164
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings in Two Siblings By M. G. Harbord, A. Harden, B. Harding, E. M. Brett and M. Baraitser Hospitals for Siek Children, Great Ormond Street, London, Great Britain
Case report
A progressive neurological condition characterised by megalencephaly, spasticity, ataxia and seizures in two siblings of consanguineous parents is described. The electroencephalogram showed posterior discharges and an unusual photoparoxysmal response whereas brainstem auditory evoked potential findings were consistent with a white matter disorder. Computerized tomography scans revealed diffuse hypodensity of the white matter and a brain biopsy on one sibling showed features of dysmyelination without evidence of demyelination, Rosenthai fibres or the spongy changes characteristic of Canavan's disease. There was no detectable biochemical abnormality. This combination of clinical, neurophysiological and neuropathological abnormalities has not previously been described.
Keywords Megalencephaly, spasticity, ataxia and seizures, progressive neurological condition - Distinctive neurophysiological findings
Case 1 The first born child in the family, a girl, was delivered at term following anormal pregnancy, weighing 3.5 kg with no neonataI problems. Her parents, originally from Iraq, were first cousins. The early developmental milestones were normal; she crawled and stood with support at 9 months but her gross motor development then slowed and she did not walk unaided until 30 months. Within a few months, she became unable to walk without support, although she continued to learn new speech skiIls and was successfully toilet trained. At 2 years and 6·months she began to have infrequent generalised tonic clonic seizures lasting up to 15 minutes. These occurred every 4-6 months and were not associated with fever or precipitated by flickering lights. Her parents had noticed that she had a large head size and this had become particularly evident after 6 months of age. On examination at age 4 years and 6 months she was an alert child who spoke in sentences. Her head circumference (58.5 cm) was 6 cm above the 98th centile while her weight was on the 20th centile. There were no dysmorphic features and visuaI acuity, pupil reactions, optic fundi, hearing and craniaI nerves were normal (Fig. 1). Her parents had ,no neuro-
Introductlon The combination of megalencephaly with diffuse white matter hypodensity on brain imaging is seen in few conditions. These include Alexander's disease, Canavan's disease and Gm 1 gangliosidosis (2, 4, 7). Biochemical defects involving aspartoacylase and beta-galactosidase are found in the second and third conditions respectively, while Alexander's disease has characteristic neuropathologicaI features (4). We describe two siblings with no detectable biochemical defect who have a progressive neurological condition characterised by megalencephaly and diffuse white matter hypodensity on computerised tomography (CT). The electroencephalogram (EEG) and neuropathological findings on brain biopsy distinguish this condition from previously recognized conditions with megalencephaly.
Received January 22, 1990; accepted January 24, 1990 Neuropediatrics 21 (1990) 164-168 © Hippokrates Verlag Stuttgart
Fig. 1 (Left to Right) Case 1 at 4 years and Case 2 at 3 years showing distinct macrocephaly.
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Abstract
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings
Neuropediatrics 21 (1990)
165
unaccompanied by any clinical changes. The flash electroretinogram (ERG) and visual evoked potential (VEP) were normal (Fig. 4 a). AgQ 4y
cr
Fig. 2 scan of Case 1 showing diffuse white matter hypodensity and normal lateral ventricles.
logical abnormalities although her father's head circumference was just above the 98th centile (61.5 cm), while her mother's head circumference (54 cm) was on the 30th centile. There was generalised weakness and spasticity of all limbs with hyperreflexia and Babinski responses. She could not walk without support. She also had ataxia when attempting to build a tower of blocks but no demonstrable sensory loss. The remainder of the examination was normal.
Investigations A computerised tomography (CT) head scan (Fig. 2) showed diffuse white matter hypodensity with no evidence of hydrocephalus. Urine screen for metachromatic granules, mucopolysaccharides, amino and organic acids was normal and in particular, there was no elevation of N-acetyl aspartate.
Fig. 3 EEG of older sibling (Case 1) shows discharges over posterior regions occurring spontaneously (upper left trace) and bursts of generalised polyspikes associated with some slow components on eye c10sure (upper right trace). During photic stimulation, spikes are sometimes seen posteriorly in response to a single flash and generalised discharges evoked by flash rates of 6/s (Iower trace).
