (ADSL-E.C.4.3.2.2.) deficiency is a rare autosomal recessive metabolic disease of purines nucleotide synthesis affecting predominantly the central nervous system. We present a case of a 4.5-year-old boy with ADSL deficiency, developmental delay, hypotonia and epilepsy. In a series of three consecutive magnetic resonance examinations we observed not only reduced myelination and progressive atrophy of the brain that were reported before but also demyelination of previously normal white matter, correlating with clinical deterioration. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Background
2. Case report
Adenylosuccinate lyase (ADSL-E.C.4.3.2.2.) deficiency is a rare autosomal recessive metabolic disease of purines nucleotide synthesis affecting predominantly the central nervous system. ADSL converts succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR) and adenylosuccinate (S-AMP) into adenosine monophosphate (AMP). SAICAR and S-AMP are accumulated and dephosphorylated to SAICA riboside (SAICAr) and succinyladenosine (S-Ado) as a result of the enzyme deficiency. SAICAr can be detected in urine using TLC method [1]. Two metabolites (S-Ado and SAICAr) are analysed in cerebrospinal fluid (CSF) using HPLC with UV–vis detection method. The S-Ado/SAICAr ratio differentiates between types of ADSL deficiency and phenotype severity. In most cases ADSL deficiency leads to profound developmental delay and epilepsy.
A boy aged 4.5 years, was born as a first child of nonconsanguineous parents. Pregnancy was complicated by mother’s arterial hypertension; delivery was uneventful. Birth weight was 3300 g, head circumference: 34 cm, Apgar score: 9 points. From the second month of life developmental delay was observed. In neurological examination marked hypotonia, stereotyped movements and lack of eye contact were noticed. At the age of 1 year generalized convulsions started and anitiepileptic therapy with valproic acid was introduced with success. At the age of 4.5 years transient deterioration of neurological status was observed after lumbar puncture. Biochemical studies showed high concentration of S-Ado and SAICAr in CSF. SAICAr excretion in urine confirmed ADSL deficiency. The ratio of S-ado/SAICAr was 2,44. At the age of 3.5 months brain MRI revealed diffuse hypomyelination of brain stem and of the pre- and postcentral gyrus region (Fig. 1a and b). The subarachnoid spaces were dilated and Sylvian fissures were wide open. The second MRI, performed 2 years later, showed dilatation of the ventricular system corresponding to cerebral atrophy. Thin rim of T2-hyperintense signal was observed in the white matter surrounding the lateral ventricles. It might have represented hypomyelination/dysmyelination. The supratentorial white matter was otherwise normal, including the previously unmyelinated perirolandic region (Fig. 2a). The brain stem was also myelinated except for its dorsal part in which symmetrical hyperintense lesions were found, suggesting demyelinating process (Fig. 2b).
∗ Corresponding author. Tel.: +48 22 32 77 156 fax: +48 22 32 77 300. E-mail addresses: m.fi[email protected] (M. Bekiesinska-Figatowska), [email protected] (K. Szymanska), [email protected] (B. Schmidt-Sidor), [email protected] (H. Mierzewska), [email protected] (A. Bogdanska), k [email protected] (K. Kusmierska), [email protected] (A. Romaniuk-Doroszewska). 1 Tel.: +48 22 32 77 209; fax: +48 22 32 77 300. 2 Tel.: +48 22 45 82 646; fax: +48 22 651 93 01. 3 Tel.: +48 22 815 17 76; fax: +48 22 815 17 89. 1571-4675/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrex.2009.01.010
e4
M. Bekiesinska-Figatowska et al. / European Journal of Radiology Extra 71 (2009) e3–e5
3. Discussion This is the eighth Polish case of adenylosuccinate lyase deficiency. We found in literature 5 reports on MRI findings in children with this disease [2–6]. Hypomyelination, diffuse white matter hyperintensities and cerebral atrophy have already been reported. To our knowledge this is the first report of serial MR examinations in one patient showing the evidence not only of reduced myelination and progressive atrophy of the brain but also of demyelination of previously normal white matter, correlating with clinical deterioration. The previous detailed description of MRI and neuropathological findings in a case of ADSL deficiency with rapid clinical deterioration and repeated MRI concerned an infant examined at the age of 1 and 2 months, in the period of life when myelination is in progress [7,8]. Although the process of myelination lasts for at least two first decades of life, MRI shows its progress up to the age of 18 months. Before this age it is then very difficult to assess with a single MR examination and standard MRI technique whether T2hyperintensities result from delayed myelination/hypomyelination or from demyelination. After 2 years of age MRI displays adult pattern of myelination. Also after this age it is difficult to determine the character of hyperintensity in a single MR study. In our case we had a series of three consecutive examinations, showing the delay of myelination first, then its progression and finally damage of the white matter. Hyperintense lesions found at the age of 4.5
Fig. 1. First MRI at the age of 3.5 months. FSE/T2WI/ax. a: Hypomyelination of the region of pre- and postcentral gyrus. b: Hypomyelination of brain stem. Normal size of brain stem and of the fourth ventricle. (Courtesy of Prof. T. Bieganski, Head of Dept. of Diagnostic Imaging, Polish Mother’s Memorial Hospital–Research Institute.)
