Two cases of glutaric aciduria type 1: Clinical and neuropathological findings

JOURNAL OF THE

NEUROLOGICAL SCIENCES EI£EVIER

Journal of the Neurological Sciences 123 (1994) 38-43

Two cases of glutaric aciduria type 1" clinical and neuropathological findings Seiji K i m u r a

a,*,

M a s a m i c h i Hara b A t u o N e z u a H i t o s h i O s a k a a, Shin Y a m a z a k i ~t Kazuyo Saitoh ~l

Department of " Pediatrics and b Division of" Pathology, Urafune Hospital of Yokohama City University School of Medicine, 3-46, Urafime-cho, Minami-ku, Yokohama 232, Kanagawa, Japan (Received 13 September 1993; revised I December 1993; accepted 17 December 1993}

Abstract

We report clinical and neuropathological studies of 2 patients with glutaric aciduria type 1. A 10-month-old male with involuntary movements expired suddenly at home. The second, a 15-year-old female, died after three episodes of acute encephalopathy including a Reye syndrome-like episode and an episode of severe hypoglycemia. Hypocarnitinemia was also present. Selective involvement of type II muscle fibers was observed during the Reye syndrome-like episode. Magnetic resonance imaging of the 2 patients showed marked widening of the sylvian fissure, atrophy of the basal ganglia, and white matter lesions. Neuropathology of the 10-month-old patient showed: (1) temporal and frontal lobe hypoplasia, (2) degeneration of the putamen and the pallidum, (3) mild status spongiosus in the cerebral white matters, (4) heterotopic neurons in the cerebellum, and (5) hypoplasia of the cerebral white matter. This patient appeared to manifest a migration and/or maturation abnormality of the brain as well as previously observed basal ganglia and white matter degeneration,

Key words: Glutaric aciduria; Hypocarnitinemia; Migration anomaly

I. Introduction

Glutaric aciduria type 1 (GA-1) is an autosomal recessive metabolic disorder characterized by deficiency of glutaryl-CoA dehydrogenase. While its clinical manifestations are variable, and some patients never have a clinical episode (Amir et al. 1989; Haworth et al. 1991), GA-1 typically presents in infancy as an acute movement disorder mainly comprising dystonia and choleathetosis. Patients also frequently have an acute encephalopathy that is often confused with Reye syndrome. Three characteristic magnetic resonance imaging (MRI) findings have been reported in patients with GA-1, with or without clinical symptomatology (Altman et al. 1991; Amir et al. 1989; Bergman et al. 1989; Chow et al. 1988; Dunger and Snodgrass 1984; Goodman et al. 1977; Haworth et al. 1991; Lipkin et al. 1988; Mandel et al. 1991; Osaka et al. 1993; Softer et

* Corresponding author. Tel.: (81-45) 261-5656; Fax: (81-45) 243-3886. 0022-510X/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved

SSDI 0022-51 0 X ( 9 4 ) 0 0 0 0 7 - B

al. 1992; Yager et al. 1988; Yamaguchi et al. 1987): (1) widening of the sylvian fissures, (2) atrophic lesions of the basal ganglia, and (3) white matter lesions. Although widening of the sylvian fissures has been the most prominent finding in this disease, it has not been clear whether this lesion was due to atrophy or hypoplasia. We now report on clinical variability, MRI and neuropathological findings in patients with GA-I.

2. Case reports Patient 1 was the second child of unrelated healthy parents. His birth weight was 3550 g after a lull term gestation. He reached appropriate developmental milestones until 5 months of age, but then began to suffer frequent partial motor seizures, irritability, and involuntary movements including oral dyskinesia. His head circumference was 43.5 cm (70th percentile). Computed tomography (CT) and MRI at the age of 5 months showed marked widening of both sylvian fissures (Fig. 1). Bilateral chronic subdural hematomas were present. Urinalysis revealed increased excretion Of 3-hydroxyglutaric acids, suggesting GA-1. No glutaryt-CoA dehydrogenase activity could be detected in cultured fibrobtasts isolated from the patient. Involun-

,S'. Kimura et al. /.hmrmd o]' the Neurological Sciences 123 (1994/38-43 lary movements persisted despite a low lysine diet, and the patient died suddenly at homc at the age ol 10 months. The pathogenesis of his chronic subdural hemaloma was considered to be the disproportional temporal lobe hypoplasia with tearing of the arachnoidal membrane (Osaka et ah 1993). Ten hours post-mortem, the brain weighed 8(1tl g. The sylvian fissures were widened, and the temporal tips were flattened. Additiomdly, the frontal lobes appeared to be shortened. There were chronic subdural hematomas over both hemispheres, containing a small amount of a slightly yellow colored fluid. ['he lateral ventricles were widely dilated. On the cut surface, the caudate nuclei were relatively small, the lenticular nuclei were brown in color, and the white matter of the frontal and temporal lobes and corpus callosum were thin (FIG. 2). The putamen and pallidum could not be distinguished by inspection, t listologically, the laminations of the cortical cell layers were within normal limits. Although myelinalion in the while matter appeared normal, regions of the pyramidal lracts showed distortion of their fiber bundles, exhibiting non-uniIorm density. Degeneration of the putamens was prominent with marked neuronal loss, prominent astrogliosis, and hype~,asucularity i Fig. 31. Fcw of the smwiving neurons were of a large cell type. In contrast to these putaminal lesions, the cytoarchitecture of the caudate nuclei was well presmwed from head to tail. The pallidum demonstrated mild to moderate histologic lesions, with most of large cells surviving and only small nerve cell loss, mild gliosis, and