The plasma very long chain fatty acid C 26 was slightly elevated (0.67 microgmiL N 0.09-0.53), but the C26:C 22 ratio was within normal limits (0.024 N 0.0040.027). Leucocyte enzyme analyses including galactocerebrosidase (Krabbe's disease), hexosaminidase A and B, beta-galactosidase, beta-glucuronidase and I-cell screen were normal. The arylsulphatase A was slightly low (12 nano units N 22-103), but not in the homozygous range for metachromatic leucodystrophy (less than 6). The EEG (Fig. 3) showed a considerable abnormality with some 2-4/sec components especially posteriorly, where there were also frequent spikes and polyspikes occurring intermittently over both hemispheres. In addition, brief generalised paroxysmal bursts of polyspikes mixed with slow waves occurred which were facilitated by eye closure. During photic stimulation, posterior spikes were sometimes enhanced by single flashes of light and the generalised paroxysmal bursts were seen with flash rates as low as 5-6/sec,
Fig. 4 a
SO 100 150 200M Normal flash ERG and VEP findings in older sibling (Case 1).
Downloaded by: Universite Laval. Copyrighted material.
E HELD 5
M. G. Harbord et al
Neuropediatrics 21 (1990)
AgQ 3y
BAEP I1V 4. 84m8
-vtx ] O.2uV +-Ier
v 2
4
6
8
10lls
Fig. 4 b BAEP findings in the younger sibling (Case 2) showing prolonged I-V interval.
Fig. 6 Electron-micrograph from white matter. Note the considerable extracellular space, numerous glial fibres and thin myelin sheaths,
x14000.
Fig. 5 a Brain biopsy, right frontal lobe, showing very thinly myelinated fibres in the rarefied white matter. Luxol-fast blue and cresyl violet, x 300.
were normal in number and appearance. There were scattered hypertrophie astrocytes, and GFAP immunocytochemistry demonstrated a dense fibrillary gliosis. No inflammation, Rosenthai fibres, metachromatic or sudanophilic material were present. Ultrastructural examination (Fig. 6) revealed a greatly increased extracellular space. An occasional degenerating axon was present, but most were normal. Some myelin sheaths were abnormally thin but this myelin was always compact, with no intramyelinic oedema, or lamellar splitting. Numerous astroglial fibres, normal oligodendrocytes, an occasional macrophage containing myelin debris, and hypertrophie astrocytes with copious cytoplasm, numerous organelles and normal mitochondria were also noted. The appearances were not specific but suggested dysmyelination rather than a demyelinating process. Case2
The second child in the family, another girl, was delivered at term following anormal pregnancy. Her birth weight was 3.5 kg and there were no neonatal problems.
Fig. 5 b Dense fibrillary gliosis in the white matter. Immunoperoxidase for glial fibrillary acidic protein, x 300.
At the age of four and a half years, a biopsy of the right frontal lobe was performed. The specimen was divided for histology, histochemistry and electron-microscopy. Light microscopy (Fig.5) disclosed subpial gliosis and slight astrocytosis in the molecular layer but otherwise normal cerebral cortex. The white matter was extremely rarefied, but did not show the spongy vacuolation characteristic of Canavan's disease. With myelin stains the white matter was very pale, but at high power numerous very thin myelin fibres could be seen; axons were plentiful on silver impregnation. Oligodendrocytes
She crawled at 9 months but her later development was slow and by three years of age she could only stand and walk with support. Her parents did not think that she had lost any motor skills. Speech was considered appropriate for her age and she was toilet trained at 2 years and 6 months. Two atonie seizures had occurred at the age of three years unassociated with fever or flickering lights. On examination at 3 years and 5 months, she had very similar clinical features to her older sibling (Fig. 1). Her head circumference (58.0 cm) was 7 cm above the 98th centile while her weight was on the 50th centile. Examination of cranial nerves, visual acuity, hearing, retinal fundi and pupil reactions showed no abnormality. There was generalised weakness of alllimbs with spasticity and hyperreflexia, more prominent in the lower limbs. There were Babinski responses and clonus could be elicited at the left ankle. A spastic gait was apparent when she walked with support. Mild ataxia of the upper limbs was present when building a tower of blocks. There was normal sensation to pin prick and the remainder of the examination showed no abnormality.
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166
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings
Neuropediatrics 21 (1990)
167
Investigations
Fig.7
CT scan of Case 2 showing diffuse white matter hypodensity.
