- Email: [email protected]
Sneddon syndrome, arylsulfatase A pseudodeficiency and impairment of cerebral white matter
Brain & Development 22 (2000) 390±393
www.elsevier.com/locate/braindev
Case report
Sneddon syndrome, arylsulfatase A pseudode®ciency and impairment of cerebral white matter Antonia Parmeggiani a,*, Annio Posar a, Lucilla Badiali De Giorgi b, Simonetta Sangiorgi c, Mirella Mochi c, Lucia Monari c, Annalisa Patrizi d, Paola Giovanardi Rossi a a
Department of Child Neurology and Psychiatry, Neurological Institute, University of Bologna, via Ugo Foscolo 7, 40123 Bologna, Italy b Service of Cytopathology, S. Orsola-Malpighi Hospital, Bologna, Italy c Neurological Institute, University of Bologna, Bologna, Italy d Department of Dermatology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy Received 10 September 1999; received in revised form 14 March 2000; accepted 24 June 2000
Abstract We describe a 11 year-old-boy with Sneddon syndrome, con®rmed by skin biopsy, and MR evidence of diffuse cerebral hyperintensity of white matter; he also suffered from pre-perinatal hypoxic-ischemic distress. Arylsulfatase A activity was found reduced because of arylsulfatase A pseudode®ciency. We suggest that the association of pre-perinatal distress, Sneddon syndrome and arylsulfatase A pseudode®ciency is responsible for the diffuse impairment of cerebral white matter, never reported in Sneddon syndrome and similar to described cases of delayed posthypoxic demyelination and arylsulfatase A pseudode®ciency. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Sneddon syndrome; Arylsulfatase A pseudode®ciency; Delayed posthypoxic demyelination; Hypoxia; Cerebral white matter; Brain imaging
1. Introduction Sneddon syndrome, ®rst described in 1965, is characterized by idiopathic livedo reticularis and cerebrovascular lesions [1]. The pathogenesis of the syndrome is poorly understood. However, in patients with Sneddon syndrome small to medium-sized vessels of the dermis-subcutis boundary present a progressive occlusion that probably starts as an in¯ammatory/immunologically mediated disorder developing in four stages [2]. Other clinical signs described in Sneddon syndrome are epileptic seizures, migraine, progressive dementia, neuropsychological de®cits, hypertension, heart valvulopathy, acroerythrocyanosis and Raynaud's phenomenon [3±5]. Women are more frequently affected, often with a history of miscarriages [5]. The age at onset is extremely variable: generally Sneddon syndrome develops in adulthood but rare cases have been reported in childhood [3,6]. Familial cases have been described with both autosomal dominant and recessive inheritance [3,7]. Sometimes, antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) are associated with Sneddon syndrome, implying that Sneddon syndrome might be * Corresponding author. Tel.: 139-051-585158; fax: 139-051-333725. E-mail address: [email protected] (A. Parmeggiani).
strictly related to the primary antiphospholipid antibody syndrome [8]. Abnormalities of coagulation have also been described [9], but the physiopathogenetic role of these data remains unknown. We describe a child with Sneddon syndrome and arylsulfatase A pseudode®ciency who presented a peculiar diffuse impairment of cerebral white matter more extensively than that reported for typical ischemic lesions in Sneddon syndrome [10]. 2. Case report A 11 year-old-boy had a family history positive for livedo reticularis, he is an only child, his parents were consanguineous and the mother had had a miscarriage (Fig. 1). Preperinatal hypoxic-ischemic distress was reported consisting of chronic fetal suffering due to placental insuf®ciency with premature cesarean delivery (35 weeks) for impairment of heartbeat. Livedo reticularis was present from birth. Psychomotor development was relatively normal even if congenital squint and mild right pyramidal signs (brisk tendon re¯exes, extensor plantar re¯ex) were present. At the age of seven, after an accidental fall from a bicycle that caused head trauma, he presented a transitory loss of consciousness followed by slowed speech, motor activity
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(00)0015 7-1
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
391
Fig. 1. Family pedigree showing: the consanguineity between the parents and a miscarriage; the maternal grandfather (I-3) with livedo reticularis, the father (II1) with reduced arylsulfatase A activity, and the patient (III-1) with Sneddon syndrome and reduced arylsulfatase A activity.
