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MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome
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MR Findings and Neurologic Manifestations in Lowe Oculocerebrorenal Syndrome Jiro Ono, MD**, Koushi Harada, MD*, Toshiyuki Mano, MD*, Takehisa Yamamoto, MD*, and Shintaro Okada, MD* Two patients with oculocerebrorenal syndrome are described. Both had abnormal findings on electroencephalography and developed seizure episodes. Although Patient 2 manifested abnormal electroencephalographic findings at the age of 6 years, he did not develop seizures until the age of 9 years. Phenytoin was effective for controlling seizures in both patients. On magnetic resonance examination, there were two different types of lesions. The first lesion manifested high intensity on both T 2- and proton density-weighted images, suggesting gliosis or demyelination. The second lesion manifested definitely low signals on both T r and proton density-weighted images, implying a cystic lesion. However, these lesions on magnetic resonance examination were not correlated with the severity of clinical manifestations.
MacLachan, who described the triad of congenital cataracts, mental retardation, and generalized a m i n o aciduria [I]. O C R L has been c o n v i n c i n g l y demonstrated to be an X-linked recessive disorder p r e d o m i n a n t l y affecting males [2]. The c h r o m o s o m a l location of the O C R L gene, Xq2426, was determined with the use of restriction e n z y m e fragment length p o l y m o r p h i s m (RFLP). Hodgson et al. described a girl with O C R L and an X;3 balanced transitcation, whose break point was at Xq25, suggesting additional evidence of c h r o m o s o m a l location [3]. In 1992, the O C R L gene, encoding a protein highly h o m o l o g o u s to inositol polyphosphate-5-phosphatase, was isolated [4]. Since O ' T a u m a et al. [5] described the first magnetic resonance (MR) findings in an O C R L patient (i.e., high signal intensity in periventricular white matter on T 2weighted images), several recent case reports have described similar diffuse, confluent white matter hyperintensities in O C R L patients [6-9]. Carroll et al. [6] and Demmer et al. [8] reported another white matter abnormality, which is punctate and has signal characteristics that parallel those of cerebrospinal fluid. In our study, two Japanese boys with O C R L are described and their M R and neurologic findings are presented.
Case Reports
L o w e oculocerebrorenal s y n d r o m e ( O C R L ) was initially recognized in 1952 by Lowe, Terrey, and
Patient 1. A 16-year-old Japanese boy was born weighing 2,600 gm alter a 41-week gestation. During the first 3 months of life, he developed bilateral cataracts, proteinuria, hypotonia, and motor developmental delay and a diagnosis of OCRL was made. When he was admitted to our hospital at the age of 1 year, acidosis, glucosuria, and rickets were also observed. Impairment of the proximal renal tubule was suspected. Complex partial seizures, consisting of staring, facial cyanosis, and nausea, started at the age of 13 years and were almost completely controlled with phenytoin. Electroencephalography was not performed before the first episode of his seizures. Physical examination disclosed marked motor and mental developmental delay and growth retardation. His height was 133.7 cm (-6.3 S.D.) and weight 34.9 kg (-2.9 S.D.). He also had small. deep-set eyes, frontal bossing, self-injurious behavior, and stereotypic hand waving between the eye and a light source. Electroencephalography demonstrated independent, irregular spike-and-wave foci on left midtemporal and right temporal areas. The basic rhythm was irregular and poorly recognized. MR examination was performed at the age of 15 years, using a 1.5 T superconducting magnet (Siemens MAGNETOM) with an imaging matrix of 192 x 256. T~-weighted (TR: 660 ms. TE: 15 ms), Te-weighted (TR: 2,500 ms, TE: 90 ms), and proton density-weighted (TR: 2,500 ms, TE: 15 ms) images were obtained in the axial and sagittal multislice plane. He manifested bilateral confluent high intensity lesions both on T:- and proton density-weighted images, which were of relatively low intensity on T~-weighted images (Fig 1). There were other
From the *Department of Pediatrics; Faculty of Medicine; Osaka University; Suita, Osaka; *Division of Pediatrics; Toyonaka Municipal Hospital; Toyonaka, Osaka; *Division of Radiology; Kaizuka Municipal Hospital; Kaizuka, Osaka, Japan.