The EEG (Fig. 8) showed infrequent isolated spikes and poly spikes posteriorly, more pronounced over the left hemisphere, while some alpha rhythm was preserved on eye closure. Occasional brief generalised bursts of spikes and polyspikes mixed with slow waves were seen, facilitated by photic stimulation at rates of 12-16/sec, unaccompanied by any clinical change. The brainstem auditory evoked potential (BAEP) (Fig. 4 b) showed a prolonged I-V interval of 4.84 ms, (normal upper limit 4.24 ms) consistent with altered myelination in the brainstem, while the ERG and flash VEP were normal.
Discussion
"ge
3y
E HELD 5
The presence of a progressive neurological condition with similar clinical and neurophysiological features in two siblings whose parents were first cousins suggests that this is an autosomal recessive disorder. Clinically, at presentation, the most likely diagnosis was thought to be Canavan's disease. However, the children had at the ages of 3 and 4 years no clear evidence of cognitive regression, optic atrophy or visual impairment which are typical features of Canavan's disease and had survived longerthan is usual in this condition (2, 9, 13). In addition, there was no evidence of N acetylaspartic acid in the urine which has recently been reported as a biochemical indicator of Canavan 's disease, associated with a defect of aspartoacylase (10). Canavan's disease shows typical spongy changes and ultrastructural findings on brain biopsy which were not present in the children in this report (1, 2). Alexander's disease is also manifest clinically by megalencephaly with seizures and spasticity but has only rarely been reported in siblings and most cases are isolated (3). Brain imaging usually shows a predominantly frontal involvement unlike the diffuse white matter changes seen in the children in this report (12). The neuropathological hallmark of Alexander's disease is the presence of Rosenthai fibres, in addition to demyelination secondary to astrocytic dysfunction (4). No Rosenthai fibres were seen in the brain biopsy of Case 1 and the myelin appearance suggested dysmyelination rather than demyelination.
Fig. 8 EEG of younger sibling (Case 2) often shows isolated asymmetrical discharges posteriorly (upper left trace) but some alpha rhythm is present on eye c10sure (upper right trace). During photic stimulation, generalised spikes/polyspikes and slow waves are seen with flash rates around 14/s (Iower trace).
The only other likely diagnosis is Gm 1 gangliosidosis, which was excluded by normal betagalactosidase levels. Other causes of megalencephaly such as Tay Sachs disease and a leucodystrophy such as Krabbe's disease were also excluded by biochemical analysis and neuropathology. The abnormally low level of arylsulphatase A in our patients is consistent with the multiple allelism described in heterozygotes for metachromatic leucodystrophy (11) and was not considered to be contributing to the clinical condition.
Downloaded by: Universite Laval. Copyrighted material.
A CT head scan (Fig. 7) revealed identical features to her eIder sister, with diffuse white matter hypodensity. Urine amino and organic acids were normal with no elevation of N-acetyl aspartate, while gas chromatography - mass spectrometry of the urine showed no abnormal peaks. There was no evidence of a peroxisomal disorder. Leucocyte enzyme analysis showed that she was also heterozygous for metachromatic leucodystrophy with an arylsulphatase A level of 8 nano units, but no other abnormality.