and swallowing and VII right cranial nerve paresis. Steroid therapy led to clinical improvement. Epileptic seizures never occurred. The ®rst brain MR in PD and T2 weighted images, performed four days after trauma for the neurologic symptoms, showed diffuse white matter hyperintensity also localized over the pons and basal ganglia (Fig. 2). Other cerebral MR scans repeated during the follow-up and examined by the same neuroradiologist were unchanged. On our ®rst observation at the age of nine years, neurological examination showed livedo reticularis, squint, hypotonia, pyramidal signs in the right arm and lower limbs; blood pressure was normal; intelligence quotient score was 83 (borderline). During the follow-up this picture remained unchanged. All laboratory investigations were negative: metabolic (amino acids; organic acids; very long chain fatty acids; beta-hexosaminidase; beta-galactosidase; oligosaccharides; mucopolysaccharides; galactocerebrosidase; adrenal and thyroid functions; basal pyruvic and lactic acids and lactate after muscular standardized effort), genetic (karyotype; chromosome 19 mutation associated with hemiplegic migraine; mtDNA point mutations associated with MELAS, MERRF, NARP); antiphospholipid antibodies, coagulation factors; cerebrospinal ¯uid. Only arylsulfatase A activity was impaired: 40.4 units/mg protein/h (normal values 65±120); genetic DNA study showed that the boy was heterozygous for arylsulfatase A pseudode®ciency; no metachromatic leukodystrophy mutations 459 1 1G (A)
and P426L were found. EEG showed slowing of background activity and multifocal paroxysmal abnormalities. Brainstem and visual evoked potentials were delayed. ECG and echocardiography were normal. Skin biopsy with electron microscopy showed focal vascular lesions of the terminal small arteries (Fig. 3). Muscle biopsy revealed mild aspeci®c changes. The parents underwent tests for arylsulfatase A activity, antiphospholipid antibodies, coagulation factors and cerebral MR: all investigations were normal except reduced arylsulfatase A activity in the father (21.1 units/mg protein/h). 3. Discussion Sneddon syndrome is dif®cult to diagnose because the clinical picture may appear to be restricted to livedo reticularis at onset and during evolution. For this reason, Sneddon syndrome may be underestimated. The symptomatology and age at onset are also extremely variable [3,5,6]. In our case Sneddon syndrome was diagnosed for several reasons: 1. presence of skin livedo reticularis; 2. typical skin biopsy for focal vascular lesions documented by electron microscopy;
392
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
Fig. 2. Axial T2 weighted MR image of the patient showing a diffuse and inhomogeneous hyperintensity of the centra semiovale white matter.
3. clinical picture: in particular the episode happened at seven years of age probably compatible with an ischemic attack, because there was a complex neurologic symptomatology which slowly improved as in cerebrovascular accidents; borderline intelligence quotient; non progressive neurological signs lasting after the acute event; 4. at the end of the follow-up, our patient did not present a progressive evolution of the clinical and brain imaging picture, as happens in cases of Sneddon syndrome without recurrent cerebrovascular attacks. All these data, particularly the non progressive course, are incompatible with the diagnosis of `leukoencephalopathy with vanishing white matter', even if brain imaging ®ndings may overlap those of our patient [11], and in general other metabolic conditions. On the other hand, MR images in our case showed a picture not fully compatible with literature reports of Sneddon syndrome [10]. These brain imaging data prompted us to perform the numerous investigations reported that were all negative except for arylsulfatase A activity. The reduction of arylsulfatase A activity, known as arylsulfatase A pseudode®ciency, can occur in healthy indivi-
duals, but it has also been described in association with non progressive neurologic/psychiatric diseases in single cases [12] and in samples of selected patients [13]. Residual arylsulfatase A activity in subjects with arylsulfatase A pseudode®ciency is apparently suf®cient to prevent sulfatide storage in oligodendrocyte and Schwann cell lysosomals disrupting myelin metabolism, typical of metachromatic leukodystrophy. However, literature reports described only two adults with arylsulfatase A pseudode®ciency who presented a delayed posthypoxic demyelination: the authors suggested that arylsulfatase A pseudode®ciency might be implicated in the pathogenesis of this rare complication of hypoxic brain injury [14,15]. Our patient presented pre-perinatal distress compatible with early hypoxic insult and at seven years an episode which may have been an ischemic attack. Similarly to the cases described by Weinberger et al. and Gottfried et al. [14,15], we speculate that in our patient pre-perinatal hypoxia and Sneddon syndrome, whose ischemic lesions are described as a result of progressive vascular occlusion, in conjunction with the arylsulfatase A pseudode®ciency contributed to produce widespread involvement of cerebral white matter similar to delayed posthypoxic demyelination.