Communications should be addressed to: Dr. Ono; Division of Pediatrics; Toyonaka Municipal Hospital; Okakaminocho 2-1-1, Toyonaka; Osaka 560, Japan. Received October 3, 1995; accepted December 11, 1995.
O n o J, Harada K, M a n o T, Y a m a m o t o T, Okada S. M R findings and neurologic manifestations in L o w e oculocerebrorenal syndrome. Pediatr Neurol 1996;14:162-164.
Introduction
162 PEDIATRIC NEUROLOGY Vol. 14 No. 2
© 1996 by Elsevier Science Inc. All rights reserved. PII S0887-8994(96)0009-1 0887-8994/96/$15.00
initiated, the brief tonic seizures and generalized tonic convulsions disappeared and complex partial seizures decreased in frequency. Cranial MR examination, performed at the age of 8 years using the same instrument and sequences as for Patient 1, disclosed dilated lateral ventricles and multiple, bilateral, well-defined bright spots on T 2- and proton density-weighted images (Fig 2). There were also different lesions with definite low intensity on T t- and proton density-weighted images. The high intensity region on T~-weighted image, which was expected to appear at the posterior lobe of the pituitary gland, was not observed (data not displayed). This suggests that our patient's diabetes insipidus was the result of lowered secretion of antidiuretic hormone.
Discussion Inositol 1,4,5-triphosphate is a second messenger which regulates intracellular calcium levels [10]. This signaling molecule is formed directly or indirectly by the action of phosphatidylinositol-specific phospholipase C and inactivated by inositol polyphosphate-5-phosphatase (5phosphatase). A cDNA encoding human platelet 5-phosphatase has been isolated and cloned by Ross et al. [11]. Attree et al. [4] demonstrated that the OCRL gene encodes
Figure I. MR images of Patient 1. (a,b) Tz-weighted images (TR: 660 ms, TE: 15 ms); (c,d) T2-weighted images (TR: 2,500 ms, TE: 90 ms); (e,f) proton density-weighted images (TR: 2,500 ms, TE: 15 ms). Several confluent high intensity lesions on T2-weighted images are observed in the deep white matter, especially the posterior lobes (black arrowheads). These lesions are relatively high intensity on proton density-weighted images and relatively low on Tz-weighted images (white arrows on black arrowheads). In the deep white matter of the right frontal lobe, a low intensity lesion on T 1- and proton density-weighted images is also observed (black arrows). This lesion displays extremely high intensity on the Te-weighted image (black arrows). On proton density-weighted images this low intensit3, lesion is partly surrounded by a high intensity lesion.
lesions which were of high intensity on T2-weighted and definite low intensity on T~- and proton density-weighted images. Patient 2. A 9-year-old Japanese boy was referred to our hospital at the age of 6 months because of severely delayed motor development and hypotonia. He was born after a 33-week gestation with a birth weight of 2,512 gm. After birth, poor feeding, hypotonia, and decreased spontaneous movements were observed. Bilateral cataracts had been removed surgically at day 12. He manifested hypophosphatemia (2.4 mg/dl), lowered tubular reabsorption of phosphorus (%TRP) (69.9%), proteinuria, and generalized amino aciduria, in addition to hypotonia and severe mental and motor developmental delay. A diagnosis of OCRL was made. At the age of 9 years, he could not walk alone nor speak a sentence. His height was 95.6 cm (-6.6 S.D.) and weight 15.5 kg (-2.6 S.D.). His developmental quotient score was 14. He also had diabetes insipidus. Electroencephalography, performed at the age of 6 years, revealed bilateral midtemporal irregular slow waves and spike-and-wave complexes, polyspikes in the right midtemporal area spreading into the right hemisphere, and 1-3 Hz diffuse high voltage slow wave bursts. Nevertheless, he did not develop seizures until the age of 9 years, when he manifested brief tonic seizures with head drop which then generalized into tonic convulsions. Seven months later, he developed complex partial seizures, consisting of staring and loss of consciousness. After phenytoin was
Figure 2. MR images of Patient 2. (a,b) Ti-weighted images; (c,d) R-weighted images; (e,f) proton density-weighted images; the sequences are same as in Figure 1. Multiple small high intensity lesions on T2- and proton density-weighted images are observed predominantly in the right deep white matter (black arrowheads). These lesions are isointense to the white matter on Trweighted images. There is a small low intensity lesion adjacent to the lateral ventricle in the right deep white matter on T Iweighted images (white arrow). This lesion displays high intensi~." on T2-weighted images (black arrow). On proton density-weighted images, this low intensity lesion (white arrow) i.s surrounded by a high intensity lesion.