Neuropediatrics 21 (1990)
The presence of evolving spasticity does not necessarily imply a demyelinating disorder as it can also be found in dysmyelination. One possible cause of dysmyelination which has no detectable biochemical abnormality at present is Pelizaeus-M erzbacher disease, but this condition is usually X-linked and is not associated with megalencephaly. In addition, nystagmus and dystonia are prominent clinical findings, neither of which were present in our two children (5). Dysmyelination has also been reported with phenylketonuria and maple syrup urine disease (6), but both these were excluded by investigations. Similar EEG abnormalities were seen in both siblings, being more marked in the older girl. Prominent discharges and photoparoxysmal responses are very unusual features in white matter disorders and suggest cortical involvement at least posteriorly, where the discharges were most obvious. Furthermore, photoparoxysmal responses especially at relatively slow flash rates are not commonly seen in children under five years of age and the very marked photosensitivity with discharges sometimes elicited by a single flash, seen in the older sibling, is an EEG finding more often associated with myoclonic seizures (14) which did not occur in our patients. In addition, the ERG was normal and the VEP was not enlarged, which contrasts with the findings seen in late infantile Batten's disease (8). Whilst a prolonged I-V interval in the BAEP is highly suggestive of a white matter disorder involving the brainstem and is found in most leucodystrophies, the combination of this finding with the EEG abnormalities seen in these two siblings has not been previously recognised in any of the known neurodegenerative disorders of childhood (8). We consider that these two siblings have an autosomal recessive condition characterised by megalencephaly, spasticity, ataxia, seizures, a photoparoxysmal EEG response and both· neurophysiological (BAEP) and neuropathological findings consistent with dysmyelination. This combination of abnormalities has no recognised biochemical defect and has not previously been reported
M. G. Harbord et al
References 1
Adachi, M., B. Volk: Protraeted form of spongy degeneration of the een-
tral nervous system. Neurology 18 (1968) 1084-1092 Banker, B. Q.,J. T Robertson, M. Victor: Spongy degeneration of the eentral nervous system in infaney. Neurology 14 (1964) 981-1001 3 Baraitser, M.: The Genetics of Neurological Disorders. Oxford, Oxford University Press (1985) 325-353 4 Borrett, D., L. E. Becker: Alexander's disease - a disease of astroeytes. Brain 108 (1985) 367-385 5 Boulloche, J., J. Aicardi: Pelizaeus-Merzbaeher disease: clinieal and nosological study. J. Child. Neurol. 1 (1986) 233-239 6 Brody, B. A., H. C. Kinney, A. S. Kloman, F. H. Gilles: Sequenee of eentral nervous system myelination in human infaney. 1. An autopsy study of myelination. J. Neuropathol. 46 (3) (1987) 283-301 7 Curless, R. G.: Computed tomography of GMI gangliosidosis. J. Pediatr. 105(1984)964-966 8 Harden, A.: Eleetroeneephalography and evoked potentials in ehildren with neurometabolic brain disease. Clin. Neurol. Neurosurg. Supp!. to Vol. 89-2 (1987) 46-51 9 Mahloudji, M., K. Daneshbod, M. Karjoo: Familial spongy degeneration ofthe brain. Areh. Neurol. 22 (1970) 294-298 10 Matalon, R., K. Michals, D. Sebesta, M. Deanching, P. Gashko.fJ,J. Casanova: Aspartoaeylase defieieney and N -aeetylaspartie aeiduria in patients with Canavan disease. Am. J. Med. Genet. 29 (1988) 463-471 11 McKhann, G. M.: Metaehromatie leukodystrophy: clinical and enzymatie parameters. Neuropediatries 15 (suppl) (1984) 4-10 12 Nagao, H., K. Kida, H. Matsuda, T Shishido, K. Matsuoka, 1. Nonaka: Alexander disease: clinieal, eleetrodiagnostie and radiographie studies. Neuropediatries 12 (1981) 22-32 13 Ungar, M., R. M. Goodman: Spongy degeneration of the brain in Israel: a retrospective study. Clin. Genet. 23 (1983) 23-29 14 Wolj; P., R. Goosses: Relation of photosensitivity to epileptie syndromes. J. Neurol. Neurosurg. Psyehiatry49 (1986) 1386-1391 2
Dr. M. Baraitser Department of Clinieal Genetics Hospitals for Siek Children Great Ormond Street London WC1 N3JH, Great Britain
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168
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings in Two Siblings By M. G. Harbord, A. Harden, B. Harding, E. M. Brett and M. Baraitser Hospitals for Siek Children, Great Ormond Street, London, Great Britain
Case report
A progressive neurological condition characterised by megalencephaly, spasticity, ataxia and seizures in two siblings of consanguineous parents is described. The electroencephalogram showed posterior discharges and an unusual photoparoxysmal response whereas brainstem auditory evoked potential findings were consistent with a white matter disorder. Computerized tomography scans revealed diffuse hypodensity of the white matter and a brain biopsy on one sibling showed features of dysmyelination without evidence of demyelination, Rosenthai fibres or the spongy changes characteristic of Canavan's disease. There was no detectable biochemical abnormality. This combination of clinical, neurophysiological and neuropathological abnormalities has not previously been described.