Fig. 1, T2-weighted images of patient 1. The sylvian fissures are markedb widened. The whole brain is atrophic with mild ventricular dilatation.

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Fig. 2. The caudate and lenticular nuclei appear small and the lenticular nuclei are brown in color in patient 1. White matter in the temporal lobes and partly in the central lobes, and corpus callosum were very thin.

scattered calcified nodules. There were diffusely scattered small loci of spongy lesions in the cerebral white matter, and several ectopic nerve cell clusters were seen in the cerebellar white matters (Fig. 4). Patient 2 was the daughter of unrelated healthy parents. She was born after 38 gestational weeks weighing 2500 G- l ler developmental milestones were delayed, with head control appearing at 6 months and sitting at 12 months. She spoke her first meaningful word at 12 months. At 1 year 9 months she had a first episode of acute encephalopathy, but she recovered well. At 2 years 6 months, she showed hypotonia and a delay in psychomotol dcvelopment. There were no pyramidal or extrapyramidal signs. At 3 years I I months she had an episode of confusion fl)llowed by coma, and was found to have hypoglycemia (12 m g / d l ) w i t h o u t ketonuria. She recovered rapidly from the coma after intravenous infusion of glucose. ,.\t 4 years 2 months she developed an acute enccphalopathy clinically indistinguishable from Reye syndrome. Serunl GOT ( 145(} U), (}PT (1050 U), and CK (3500 U) were high, and N i l , was miktly elevated: all peaked rapidly, within 24 I1, and normalized wdhin I week. A needle biopsy of muscle from the quadriceps muscle, done in response to the high serum CK, revealed type II fiber myolysis. The electron microscopical findings of the muscle have bcen previously reported (Kimura et al. 1989). although the diagnosis of GA-I was not made at the time. CT scan showed widening of the sylvian fissures (Fig. 5). The patient became bedridden, and dystonic involuntap,/ movements appeared after this episode, ftypocarnitinemia was first noticed at the age 9, and a muscle biopsy at that lime showed no abnormality, tter general status lemained stable until age 14. Her head circumference was rather largc, 71)th percentile. At age 14. slle was admitted to our hospital, and a tracheotomy was performed. MRI at that age revealed multicystic le',ions in the subcortical white matter, irregular shaped abnormal signals in the basal Ganglia, mainly m lenticular nuclei, and marked widening of the sylvian fissures (FIG. 6). GlutaryI-CoA dehydrogenase activity of the cultured fibroblasts, performed at the age ol 15. could not be detected. She died suddenly at the age of 15. Autopsy was not done.

S. Kimura et al. /Journal of the Neurological Sciences 123 (1994) 38-43

4[)

Fig. 3. Loss of nerve cells and astrogliosis with increasing vascularity ( × 400) in the putamen. H E stain in patient 1.

3. Discussion The clinical manifestations of GA-1 are variable (Amir et al. 1989; Haworth et al. 1991). A few patients with biochemical abnormalities have no clinical symptoms, but, GA-1 typically presents in infancy acutely with involuntary movements or encephalopathy often is confused with Reye syndrome. Patient 1 was a typical infantile case of GA-1 who had early onset of involun-

tary movements at the age of five months. Patient 2 had three episodes of metabolic crisis. One of the episodes was due to severe hypoglycemia without ketonuria, which is rare in GA-1 (Dunger and Snodgrass 1984). The episode at age 4 was similar to Reye syndrome. Serum G O T and GTP were more than ten times normal, and NH3 was slightly elevated. These values peaked within 24 h and returned to normal within a week. as is characteristic of Reye syndrome.

Table 1 Summary of neuropathological findings in patients with glutaric aciduria type-1 (Case) A u t h o r

(1) G o o d m a n et al. (2) Chow et al. (3) Chow et al. (4) Chow et al. (5) B e r g m a n et al. (6) Softer et al. (7) Present case

Age/sex

10 y r s . / M 2 yrs./F 7 yrs./F 9 yrs./F 13 m o s . / M 6 yrs./M 9 mos./M

a No distinct nerve cell loss, but positive gliosis. b Myelin splitting by electron microscopy. c Tail of the caudate appeared normal.