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
393
Fig. 3. Electron microscopy showing an intradermic capillary with hypertrophied endothelial cells occluding the vessel lumen; the surrounding basal lamina appears thickened and reduplicated. A pericapillary lymphoid in®ltrate is seen around the microvascular structure. TEM £ 11.500.
Acknowledgements The authors wish to thank Mr Massimo Armaroli, Ms Elena Zoni and Ms Sabrina FarneÁ for technical assistance and Ms Anne Collins for linguistic revision. References [1] Sneddon IB. Cerebrovascular lesions and livedo reticularis. Br J Dermatol 1965;77:180±185. [2] Sepp N, Zelger B, Schuler G, Romani N, Fritsch P. Sneddon's syndrome-an in¯ammatory disorder of small arteries followed by smooth muscle proliferation. Immunohistochemical and ultrastructural evidence. Am J Surg Pathol 1995;19:448±453. [3] Rebollo M, Val JF, Garijo F, Quintana F, Berciano J. Livedo reticularis and cerebrovascular lesions (Sneddon's syndrome). Clinical, radiological and pathological features in eight cases. Brain 1983;106:965±979. [4] Martinelli A, Martinelli P, Ippoliti M, Giuliani S, Coccagna G. Sneddon syndrome presenting with hemicranic attacks: a case report. Acta Neurol Scand 1991;83:201±203. [5] Weissenborn K, RuÈckert N, Ehrenheim C, Schellong S, Goetz C, Lubach D. Neuropsychological de®cits in patients with Sneddon's syndrome. J Neurol 1996;243:357±363. [6] Wheeler PG, Medina S, Dusick A, Bull MJ, Andreoli SP, EdwardsBrown M, et al. Livedo reticularis, developmental delay and strokelike episode in a 7-year-old male. Clin Dysmorphol 1998;7:69±74.
[7] Rehany U, Kassif Y, Rumelt S. Sneddon's syndrome: neuro-ophthalmologic manifestations in a possible autosomal recessive pattern. Neurology 1998;51:1185±1187. [8] Lousa M, Sastre JL, Cancelas JA, Gobernado JM, Pardo A. Study of antiphospholipid antibodies in patient with Sneddon's syndrome and her family. Stroke 1994;25:1071±1074. [9] Gilmore HE, Yunis J, Steele D, Naeem R. Sneddon syndrome and factor V Leiden mutation. Brain Dev 1998;20:472. [10] Tourbah A, Piette JC, Iba-Zizen MT, Lyon-Caen O, Godeau P, FranceÁs C. The natural course of cerebral lesions in Sneddon syndrome. Arch Neurol 1997;54:53±60. [11] Van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998;51:540±547. [12] Hohenschutz C, Friedl W, SchloÈr KH, Waheed A, Conzelmann E, Sandhoff K, et al. Probable metachromatic leukodystrophy/pseudode®ciency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology. Am J Med Genet 1988;31:169±175. [13] Sangiorgi S, Ferlini A, Zanetti A, Mochi M. Reduced activity of arylsulfatase A and predisposition to neurological disorders: analysis of 140 pediatric patients. Am J Med Genet 1991;40:365±369. [14] Weinberger LM, Schmidley JW, Schafer IA, Raghavan S. Delayed postanoxic demyelination and arylsulfatase-A pseudode®ciency. Neurology 1994;44:152±154. [15] Gottfried JA, Mayer SA, Shungu DC, Chang Y, Duyn JH. Delayed posthypoxic demyelination. Association with arylsulfatase A de®ciency and lactic acidosis on proton MR spectroscopy. Neurology 1997;49:1400±1404.