The boy was referred to the third examination at the age of 4.5 years because of deterioration of neurological status and regression of psychomotor development. Extensive hyperintense areas were found symmetrically in the white matter of both cerebral hemispheres (Fig. 3a and b). These changes were not present previously which led us to the conclusion that demyelination must have occured in these areas. Hyperintense signal in T2weighted images was observed in the dorsal part of brain stem as previously as well as cerebral atrophy and thin corpus callosum. Progression of cerebellar and brain stem atrophy was also noted.
Fig. 2. Second MRI 2 years later. a: FLAIR/ax image corresponding to Fig. 1a. Normally myelinated white matter. b: FSE/T2WI/ax. Demyelination of the dorsal part of brain stem. Cerebral, cerebellar and brain stem atrophy.
M. Bekiesinska-Figatowska et al. / European Journal of Radiology Extra 71 (2009) e3–e5
e5
The neuropathological data in ADSL deficiency are very scanty and refer to the lesions as to microcystic encephalopathy. The neuropathological examination of one case showed severe microcystic encephalopathy with damage of all morphological elements of the brain (neurons, their processes, astroglia cells, oligodendroglia cells, myelin and also vessels). Neuropathological data indicate probability of two explanations of white matter injury in ADSL deficiency. The first may be damage to oligodendroglia described in electron microscopy examination, the second one may be damage to neurons and lack of their axons which are the substrate for myelination [7]. The same processes may be the cause of white matter hyperintensities depicted on MRI. Conflict of interest The authors and authors’ institutions have no conflicts of interest. Disclosure The authors confirm the fact that the article is not under consideration for publication elsewhere. No part of this article has been sent by mail. Each author has participated sufficiently in this submission to take public responsibility for its content. References
Fig. 3. Third MRI at the age of 4.5 years. a and b: FLAIR/ax. Extensive demyelination of previously normal white matter of both cerebral hemispheres.
years in the regions which were normal 2 years earlier make it clear that a devastating process occured in the previously normal regions of white matter. That is why we draw the conclusion that not only hypomyelination but also demyelination can be depicted in the course of ADSL deficiency.
[1] de Bree PK, Wadman SK, Duran M, et al. Diagnosis of inherited adenylosuccinase deficiency by thin-layer chromatography of urinary imidazoles and by automated cation exchange column chromatography of purines. Clin Chim Acta 1986;156:279–88. [2] Kohler M, Assmann B, Brautigam C, et al. Adenylosuccinase deficiency: possibly under diagnosed encephalopathy with variable clinical features. Eur J Paediatr Neurol 1999;3:3–6. [3] Nassogne M, Henrot B, Aubert G, et al. Adenylosuccinase deficiency: an unusual cause of early-onset epilepsy associated with acquired microcephaly. Brain Dev 2000;22:383–6. [4] Marinaki AM, Champion M, Kurian MA, et al. Adenylosuccinate lyase deficiency—first British case. Nucleos Nucleot Nucl Acids 2004;23:1231–3. [5] Mouchegh K, Zikanova M, Hoffman GF, et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of six patients in four families. J Pediatr 2007;150:57–61. [6] Jurkiewicz E, Mierzewska H, Kusmierska K. Adenylosuccinate lyase deficiency: the first identified Polish patient. Brain Dev 2007;29:600–2. [7] Mierzewska H, Schmidt-Sidor B, Lewandowska E, et al. Clinical, biochemical, neuropathological an molecular findings of the first polish case of adenylosuccinase deficiency. Folia Neuropathol 2008;46(1):81–91. [8] Jurecka A, Tylki-Szymanska A, Bogdanska A, et al. Adenylsuccinate lyase deficiency—diagnostics and clinical characterization of 7 Polish cases. Pediatr Pol 2007;7:526–32.