Keywords Megalencephaly, spasticity, ataxia and seizures, progressive neurological condition - Distinctive neurophysiological findings
Case 1 The first born child in the family, a girl, was delivered at term following anormal pregnancy, weighing 3.5 kg with no neonataI problems. Her parents, originally from Iraq, were first cousins. The early developmental milestones were normal; she crawled and stood with support at 9 months but her gross motor development then slowed and she did not walk unaided until 30 months. Within a few months, she became unable to walk without support, although she continued to learn new speech skiIls and was successfully toilet trained. At 2 years and 6·months she began to have infrequent generalised tonic clonic seizures lasting up to 15 minutes. These occurred every 4-6 months and were not associated with fever or precipitated by flickering lights. Her parents had noticed that she had a large head size and this had become particularly evident after 6 months of age. On examination at age 4 years and 6 months she was an alert child who spoke in sentences. Her head circumference (58.5 cm) was 6 cm above the 98th centile while her weight was on the 20th centile. There were no dysmorphic features and visuaI acuity, pupil reactions, optic fundi, hearing and craniaI nerves were normal (Fig. 1). Her parents had ,no neuro-
Introductlon The combination of megalencephaly with diffuse white matter hypodensity on brain imaging is seen in few conditions. These include Alexander's disease, Canavan's disease and Gm 1 gangliosidosis (2, 4, 7). Biochemical defects involving aspartoacylase and beta-galactosidase are found in the second and third conditions respectively, while Alexander's disease has characteristic neuropathologicaI features (4). We describe two siblings with no detectable biochemical defect who have a progressive neurological condition characterised by megalencephaly and diffuse white matter hypodensity on computerised tomography (CT). The electroencephalogram (EEG) and neuropathological findings on brain biopsy distinguish this condition from previously recognized conditions with megalencephaly.
Received January 22, 1990; accepted January 24, 1990 Neuropediatrics 21 (1990) 164-168 © Hippokrates Verlag Stuttgart
Fig. 1 (Left to Right) Case 1 at 4 years and Case 2 at 3 years showing distinct macrocephaly.
Downloaded by: Universite Laval. Copyrighted material.
Abstract
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings
Neuropediatrics 21 (1990)
165
unaccompanied by any clinical changes. The flash electroretinogram (ERG) and visual evoked potential (VEP) were normal (Fig. 4 a). AgQ 4y
cr
Fig. 2 scan of Case 1 showing diffuse white matter hypodensity and normal lateral ventricles.
logical abnormalities although her father's head circumference was just above the 98th centile (61.5 cm), while her mother's head circumference (54 cm) was on the 30th centile. There was generalised weakness and spasticity of all limbs with hyperreflexia and Babinski responses. She could not walk without support. She also had ataxia when attempting to build a tower of blocks but no demonstrable sensory loss. The remainder of the examination was normal.
Investigations A computerised tomography (CT) head scan (Fig. 2) showed diffuse white matter hypodensity with no evidence of hydrocephalus. Urine screen for metachromatic granules, mucopolysaccharides, amino and organic acids was normal and in particular, there was no elevation of N-acetyl aspartate.
Fig. 3 EEG of older sibling (Case 1) shows discharges over posterior regions occurring spontaneously (upper left trace) and bursts of generalised polyspikes associated with some slow components on eye c10sure (upper right trace). During photic stimulation, spikes are sometimes seen posteriorly in response to a single flash and generalised discharges evoked by flash rates of 6/s (Iower trace).
The plasma very long chain fatty acid C 26 was slightly elevated (0.67 microgmiL N 0.09-0.53), but the C26:C 22 ratio was within normal limits (0.024 N 0.0040.027). Leucocyte enzyme analyses including galactocerebrosidase (Krabbe's disease), hexosaminidase A and B, beta-galactosidase, beta-glucuronidase and I-cell screen were normal. The arylsulphatase A was slightly low (12 nano units N 22-103), but not in the homozygous range for metachromatic leucodystrophy (less than 6). The EEG (Fig. 3) showed a considerable abnormality with some 2-4/sec components especially posteriorly, where there were also frequent spikes and polyspikes occurring intermittently over both hemispheres. In addition, brief generalised paroxysmal bursts of polyspikes mixed with slow waves occurred which were facilitated by eye closure. During photic stimulation, posterior spikes were sometimes enhanced by single flashes of light and the generalised paroxysmal bursts were seen with flash rates as low as 5-6/sec,
Fig. 4 a
SO 100 150 200M Normal flash ERG and VEP findings in older sibling (Case 1).