www.elsevier.com/locate/braindev
Case report
Sneddon syndrome, arylsulfatase A pseudode®ciency and impairment of cerebral white matter Antonia Parmeggiani a,*, Annio Posar a, Lucilla Badiali De Giorgi b, Simonetta Sangiorgi c, Mirella Mochi c, Lucia Monari c, Annalisa Patrizi d, Paola Giovanardi Rossi a a
Department of Child Neurology and Psychiatry, Neurological Institute, University of Bologna, via Ugo Foscolo 7, 40123 Bologna, Italy b Service of Cytopathology, S. Orsola-Malpighi Hospital, Bologna, Italy c Neurological Institute, University of Bologna, Bologna, Italy d Department of Dermatology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy Received 10 September 1999; received in revised form 14 March 2000; accepted 24 June 2000
Abstract We describe a 11 year-old-boy with Sneddon syndrome, con®rmed by skin biopsy, and MR evidence of diffuse cerebral hyperintensity of white matter; he also suffered from pre-perinatal hypoxic-ischemic distress. Arylsulfatase A activity was found reduced because of arylsulfatase A pseudode®ciency. We suggest that the association of pre-perinatal distress, Sneddon syndrome and arylsulfatase A pseudode®ciency is responsible for the diffuse impairment of cerebral white matter, never reported in Sneddon syndrome and similar to described cases of delayed posthypoxic demyelination and arylsulfatase A pseudode®ciency. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Sneddon syndrome; Arylsulfatase A pseudode®ciency; Delayed posthypoxic demyelination; Hypoxia; Cerebral white matter; Brain imaging
1. Introduction Sneddon syndrome, ®rst described in 1965, is characterized by idiopathic livedo reticularis and cerebrovascular lesions [1]. The pathogenesis of the syndrome is poorly understood. However, in patients with Sneddon syndrome small to medium-sized vessels of the dermis-subcutis boundary present a progressive occlusion that probably starts as an in¯ammatory/immunologically mediated disorder developing in four stages [2]. Other clinical signs described in Sneddon syndrome are epileptic seizures, migraine, progressive dementia, neuropsychological de®cits, hypertension, heart valvulopathy, acroerythrocyanosis and Raynaud's phenomenon [3±5]. Women are more frequently affected, often with a history of miscarriages [5]. The age at onset is extremely variable: generally Sneddon syndrome develops in adulthood but rare cases have been reported in childhood [3,6]. Familial cases have been described with both autosomal dominant and recessive inheritance [3,7]. Sometimes, antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) are associated with Sneddon syndrome, implying that Sneddon syndrome might be * Corresponding author. Tel.: 139-051-585158; fax: 139-051-333725. E-mail address: [email protected] (A. Parmeggiani).
strictly related to the primary antiphospholipid antibody syndrome [8]. Abnormalities of coagulation have also been described [9], but the physiopathogenetic role of these data remains unknown. We describe a child with Sneddon syndrome and arylsulfatase A pseudode®ciency who presented a peculiar diffuse impairment of cerebral white matter more extensively than that reported for typical ischemic lesions in Sneddon syndrome [10]. 2. Case report A 11 year-old-boy had a family history positive for livedo reticularis, he is an only child, his parents were consanguineous and the mother had had a miscarriage (Fig. 1). Preperinatal hypoxic-ischemic distress was reported consisting of chronic fetal suffering due to placental insuf®ciency with premature cesarean delivery (35 weeks) for impairment of heartbeat. Livedo reticularis was present from birth. Psychomotor development was relatively normal even if congenital squint and mild right pyramidal signs (brisk tendon re¯exes, extensor plantar re¯ex) were present. At the age of seven, after an accidental fall from a bicycle that caused head trauma, he presented a transitory loss of consciousness followed by slowed speech, motor activity
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(00)0015 7-1
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
391
Fig. 1. Family pedigree showing: the consanguineity between the parents and a miscarriage; the maternal grandfather (I-3) with livedo reticularis, the father (II1) with reduced arylsulfatase A activity, and the patient (III-1) with Sneddon syndrome and reduced arylsulfatase A activity.