Contents lists available at ScienceDirect
European Journal of Radiology Extra journal homepage: intl.elsevierhealth.com/journals/ejrex
Novel MRI and clinical findings in a boy with adenylosuccinate lyase deficiency Monika Bekiesinska-Figatowska a,∗ , Krystyna Szymanska b,1 , Bogna Schmidt-Sidor c,2 , Hanna Mierzewska b,1 , Anna Bogdanska d,3 , Katarzyna Kusmierska d,3 , Anna Romaniuk-Doroszewska a a
Department of Diagnostic Imaging, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland Department of Neurology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland c Department of Neuropathology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland d Department of Biochemistry and Experimental Medicine, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland b
a r t i c l e
i n f o
Article history: Received 7 December 2008 Accepted 22 January 2009 Keywords: ADSL deficiency Brain MRI Demyelination
a b s t r a c t Adenylosuccinate lyase (ADSL-E.C.4.3.2.2.) deficiency is a rare autosomal recessive metabolic disease of purines nucleotide synthesis affecting predominantly the central nervous system. We present a case of a 4.5-year-old boy with ADSL deficiency, developmental delay, hypotonia and epilepsy. In a series of three consecutive magnetic resonance examinations we observed not only reduced myelination and progressive atrophy of the brain that were reported before but also demyelination of previously normal white matter, correlating with clinical deterioration. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Background
2. Case report
Adenylosuccinate lyase (ADSL-E.C.4.3.2.2.) deficiency is a rare autosomal recessive metabolic disease of purines nucleotide synthesis affecting predominantly the central nervous system. ADSL converts succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR) and adenylosuccinate (S-AMP) into adenosine monophosphate (AMP). SAICAR and S-AMP are accumulated and dephosphorylated to SAICA riboside (SAICAr) and succinyladenosine (S-Ado) as a result of the enzyme deficiency. SAICAr can be detected in urine using TLC method [1]. Two metabolites (S-Ado and SAICAr) are analysed in cerebrospinal fluid (CSF) using HPLC with UV–vis detection method. The S-Ado/SAICAr ratio differentiates between types of ADSL deficiency and phenotype severity. In most cases ADSL deficiency leads to profound developmental delay and epilepsy.
A boy aged 4.5 years, was born as a first child of nonconsanguineous parents. Pregnancy was complicated by mother’s arterial hypertension; delivery was uneventful. Birth weight was 3300 g, head circumference: 34 cm, Apgar score: 9 points. From the second month of life developmental delay was observed. In neurological examination marked hypotonia, stereotyped movements and lack of eye contact were noticed. At the age of 1 year generalized convulsions started and anitiepileptic therapy with valproic acid was introduced with success. At the age of 4.5 years transient deterioration of neurological status was observed after lumbar puncture. Biochemical studies showed high concentration of S-Ado and SAICAr in CSF. SAICAr excretion in urine confirmed ADSL deficiency. The ratio of S-ado/SAICAr was 2,44. At the age of 3.5 months brain MRI revealed diffuse hypomyelination of brain stem and of the pre- and postcentral gyrus region (Fig. 1a and b). The subarachnoid spaces were dilated and Sylvian fissures were wide open. The second MRI, performed 2 years later, showed dilatation of the ventricular system corresponding to cerebral atrophy. Thin rim of T2-hyperintense signal was observed in the white matter surrounding the lateral ventricles. It might have represented hypomyelination/dysmyelination. The supratentorial white matter was otherwise normal, including the previously unmyelinated perirolandic region (Fig. 2a). The brain stem was also myelinated except for its dorsal part in which symmetrical hyperintense lesions were found, suggesting demyelinating process (Fig. 2b).
∗ Corresponding author. Tel.: +48 22 32 77 156 fax: +48 22 32 77 300. E-mail addresses: m.fi[email protected] (M. Bekiesinska-Figatowska), [email protected] (K. Szymanska), [email protected] (B. Schmidt-Sidor), [email protected] (H. Mierzewska), [email protected] (A. Bogdanska), k [email protected] (K. Kusmierska), [email protected] (A. Romaniuk-Doroszewska). 1 Tel.: +48 22 32 77 209; fax: +48 22 32 77 300. 2 Tel.: +48 22 45 82 646; fax: +48 22 651 93 01. 3 Tel.: +48 22 815 17 76; fax: +48 22 815 17 89. 1571-4675/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrex.2009.01.010
e4
M. Bekiesinska-Figatowska et al. / European Journal of Radiology Extra 71 (2009) e3–e5
3. Discussion This is the eighth Polish case of adenylosuccinate lyase deficiency. We found in literature 5 reports on MRI findings in children with this disease [2–6]. Hypomyelination, diffuse white matter hyperintensities and cerebral atrophy have already been reported. To our knowledge this is the first report of serial MR examinations in one patient showing the evidence not only of reduced myelination and progressive atrophy of the brain but also of demyelination of previously normal white matter, correlating with clinical deterioration. The previous detailed description of MRI and neuropathological findings in a case of ADSL deficiency with rapid clinical deterioration and repeated MRI concerned an infant examined at the age of 1 and 2 months, in the period of life when myelination is in progress [7,8]. Although the process of myelination lasts for at least two first decades of life, MRI shows its progress up to the age of 18 months. Before this age it is then very difficult to assess with a single MR examination and standard MRI technique whether T2hyperintensities result from delayed myelination/hypomyelination or from demyelination. After 2 years of age MRI displays adult pattern of myelination. Also after this age it is difficult to determine the character of hyperintensity in a single MR study. In our case we had a series of three consecutive examinations, showing the delay of myelination first, then its progression and finally damage of the white matter. Hyperintense lesions found at the age of 4.5
Fig. 1. First MRI at the age of 3.5 months. FSE/T2WI/ax. a: Hypomyelination of the region of pre- and postcentral gyrus. b: Hypomyelination of brain stem. Normal size of brain stem and of the fourth ventricle. (Courtesy of Prof. T. Bieganski, Head of Dept. of Diagnostic Imaging, Polish Mother’s Memorial Hospital–Research Institute.)