Downloaded by: Universite Laval. Copyrighted material.
E HELD 5
M. G. Harbord et al
Neuropediatrics 21 (1990)
AgQ 3y
BAEP I1V 4. 84m8
-vtx ] O.2uV +-Ier
v 2
4
6
8
10lls
Fig. 4 b BAEP findings in the younger sibling (Case 2) showing prolonged I-V interval.
Fig. 6 Electron-micrograph from white matter. Note the considerable extracellular space, numerous glial fibres and thin myelin sheaths,
x14000.
Fig. 5 a Brain biopsy, right frontal lobe, showing very thinly myelinated fibres in the rarefied white matter. Luxol-fast blue and cresyl violet, x 300.
were normal in number and appearance. There were scattered hypertrophie astrocytes, and GFAP immunocytochemistry demonstrated a dense fibrillary gliosis. No inflammation, Rosenthai fibres, metachromatic or sudanophilic material were present. Ultrastructural examination (Fig. 6) revealed a greatly increased extracellular space. An occasional degenerating axon was present, but most were normal. Some myelin sheaths were abnormally thin but this myelin was always compact, with no intramyelinic oedema, or lamellar splitting. Numerous astroglial fibres, normal oligodendrocytes, an occasional macrophage containing myelin debris, and hypertrophie astrocytes with copious cytoplasm, numerous organelles and normal mitochondria were also noted. The appearances were not specific but suggested dysmyelination rather than a demyelinating process. Case2
The second child in the family, another girl, was delivered at term following anormal pregnancy. Her birth weight was 3.5 kg and there were no neonatal problems.
Fig. 5 b Dense fibrillary gliosis in the white matter. Immunoperoxidase for glial fibrillary acidic protein, x 300.
At the age of four and a half years, a biopsy of the right frontal lobe was performed. The specimen was divided for histology, histochemistry and electron-microscopy. Light microscopy (Fig.5) disclosed subpial gliosis and slight astrocytosis in the molecular layer but otherwise normal cerebral cortex. The white matter was extremely rarefied, but did not show the spongy vacuolation characteristic of Canavan's disease. With myelin stains the white matter was very pale, but at high power numerous very thin myelin fibres could be seen; axons were plentiful on silver impregnation. Oligodendrocytes
She crawled at 9 months but her later development was slow and by three years of age she could only stand and walk with support. Her parents did not think that she had lost any motor skills. Speech was considered appropriate for her age and she was toilet trained at 2 years and 6 months. Two atonie seizures had occurred at the age of three years unassociated with fever or flickering lights. On examination at 3 years and 5 months, she had very similar clinical features to her older sibling (Fig. 1). Her head circumference (58.0 cm) was 7 cm above the 98th centile while her weight was on the 50th centile. Examination of cranial nerves, visual acuity, hearing, retinal fundi and pupil reactions showed no abnormality. There was generalised weakness of alllimbs with spasticity and hyperreflexia, more prominent in the lower limbs. There were Babinski responses and clonus could be elicited at the left ankle. A spastic gait was apparent when she walked with support. Mild ataxia of the upper limbs was present when building a tower of blocks. There was normal sensation to pin prick and the remainder of the examination showed no abnormality.
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166
Megalencephaly with Dysmyelination, Spasticity, Ataxia, Seizures and Distinctive Neurophysiological Findings
Neuropediatrics 21 (1990)
167
Investigations
Fig.7
CT scan of Case 2 showing diffuse white matter hypodensity.
The EEG (Fig. 8) showed infrequent isolated spikes and poly spikes posteriorly, more pronounced over the left hemisphere, while some alpha rhythm was preserved on eye closure. Occasional brief generalised bursts of spikes and polyspikes mixed with slow waves were seen, facilitated by photic stimulation at rates of 12-16/sec, unaccompanied by any clinical change. The brainstem auditory evoked potential (BAEP) (Fig. 4 b) showed a prolonged I-V interval of 4.84 ms, (normal upper limit 4.24 ms) consistent with altered myelination in the brainstem, while the ERG and flash VEP were normal.