and swallowing and VII right cranial nerve paresis. Steroid therapy led to clinical improvement. Epileptic seizures never occurred. The ®rst brain MR in PD and T2 weighted images, performed four days after trauma for the neurologic symptoms, showed diffuse white matter hyperintensity also localized over the pons and basal ganglia (Fig. 2). Other cerebral MR scans repeated during the follow-up and examined by the same neuroradiologist were unchanged. On our ®rst observation at the age of nine years, neurological examination showed livedo reticularis, squint, hypotonia, pyramidal signs in the right arm and lower limbs; blood pressure was normal; intelligence quotient score was 83 (borderline). During the follow-up this picture remained unchanged. All laboratory investigations were negative: metabolic (amino acids; organic acids; very long chain fatty acids; beta-hexosaminidase; beta-galactosidase; oligosaccharides; mucopolysaccharides; galactocerebrosidase; adrenal and thyroid functions; basal pyruvic and lactic acids and lactate after muscular standardized effort), genetic (karyotype; chromosome 19 mutation associated with hemiplegic migraine; mtDNA point mutations associated with MELAS, MERRF, NARP); antiphospholipid antibodies, coagulation factors; cerebrospinal ¯uid. Only arylsulfatase A activity was impaired: 40.4 units/mg protein/h (normal values 65±120); genetic DNA study showed that the boy was heterozygous for arylsulfatase A pseudode®ciency; no metachromatic leukodystrophy mutations 459 1 1G (A)
and P426L were found. EEG showed slowing of background activity and multifocal paroxysmal abnormalities. Brainstem and visual evoked potentials were delayed. ECG and echocardiography were normal. Skin biopsy with electron microscopy showed focal vascular lesions of the terminal small arteries (Fig. 3). Muscle biopsy revealed mild aspeci®c changes. The parents underwent tests for arylsulfatase A activity, antiphospholipid antibodies, coagulation factors and cerebral MR: all investigations were normal except reduced arylsulfatase A activity in the father (21.1 units/mg protein/h). 3. Discussion Sneddon syndrome is dif®cult to diagnose because the clinical picture may appear to be restricted to livedo reticularis at onset and during evolution. For this reason, Sneddon syndrome may be underestimated. The symptomatology and age at onset are also extremely variable [3,5,6]. In our case Sneddon syndrome was diagnosed for several reasons: 1. presence of skin livedo reticularis; 2. typical skin biopsy for focal vascular lesions documented by electron microscopy;
392
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
Fig. 2. Axial T2 weighted MR image of the patient showing a diffuse and inhomogeneous hyperintensity of the centra semiovale white matter.
3. clinical picture: in particular the episode happened at seven years of age probably compatible with an ischemic attack, because there was a complex neurologic symptomatology which slowly improved as in cerebrovascular accidents; borderline intelligence quotient; non progressive neurological signs lasting after the acute event; 4. at the end of the follow-up, our patient did not present a progressive evolution of the clinical and brain imaging picture, as happens in cases of Sneddon syndrome without recurrent cerebrovascular attacks. All these data, particularly the non progressive course, are incompatible with the diagnosis of `leukoencephalopathy with vanishing white matter', even if brain imaging ®ndings may overlap those of our patient [11], and in general other metabolic conditions. On the other hand, MR images in our case showed a picture not fully compatible with literature reports of Sneddon syndrome [10]. These brain imaging data prompted us to perform the numerous investigations reported that were all negative except for arylsulfatase A activity. The reduction of arylsulfatase A activity, known as arylsulfatase A pseudode®ciency, can occur in healthy indivi-
duals, but it has also been described in association with non progressive neurologic/psychiatric diseases in single cases [12] and in samples of selected patients [13]. Residual arylsulfatase A activity in subjects with arylsulfatase A pseudode®ciency is apparently suf®cient to prevent sulfatide storage in oligodendrocyte and Schwann cell lysosomals disrupting myelin metabolism, typical of metachromatic leukodystrophy. However, literature reports described only two adults with arylsulfatase A pseudode®ciency who presented a delayed posthypoxic demyelination: the authors suggested that arylsulfatase A pseudode®ciency might be implicated in the pathogenesis of this rare complication of hypoxic brain injury [14,15]. Our patient presented pre-perinatal distress compatible with early hypoxic insult and at seven years an episode which may have been an ischemic attack. Similarly to the cases described by Weinberger et al. and Gottfried et al. [14,15], we speculate that in our patient pre-perinatal hypoxia and Sneddon syndrome, whose ischemic lesions are described as a result of progressive vascular occlusion, in conjunction with the arylsulfatase A pseudode®ciency contributed to produce widespread involvement of cerebral white matter similar to delayed posthypoxic demyelination.