Ono et al: Lowe Oculocerebrorenal Syndrome
163
a protein highly homologous to inositol polyphosphate-5phosphatase and indicated that OCRL might be an inborn error of inositol phosphate metabolism. Clinically, OCRL is characterized by congenital cataracts, muscular hypotonia, mental retardation, and generalized aminoaciduria. Neurologic complications include cognitive impairment, behavioral disturbances, hypotonia with motor milestone delay, areflexia, and seizures [6,12]. Two Japanese boys with OCRL, who demonstrated these manifestations, are described above. In a survey of 54 patients with OCRL, Charnas [13] found 18 patients with a clinical history of seizures. Several seizure types occurred, including infantile spasms, staring spells, and mixed staring and generalized tonicclonic seizures. Generalized tonic-clonic seizures were the most common type. Although Patient 1 manifested only complex partial seizures, Patient 2 demonstrated a variety of seizures, brief tonic seizures, generalized tonic convulsions, and complex partial seizures. In our experience, phenytoin was effective in both patients. Bromfield et al. [14] performed electroencephalography on 17 patients and found abnormalities in 9 patients, 8 of whom had clinical seizures. A markedly abnormal electroencephalogram with epileptiform spikes or disorganization was observed only in those patients with a history of seizures. Although Patient 2 had definite abnormal findings on EEG at the age of 6 years, he did not manifest any seizure episodes until the age of 9 years. OCRL patients with abnormal EEG findings should be followed for evidence of seizures. New insight into the variability and significance of the neurologic findings in OCRL has been obtained through the use of MR imaging. O'Tauma et al. [5] reported the first MR findings in an OCRL patient: high signal intensity in the periventricular white matter on To-weighted images. Two unrelated, severely retarded OCRL patients were also reported to manifest severe, diffuse white matter changes on MR [7]. Subsequent study of several OCRL patients with MR has demonstrated marked heterogeneity in the white matter changes, ranging from diffuse highintensity signal to no demonstrable changes. Demmer et al. [8] reported striking cystic changes in the periventricular white matter, with clearly low signals on proton density- and Tl-weighted images. Cystic changes in the white matter are nonspecific and may occur in a variety of disorders including infarction with resultant encephalomalacia, multicystic encephalomalacia, and periventricular leukomalacia. Carroll et al. [6] also found similar lesions and speculated that the smaller punctate lesions represent focal areas of encephalomalacia and the confluent hyperintense white matter lesions represent focal areas of gliosis or demyelination. Our 2 patients also manifested these two different types of lesions. However, Patient 1 demonstrated larger diffuse confluent white matter lesions compared to those of Patient 2. In our patients, the cystic lesions were not as remarkable as those of Demmer et al. and Carroll et al.
164
PEDIATRIC NEUROLOGY
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How are these abnormal MR changes related to pathology? Pathologic findings of the brain have been reported in 21 patients with OCRL, but no consistent neuropathologic findings have emerged. The most intriguing findings were slight myelin pallor, either diffuse or focal, in 7 patients, without evidence of myelin breakdown; gliosis, reported as increased numbers of glial nuclei; and impaired maturation of myelination [12]. Matin and Schlote [15] concluded that, at least in older children, the myelin pallor corresponded to gliosis. The accumulation of detailed information concerning these lesions by MR imaging and histologic findings may provide clues for clarifying the relationship between these lesions and underlying inborn metabolic disorders.
The authors thank Philip D. Walson, MD, Children's Hospital, Columbus, Ohio, for his helpful suggestions; Kosuke Sakurai, MD, Department of Radiology, Faculty of Medicine, Osaka University, for his skillful suggestions; and Noriko Kawanishi for secretarial assistance.