Discussion
"ge
3y
E HELD 5
The presence of a progressive neurological condition with similar clinical and neurophysiological features in two siblings whose parents were first cousins suggests that this is an autosomal recessive disorder. Clinically, at presentation, the most likely diagnosis was thought to be Canavan's disease. However, the children had at the ages of 3 and 4 years no clear evidence of cognitive regression, optic atrophy or visual impairment which are typical features of Canavan's disease and had survived longerthan is usual in this condition (2, 9, 13). In addition, there was no evidence of N acetylaspartic acid in the urine which has recently been reported as a biochemical indicator of Canavan 's disease, associated with a defect of aspartoacylase (10). Canavan's disease shows typical spongy changes and ultrastructural findings on brain biopsy which were not present in the children in this report (1, 2). Alexander's disease is also manifest clinically by megalencephaly with seizures and spasticity but has only rarely been reported in siblings and most cases are isolated (3). Brain imaging usually shows a predominantly frontal involvement unlike the diffuse white matter changes seen in the children in this report (12). The neuropathological hallmark of Alexander's disease is the presence of Rosenthai fibres, in addition to demyelination secondary to astrocytic dysfunction (4). No Rosenthai fibres were seen in the brain biopsy of Case 1 and the myelin appearance suggested dysmyelination rather than demyelination.
Fig. 8 EEG of younger sibling (Case 2) often shows isolated asymmetrical discharges posteriorly (upper left trace) but some alpha rhythm is present on eye c10sure (upper right trace). During photic stimulation, generalised spikes/polyspikes and slow waves are seen with flash rates around 14/s (Iower trace).
The only other likely diagnosis is Gm 1 gangliosidosis, which was excluded by normal betagalactosidase levels. Other causes of megalencephaly such as Tay Sachs disease and a leucodystrophy such as Krabbe's disease were also excluded by biochemical analysis and neuropathology. The abnormally low level of arylsulphatase A in our patients is consistent with the multiple allelism described in heterozygotes for metachromatic leucodystrophy (11) and was not considered to be contributing to the clinical condition.
Downloaded by: Universite Laval. Copyrighted material.
A CT head scan (Fig. 7) revealed identical features to her eIder sister, with diffuse white matter hypodensity. Urine amino and organic acids were normal with no elevation of N-acetyl aspartate, while gas chromatography - mass spectrometry of the urine showed no abnormal peaks. There was no evidence of a peroxisomal disorder. Leucocyte enzyme analysis showed that she was also heterozygous for metachromatic leucodystrophy with an arylsulphatase A level of 8 nano units, but no other abnormality.
Neuropediatrics 21 (1990)
The presence of evolving spasticity does not necessarily imply a demyelinating disorder as it can also be found in dysmyelination. One possible cause of dysmyelination which has no detectable biochemical abnormality at present is Pelizaeus-M erzbacher disease, but this condition is usually X-linked and is not associated with megalencephaly. In addition, nystagmus and dystonia are prominent clinical findings, neither of which were present in our two children (5). Dysmyelination has also been reported with phenylketonuria and maple syrup urine disease (6), but both these were excluded by investigations. Similar EEG abnormalities were seen in both siblings, being more marked in the older girl. Prominent discharges and photoparoxysmal responses are very unusual features in white matter disorders and suggest cortical involvement at least posteriorly, where the discharges were most obvious. Furthermore, photoparoxysmal responses especially at relatively slow flash rates are not commonly seen in children under five years of age and the very marked photosensitivity with discharges sometimes elicited by a single flash, seen in the older sibling, is an EEG finding more often associated with myoclonic seizures (14) which did not occur in our patients. In addition, the ERG was normal and the VEP was not enlarged, which contrasts with the findings seen in late infantile Batten's disease (8). Whilst a prolonged I-V interval in the BAEP is highly suggestive of a white matter disorder involving the brainstem and is found in most leucodystrophies, the combination of this finding with the EEG abnormalities seen in these two siblings has not been previously recognised in any of the known neurodegenerative disorders of childhood (8). We consider that these two siblings have an autosomal recessive condition characterised by megalencephaly, spasticity, ataxia, seizures, a photoparoxysmal EEG response and both· neurophysiological (BAEP) and neuropathological findings consistent with dysmyelination. This combination of abnormalities has no recognised biochemical defect and has not previously been reported
M. G. Harbord et al
References 1
Adachi, M., B. Volk: Protraeted form of spongy degeneration of the een-
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Dr. M. Baraitser Department of Clinieal Genetics Hospitals for Siek Children Great Ormond Street London WC1 N3JH, Great Britain
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