Status spongiosus

Nerve cell loss Caudate

Putamen

PaUidum

marked marked marked marked none marked " none

mild marked marked marked marked marked marked

none none a none a none a none none mild

none

marked marked marked present b marked b mild

S. Kimura et al. /Journal of the Neurological Sciences 123 (1994) 38-43

Serum CK rose to more than 30 times the normal values. In this episode, acute type II fiber myolysis was observed on a muscle needle biopsy, which has not been previously reported in patients with GA-1. This myolytic change was transient, as in a Reye syndromelike episode. Although more than 40 patients with GA-1 have been reported, only six have had detailed neuropathologies (Chow et al. 1988; Goodman et al. 1977; Softer et al. 1992) (Table 1). They ranged from 13 months to 10 years of age. Because our patient is the youngest autopsied individual with GA-1, his lesions may be representative of early lesions typical of this disease. These lesions were mild to moderate nerve cell loss with gliosis in the pallidum, and severe nerve cell loss, including large and small ceils, with gliosis in the putamen. The caudate nuclei, which have the same developmental origin as the putamen, showed no nerve cell loss. Our cases continue the variability in the severity of the lesions reported for GA-1 (Table 1). Most lesions in the basal ganglia were in the caudate and putamen. Basal ganglia lesions may differ in severity by age groups at autopsy. In early infancy, the caudate nuclei are not involved (Bergman et al. 1989;

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and our case). This suggests that the putamen may be the first region affected by GA-1. Our case has pallidal lesions, which have not been described previously. Scattered status spongiosus was found in the white matter. Patient 1 showed selective hypoplasia of the frontal and temporal lobes probably due to the hypoplasia of the cerebral white matter, and the presence of heterotopic gray matter in the cerebellum. This indicated the presence of migration a n d / o r maturation abnormalities in the central nervous system in patients with GA-1. These lesions might result from a deficiency of glutaryI-CoA dehydrogenasc. Cranial CT and MRI in patients with GA-1 show three characteristic findings: (1)wide sylvian fissures, (2) small basal ganglia, and (3) abnormal signal in the white matters. Widening of sylvian fissures is observed in most, but not all cases, and is seen even in asymptomatic patients (Amir et al. 1989; Goodman et al. 1977; Haworth et al. 1991). Sylvian fissure widening may be a helpful diagnostic sign, and even useful to discover a carrier with GA-1. The mechanism of this widening has not previously been attributed to hy_ pop[asia or atrophy of the frontal and temporal lobes. In this study, however, it was clear that the lesion was

Fig. 4. Two lesions with migration abnormalities in the cerebellum ( × 200). HE stain in patient 1.

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,~. Kimura ct al. /Journal ~!f the Neurological Sciences I23 (1994) 38-43

due to hypoplasia, since there was no evidence of nerve cell loss, degeneration or gliosis in the cerebral cortices or the subcortical white matter. This patient may have suffered intrauterine developmental abnormalities, caused by the cytotoxic effect of glutaric acidemia and related substances. CT and MRI of patient 1 and the first CT of patient 2 were typical of GA-1. Though the later MRI of patient 2 (Fig. 6) showed diffuse multicystic lesions in the subcortical white matter, which might have been sequelae of the Reye syndrome-like episode of 10 years before, it still had characteristic signs of GA-1, including the marked widening of the sylvian fissures and the presence of abnormal signals in the lenticular nuclei and caudates. Although the pathogenesis of these multicystic lesions was not determined, they seem likely to be characteristic of GA-1 presenting as acute encephalopathy. Because the usual sequelae of acute encephalopathy in non-metabolic diseases are diffuse, brain atrophy or hydrocephalus, and multicystic white matter lesions are rare except in cases with perinatal anoxia. In addition, patient 2 did not show microcephalus as is usual after an episode of acute encephalopathy. The white matter lesions of patient 2

Fig. 6. Tl-weighted MRI of patient 2 shows marked widening of the sylvian fissures, and multicystic lesions of the subcortical white matter.

may have been status sponglosus, one of the characteristic lesions in GA-t. accelerated by acute encephalopathy. By electron microscopy, status spongiosus in GA-1 is caused by myelin splitting (Table 2), which is also observed in mitochondrial disease and other degenerative disorders. The predominant multicystic white matter lesions of patient 2 might thus reflect be accelerated progression of such myelin splitting by acute encephalopathy.

Acknowledgement We are grateful to Dr. Seiji Yamaguchi, Department of Pediatrics of Gifu University, for his assistance in the analyses of urinary organic acids and glutarylCoA dehydrogenase of the cultured fibroblasts o f our 2 patients.

References Fig. 5. CT scan of patient 2 at the episode of acute encephalopathy. Svlvian fissures are widened.

Altman, N.R.. M.J. Rovira and M. Baue) (1991) Glutaric aciduria type 1: MR findings in two cases. \ J.N.R. 12: 966-968.

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