References
[1] Lowe CU, Terrey M, MacLachan EA. Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: A clinical entity. Am J Dis Child 1952;83:164-84. [21 Richards W, Donnell GN, Wilson WA, Stowens D, Perry T. The oculo-cerebro-renal syndrome of Lowe. Am J Dis Child 1965;109:185203. [3] llndgson SV, Heckmatt JZ, Hughes E, Crolla JA, Dubowitz V, Bobrow M. A balanced de novo X/autosome translocation in a girl with manifestations of Lowe syndrome. Am J Med Genet 1986;23:837-47. [4] Attree O, Olivos IM, Okabe I, et al. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 1992;358:239-42. [5] O'Tauma DA, Lasker DW. Oculocerebrorenal syndrome: Case report with CT and MR correlates. AJNR 1987;8:555-7. [6] Carroll WJ, Woodruff WW, Cadman TE. MR findings in oculocerebrorenal syndrome. AJNR 1993;14:449-51. [7] Charnas L, Bernar J, Pezeshkpour GH, Dalakas M, Harper GS, Gahl WA. MRI findings and peripheral neuropathy in Lowe's syndrome. Neuropediatrics 1988;19:7-9. [8] Demmer LA, Wippold FJ, Dowton SB. Periventricutar white matter cystic lesions in Lowe (oculocerebrorenal) syndrome: A new MR finding. Pediatr Radiol 1992;22:76-7. [9] Gabrielli O, Salvolini U, Coppa GV, et al. Magnetic resonance imaging in the malformative syndromes with mental retardation. Pediatr Neuro! 1990;21 : 16-9. [10l Berridge M J, lrvine RF. lnositol phosphates and cell signaling. Nature 1989;341 : 197-204. [ll] Ross TS, Jefferson AB, Mitchell CA, Majerus PW. Cloning and expression of human 75-kDa inositol polyphosphate-5-phosphatase. J Biol Chem 1991;266:20283-9. [12] Charnas LR, Gahl WA. The oculocerebrorenal syndrome of Lowe. Adv Pediatr 1991;38:75-107. [13] Charnas L. Seizures in the oculocerebrorenal syndrome of Lowe, Neurology 1989;39(suppl):276. [14] Bromfield EB, Sato S, Charnas L, Balish M, Gahl WA. EEG findings in the oculocerebrorenal syndrome of Lowe. Neurology 1989;39(suppl):221. [15] Matin J J, Schlote W. Central nervous system lesions in disorders of amino acid metabolism: A neuropathologic study. J Neurol Sci 1972;15:49-76.
MR Findings and Neurologic Manifestations in Lowe Oculocerebrorenal Syndrome Jiro Ono, MD**, Koushi Harada, MD*, Toshiyuki Mano, MD*, Takehisa Yamamoto, MD*, and Shintaro Okada, MD* Two patients with oculocerebrorenal syndrome are described. Both had abnormal findings on electroencephalography and developed seizure episodes. Although Patient 2 manifested abnormal electroencephalographic findings at the age of 6 years, he did not develop seizures until the age of 9 years. Phenytoin was effective for controlling seizures in both patients. On magnetic resonance examination, there were two different types of lesions. The first lesion manifested high intensity on both T 2- and proton density-weighted images, suggesting gliosis or demyelination. The second lesion manifested definitely low signals on both T r and proton density-weighted images, implying a cystic lesion. However, these lesions on magnetic resonance examination were not correlated with the severity of clinical manifestations.
MacLachan, who described the triad of congenital cataracts, mental retardation, and generalized a m i n o aciduria [I]. O C R L has been c o n v i n c i n g l y demonstrated to be an X-linked recessive disorder p r e d o m i n a n t l y affecting males [2]. The c h r o m o s o m a l location of the O C R L gene, Xq2426, was determined with the use of restriction e n z y m e fragment length p o l y m o r p h i s m (RFLP). Hodgson et al. described a girl with O C R L and an X;3 balanced transitcation, whose break point was at Xq25, suggesting additional evidence of c h r o m o s o m a l location [3]. In 1992, the O C R L gene, encoding a protein highly h o m o l o g o u s to inositol polyphosphate-5-phosphatase, was isolated [4]. Since O ' T a u m a et al. [5] described the first magnetic resonance (MR) findings in an O C R L patient (i.e., high signal intensity in periventricular white matter on T 2weighted images), several recent case reports have described similar diffuse, confluent white matter hyperintensities in O C R L patients [6-9]. Carroll et al. [6] and Demmer et al. [8] reported another white matter abnormality, which is punctate and has signal characteristics that parallel those of cerebrospinal fluid. In our study, two Japanese boys with O C R L are described and their M R and neurologic findings are presented.