A. Parmeggiani et al. / Brain & Development 22 (2000) 390±393
393
Fig. 3. Electron microscopy showing an intradermic capillary with hypertrophied endothelial cells occluding the vessel lumen; the surrounding basal lamina appears thickened and reduplicated. A pericapillary lymphoid in®ltrate is seen around the microvascular structure. TEM £ 11.500.
Acknowledgements The authors wish to thank Mr Massimo Armaroli, Ms Elena Zoni and Ms Sabrina FarneÁ for technical assistance and Ms Anne Collins for linguistic revision. References [1] Sneddon IB. Cerebrovascular lesions and livedo reticularis. Br J Dermatol 1965;77:180±185. [2] Sepp N, Zelger B, Schuler G, Romani N, Fritsch P. Sneddon's syndrome-an in¯ammatory disorder of small arteries followed by smooth muscle proliferation. Immunohistochemical and ultrastructural evidence. Am J Surg Pathol 1995;19:448±453. [3] Rebollo M, Val JF, Garijo F, Quintana F, Berciano J. Livedo reticularis and cerebrovascular lesions (Sneddon's syndrome). Clinical, radiological and pathological features in eight cases. Brain 1983;106:965±979. [4] Martinelli A, Martinelli P, Ippoliti M, Giuliani S, Coccagna G. Sneddon syndrome presenting with hemicranic attacks: a case report. Acta Neurol Scand 1991;83:201±203. [5] Weissenborn K, RuÈckert N, Ehrenheim C, Schellong S, Goetz C, Lubach D. Neuropsychological de®cits in patients with Sneddon's syndrome. J Neurol 1996;243:357±363. [6] Wheeler PG, Medina S, Dusick A, Bull MJ, Andreoli SP, EdwardsBrown M, et al. Livedo reticularis, developmental delay and strokelike episode in a 7-year-old male. Clin Dysmorphol 1998;7:69±74.
[7] Rehany U, Kassif Y, Rumelt S. Sneddon's syndrome: neuro-ophthalmologic manifestations in a possible autosomal recessive pattern. Neurology 1998;51:1185±1187. [8] Lousa M, Sastre JL, Cancelas JA, Gobernado JM, Pardo A. Study of antiphospholipid antibodies in patient with Sneddon's syndrome and her family. Stroke 1994;25:1071±1074. [9] Gilmore HE, Yunis J, Steele D, Naeem R. Sneddon syndrome and factor V Leiden mutation. Brain Dev 1998;20:472. [10] Tourbah A, Piette JC, Iba-Zizen MT, Lyon-Caen O, Godeau P, FranceÁs C. The natural course of cerebral lesions in Sneddon syndrome. Arch Neurol 1997;54:53±60. [11] Van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998;51:540±547. [12] Hohenschutz C, Friedl W, SchloÈr KH, Waheed A, Conzelmann E, Sandhoff K, et al. Probable metachromatic leukodystrophy/pseudode®ciency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology. Am J Med Genet 1988;31:169±175. [13] Sangiorgi S, Ferlini A, Zanetti A, Mochi M. Reduced activity of arylsulfatase A and predisposition to neurological disorders: analysis of 140 pediatric patients. Am J Med Genet 1991;40:365±369. [14] Weinberger LM, Schmidley JW, Schafer IA, Raghavan S. Delayed postanoxic demyelination and arylsulfatase-A pseudode®ciency. Neurology 1994;44:152±154. [15] Gottfried JA, Mayer SA, Shungu DC, Chang Y, Duyn JH. Delayed posthypoxic demyelination. Association with arylsulfatase A de®ciency and lactic acidosis on proton MR spectroscopy. Neurology 1997;49:1400±1404.