The boy was referred to the third examination at the age of 4.5 years because of deterioration of neurological status and regression of psychomotor development. Extensive hyperintense areas were found symmetrically in the white matter of both cerebral hemispheres (Fig. 3a and b). These changes were not present previously which led us to the conclusion that demyelination must have occured in these areas. Hyperintense signal in T2weighted images was observed in the dorsal part of brain stem as previously as well as cerebral atrophy and thin corpus callosum. Progression of cerebellar and brain stem atrophy was also noted.
Fig. 2. Second MRI 2 years later. a: FLAIR/ax image corresponding to Fig. 1a. Normally myelinated white matter. b: FSE/T2WI/ax. Demyelination of the dorsal part of brain stem. Cerebral, cerebellar and brain stem atrophy.
M. Bekiesinska-Figatowska et al. / European Journal of Radiology Extra 71 (2009) e3–e5
e5
The neuropathological data in ADSL deficiency are very scanty and refer to the lesions as to microcystic encephalopathy. The neuropathological examination of one case showed severe microcystic encephalopathy with damage of all morphological elements of the brain (neurons, their processes, astroglia cells, oligodendroglia cells, myelin and also vessels). Neuropathological data indicate probability of two explanations of white matter injury in ADSL deficiency. The first may be damage to oligodendroglia described in electron microscopy examination, the second one may be damage to neurons and lack of their axons which are the substrate for myelination [7]. The same processes may be the cause of white matter hyperintensities depicted on MRI. Conflict of interest The authors and authors’ institutions have no conflicts of interest. Disclosure The authors confirm the fact that the article is not under consideration for publication elsewhere. No part of this article has been sent by mail. Each author has participated sufficiently in this submission to take public responsibility for its content. References
Fig. 3. Third MRI at the age of 4.5 years. a and b: FLAIR/ax. Extensive demyelination of previously normal white matter of both cerebral hemispheres.
years in the regions which were normal 2 years earlier make it clear that a devastating process occured in the previously normal regions of white matter. That is why we draw the conclusion that not only hypomyelination but also demyelination can be depicted in the course of ADSL deficiency.
[1] de Bree PK, Wadman SK, Duran M, et al. Diagnosis of inherited adenylosuccinase deficiency by thin-layer chromatography of urinary imidazoles and by automated cation exchange column chromatography of purines. Clin Chim Acta 1986;156:279–88. [2] Kohler M, Assmann B, Brautigam C, et al. Adenylosuccinase deficiency: possibly under diagnosed encephalopathy with variable clinical features. Eur J Paediatr Neurol 1999;3:3–6. [3] Nassogne M, Henrot B, Aubert G, et al. Adenylosuccinase deficiency: an unusual cause of early-onset epilepsy associated with acquired microcephaly. Brain Dev 2000;22:383–6. [4] Marinaki AM, Champion M, Kurian MA, et al. Adenylosuccinate lyase deficiency—first British case. Nucleos Nucleot Nucl Acids 2004;23:1231–3. [5] Mouchegh K, Zikanova M, Hoffman GF, et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of six patients in four families. J Pediatr 2007;150:57–61. [6] Jurkiewicz E, Mierzewska H, Kusmierska K. Adenylosuccinate lyase deficiency: the first identified Polish patient. Brain Dev 2007;29:600–2. [7] Mierzewska H, Schmidt-Sidor B, Lewandowska E, et al. Clinical, biochemical, neuropathological an molecular findings of the first polish case of adenylosuccinase deficiency. Folia Neuropathol 2008;46(1):81–91. [8] Jurecka A, Tylki-Szymanska A, Bogdanska A, et al. Adenylsuccinate lyase deficiency—diagnostics and clinical characterization of 7 Polish cases. Pediatr Pol 2007;7:526–32.