Case Reports
L o w e oculocerebrorenal s y n d r o m e ( O C R L ) was initially recognized in 1952 by Lowe, Terrey, and
Patient 1. A 16-year-old Japanese boy was born weighing 2,600 gm alter a 41-week gestation. During the first 3 months of life, he developed bilateral cataracts, proteinuria, hypotonia, and motor developmental delay and a diagnosis of OCRL was made. When he was admitted to our hospital at the age of 1 year, acidosis, glucosuria, and rickets were also observed. Impairment of the proximal renal tubule was suspected. Complex partial seizures, consisting of staring, facial cyanosis, and nausea, started at the age of 13 years and were almost completely controlled with phenytoin. Electroencephalography was not performed before the first episode of his seizures. Physical examination disclosed marked motor and mental developmental delay and growth retardation. His height was 133.7 cm (-6.3 S.D.) and weight 34.9 kg (-2.9 S.D.). He also had small. deep-set eyes, frontal bossing, self-injurious behavior, and stereotypic hand waving between the eye and a light source. Electroencephalography demonstrated independent, irregular spike-and-wave foci on left midtemporal and right temporal areas. The basic rhythm was irregular and poorly recognized. MR examination was performed at the age of 15 years, using a 1.5 T superconducting magnet (Siemens MAGNETOM) with an imaging matrix of 192 x 256. T~-weighted (TR: 660 ms. TE: 15 ms), Te-weighted (TR: 2,500 ms, TE: 90 ms), and proton density-weighted (TR: 2,500 ms, TE: 15 ms) images were obtained in the axial and sagittal multislice plane. He manifested bilateral confluent high intensity lesions both on T:- and proton density-weighted images, which were of relatively low intensity on T~-weighted images (Fig 1). There were other
From the *Department of Pediatrics; Faculty of Medicine; Osaka University; Suita, Osaka; *Division of Pediatrics; Toyonaka Municipal Hospital; Toyonaka, Osaka; *Division of Radiology; Kaizuka Municipal Hospital; Kaizuka, Osaka, Japan.
Communications should be addressed to: Dr. Ono; Division of Pediatrics; Toyonaka Municipal Hospital; Okakaminocho 2-1-1, Toyonaka; Osaka 560, Japan. Received October 3, 1995; accepted December 11, 1995.
O n o J, Harada K, M a n o T, Y a m a m o t o T, Okada S. M R findings and neurologic manifestations in L o w e oculocerebrorenal syndrome. Pediatr Neurol 1996;14:162-164.
Introduction
162 PEDIATRIC NEUROLOGY Vol. 14 No. 2
© 1996 by Elsevier Science Inc. All rights reserved. PII S0887-8994(96)0009-1 0887-8994/96/$15.00
initiated, the brief tonic seizures and generalized tonic convulsions disappeared and complex partial seizures decreased in frequency. Cranial MR examination, performed at the age of 8 years using the same instrument and sequences as for Patient 1, disclosed dilated lateral ventricles and multiple, bilateral, well-defined bright spots on T 2- and proton density-weighted images (Fig 2). There were also different lesions with definite low intensity on T t- and proton density-weighted images. The high intensity region on T~-weighted image, which was expected to appear at the posterior lobe of the pituitary gland, was not observed (data not displayed). This suggests that our patient's diabetes insipidus was the result of lowered secretion of antidiuretic hormone.
Discussion Inositol 1,4,5-triphosphate is a second messenger which regulates intracellular calcium levels [10]. This signaling molecule is formed directly or indirectly by the action of phosphatidylinositol-specific phospholipase C and inactivated by inositol polyphosphate-5-phosphatase (5phosphatase). A cDNA encoding human platelet 5-phosphatase has been isolated and cloned by Ross et al. [11]. Attree et al. [4] demonstrated that the OCRL gene encodes
Figure I. MR images of Patient 1. (a,b) Tz-weighted images (TR: 660 ms, TE: 15 ms); (c,d) T2-weighted images (TR: 2,500 ms, TE: 90 ms); (e,f) proton density-weighted images (TR: 2,500 ms, TE: 15 ms). Several confluent high intensity lesions on T2-weighted images are observed in the deep white matter, especially the posterior lobes (black arrowheads). These lesions are relatively high intensity on proton density-weighted images and relatively low on Tz-weighted images (white arrows on black arrowheads). In the deep white matter of the right frontal lobe, a low intensity lesion on T 1- and proton density-weighted images is also observed (black arrows). This lesion displays extremely high intensity on the Te-weighted image (black arrows). On proton density-weighted images this low intensit3, lesion is partly surrounded by a high intensity lesion.
lesions which were of high intensity on T2-weighted and definite low intensity on T~- and proton density-weighted images. Patient 2. A 9-year-old Japanese boy was referred to our hospital at the age of 6 months because of severely delayed motor development and hypotonia. He was born after a 33-week gestation with a birth weight of 2,512 gm. After birth, poor feeding, hypotonia, and decreased spontaneous movements were observed. Bilateral cataracts had been removed surgically at day 12. He manifested hypophosphatemia (2.4 mg/dl), lowered tubular reabsorption of phosphorus (%TRP) (69.9%), proteinuria, and generalized amino aciduria, in addition to hypotonia and severe mental and motor developmental delay. A diagnosis of OCRL was made. At the age of 9 years, he could not walk alone nor speak a sentence. His height was 95.6 cm (-6.6 S.D.) and weight 15.5 kg (-2.6 S.D.). His developmental quotient score was 14. He also had diabetes insipidus. Electroencephalography, performed at the age of 6 years, revealed bilateral midtemporal irregular slow waves and spike-and-wave complexes, polyspikes in the right midtemporal area spreading into the right hemisphere, and 1-3 Hz diffuse high voltage slow wave bursts. Nevertheless, he did not develop seizures until the age of 9 years, when he manifested brief tonic seizures with head drop which then generalized into tonic convulsions. Seven months later, he developed complex partial seizures, consisting of staring and loss of consciousness. After phenytoin was
Figure 2. MR images of Patient 2. (a,b) Ti-weighted images; (c,d) R-weighted images; (e,f) proton density-weighted images; the sequences are same as in Figure 1. Multiple small high intensity lesions on T2- and proton density-weighted images are observed predominantly in the right deep white matter (black arrowheads). These lesions are isointense to the white matter on Trweighted images. There is a small low intensity lesion adjacent to the lateral ventricle in the right deep white matter on T Iweighted images (white arrow). This lesion displays high intensi~." on T2-weighted images (black arrow). On proton density-weighted images, this low intensity lesion (white arrow) i.s surrounded by a high intensity lesion.
Ono et al: Lowe Oculocerebrorenal Syndrome
163
a protein highly homologous to inositol polyphosphate-5phosphatase and indicated that OCRL might be an inborn error of inositol phosphate metabolism. Clinically, OCRL is characterized by congenital cataracts, muscular hypotonia, mental retardation, and generalized aminoaciduria. Neurologic complications include cognitive impairment, behavioral disturbances, hypotonia with motor milestone delay, areflexia, and seizures [6,12]. Two Japanese boys with OCRL, who demonstrated these manifestations, are described above. In a survey of 54 patients with OCRL, Charnas [13] found 18 patients with a clinical history of seizures. Several seizure types occurred, including infantile spasms, staring spells, and mixed staring and generalized tonicclonic seizures. Generalized tonic-clonic seizures were the most common type. Although Patient 1 manifested only complex partial seizures, Patient 2 demonstrated a variety of seizures, brief tonic seizures, generalized tonic convulsions, and complex partial seizures. In our experience, phenytoin was effective in both patients. Bromfield et al. [14] performed electroencephalography on 17 patients and found abnormalities in 9 patients, 8 of whom had clinical seizures. A markedly abnormal electroencephalogram with epileptiform spikes or disorganization was observed only in those patients with a history of seizures. Although Patient 2 had definite abnormal findings on EEG at the age of 6 years, he did not manifest any seizure episodes until the age of 9 years. OCRL patients with abnormal EEG findings should be followed for evidence of seizures. New insight into the variability and significance of the neurologic findings in OCRL has been obtained through the use of MR imaging. O'Tauma et al. [5] reported the first MR findings in an OCRL patient: high signal intensity in the periventricular white matter on To-weighted images. Two unrelated, severely retarded OCRL patients were also reported to manifest severe, diffuse white matter changes on MR [7]. Subsequent study of several OCRL patients with MR has demonstrated marked heterogeneity in the white matter changes, ranging from diffuse highintensity signal to no demonstrable changes. Demmer et al. [8] reported striking cystic changes in the periventricular white matter, with clearly low signals on proton density- and Tl-weighted images. Cystic changes in the white matter are nonspecific and may occur in a variety of disorders including infarction with resultant encephalomalacia, multicystic encephalomalacia, and periventricular leukomalacia. Carroll et al. [6] also found similar lesions and speculated that the smaller punctate lesions represent focal areas of encephalomalacia and the confluent hyperintense white matter lesions represent focal areas of gliosis or demyelination. Our 2 patients also manifested these two different types of lesions. However, Patient 1 demonstrated larger diffuse confluent white matter lesions compared to those of Patient 2. In our patients, the cystic lesions were not as remarkable as those of Demmer et al. and Carroll et al.
164
PEDIATRIC NEUROLOGY
Vol. 14 No. 2
How are these abnormal MR changes related to pathology? Pathologic findings of the brain have been reported in 21 patients with OCRL, but no consistent neuropathologic findings have emerged. The most intriguing findings were slight myelin pallor, either diffuse or focal, in 7 patients, without evidence of myelin breakdown; gliosis, reported as increased numbers of glial nuclei; and impaired maturation of myelination [12]. Matin and Schlote [15] concluded that, at least in older children, the myelin pallor corresponded to gliosis. The accumulation of detailed information concerning these lesions by MR imaging and histologic findings may provide clues for clarifying the relationship between these lesions and underlying inborn metabolic disorders.
The authors thank Philip D. Walson, MD, Children's Hospital, Columbus, Ohio, for his helpful suggestions; Kosuke Sakurai, MD, Department of Radiology, Faculty of Medicine, Osaka University, for his skillful suggestions; and Noriko Kawanishi for secretarial assistance.
References
[1] Lowe CU, Terrey M, MacLachan EA. Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: A clinical entity. Am J Dis Child 1952;83:164-84. [21 Richards W, Donnell GN, Wilson WA, Stowens D, Perry T. The oculo-cerebro-renal syndrome of Lowe. Am J Dis Child 1965;109:185203. [3] llndgson SV, Heckmatt JZ, Hughes E, Crolla JA, Dubowitz V, Bobrow M. A balanced de novo X/autosome translocation in a girl with manifestations of Lowe syndrome. Am J Med Genet 1986;23:837-47. [4] Attree O, Olivos IM, Okabe I, et al. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 1992;358:239-42. [5] O'Tauma DA, Lasker DW. Oculocerebrorenal syndrome: Case report with CT and MR correlates. AJNR 1987;8:555-7. [6] Carroll WJ, Woodruff WW, Cadman TE. MR findings in oculocerebrorenal syndrome. AJNR 1993;14:449-51. [7] Charnas L, Bernar J, Pezeshkpour GH, Dalakas M, Harper GS, Gahl WA. MRI findings and peripheral neuropathy in Lowe's syndrome. Neuropediatrics 1988;19:7-9. [8] Demmer LA, Wippold FJ, Dowton SB. Periventricutar white matter cystic lesions in Lowe (oculocerebrorenal) syndrome: A new MR finding. Pediatr Radiol 1992;22:76-7. [9] Gabrielli O, Salvolini U, Coppa GV, et al. Magnetic resonance imaging in the malformative syndromes with mental retardation. Pediatr Neuro! 1990;21 : 16-9. [10l Berridge M J, lrvine RF. lnositol phosphates and cell signaling. Nature 1989;341 : 197-204. [ll] Ross TS, Jefferson AB, Mitchell CA, Majerus PW. Cloning and expression of human 75-kDa inositol polyphosphate-5-phosphatase. J Biol Chem 1991;266:20283-9. [12] Charnas LR, Gahl WA. The oculocerebrorenal syndrome of Lowe. Adv Pediatr 1991;38:75-107. [13] Charnas L. Seizures in the oculocerebrorenal syndrome of Lowe, Neurology 1989;39(suppl):276. [14] Bromfield EB, Sato S, Charnas L, Balish M, Gahl WA. EEG findings in the oculocerebrorenal syndrome of Lowe. Neurology 1989;39(suppl):221. [15] Matin J J, Schlote W. Central nervous system lesions in disorders of amino acid metabolism: A neuropathologic study. J Neurol Sci 1972;15:49-76.