Brain Advance Access originally published online on February 2, 2005
Brain 2005 128(4):711-722; doi:10.1093/brain/awh401
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Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort
Departments of 1 Pathology, 2 Human Anatomy and Cell Science, 3 Biochemistry and Medical Genetics and 4 Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, 5 Manitoba Institute of Child Health, Winnipeg, 6 Department of Pediatrics, University of Western Ontario, London, Ontario, Canada and 7 Department of General Pediatrics, Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany.
Correspondence to: Marc R. Del Bigio MD PhD FRCPC, Canada Research Chair in Developmental Neuropathology, Department of Pathology, University of Manitoba, D212-770 Bannatyne Avenue, Winnipeg MB, R3E 0W3, Canada E-mail: delbigi{at}cc.umanitoba.ca
Received July 14, 2004. Revised December 10, 2004. Accepted December 13, 2004.
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Summary |
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Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase (GCDH) activity. GA-1 is often associated with an acute encephalopathy between 6 and 18 months of age that causes striatal damage resulting in a severe dystonic movement disorder. Ten autopsy cases have been previously described. Our goal is to understand the disorder better so that treatments can be designed. Therefore, we present the neuropathological features of six additional cases (8 months–40 years), all North American aboriginals with the identical homozygous mutation. This cohort displays similar pathological characteristics to those previously described. Four had macroencephaly. All had striatal atrophy with severe loss of medium-sized neurons. We present several novel findings. This natural time course study allows us to conclude that neuron loss occurs shortly after the encephalopathical crisis and does not progress. In addition, we demonstrate mild loss of large striatal neurons, spongiform changes restricted to brainstem white matter and a mild lymphocytic infiltrate in the early stages. Reverse transcriptase-PCR to detect the GCDH mRNA revealed normal and truncated transcripts similar to those in fibroblasts. All brain regions demonstrated markedly elevated concentrations of GA (3770–21 200 nmol/g protein) and 3-OH-GA (280–740 nmol/g protein), with no evidence of striatal specificity or age dependency. The role of organic acids as toxic agents and as osmolytes is discussed. The pathogenesis of selective neuronal loss cannot be explained on the basis of regional genetic and/or metabolic differences. A suitable animal model for GA-1 is needed.
Key Words: autopsy; glutaric acid; 3-hydroxyglutaric acid; striatum; molecular genetics
Abbreviations: ChAT = choline acetyltransferase; DAB = diaminobenzidine; H&E = haematoxylin and eosin; GA = glutaric acid; GA-1 = glutaric acidemia type 1; GCDH = glutaryl-CoA dehydrogenase; GFAP = glial fibrillary acidic protein; HLA-DR = human leucocyte antigen-DR; NMDA = N-methyl-D-aspartate; 3-OH-GA = 3 hydroxyglutaric acid; RT-PCR = Reverse transcription polymerase chain reaction
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Introduction |
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Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of amino acid metabolism caused by the deficiency of functional glutaryl-CoA dehydrogenase (GCDH) activity (Christensen, 1993
), an essential enzyme in the catabolic pathways of L-tryptophan, L-lysine and L-hydroxylysine (Goodman et al., 1977; Baric et al., 1998; Goodman and Frerman, 2001). Lack of functional GCDH activity typically leads to the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutaconic acid in the blood, urine, CSF and brain tissue (Stokke et al., 1975; Goodman et al., 1977; Baric et al., 1998). GA and 3-OH-GA might induce an imbalance in glutamatergic and GABAergic neurotransmission (Wajner et al., 2004) and 3-OH-GA might act through excitotoxic NMDA receptors to produce a neurotoxic effect (Kölker et al., 2004a,b), although this is not supported by all experimental data (Freudenberg et al., 2004; Lund et al., 2004). In one autopsy case, 3-OH-GA was relatively more abundant in the striatum (Kölker et al., 2003), where the neuronal damage is most severe.
GA-1 affected children are clinically characterized by macrocephaly appearing at, or shortly after, birth and initial normal development interrupted by abrupt onset of dystonia and choreoathetosis, which then remain relatively static. Neurological abnormalities usually appear between 6 and 18 months of age, often in conjunction with a febrile illness. Intellect seems to be relatively preserved (Goodman and Frerman, 2001). The profound neurological sequelae may lead to death in early childhood; however, some individuals survive for many years. A minority of biochemically affected individuals may remain asymptomatic or experience an insidious onset of mild neurological abnormalities. The brains of children affected with GA-1 exhibit wide Sylvian fissures and enlarged frontal ventricles due to caudate atrophy. There are only 10 published autopsy reports of GA-1 (Goodman et al., 1977; Leibel et al., 1980; Bennett et al., 1986; Chow et al., 1988; Bergman et al., 1989; Soffer et al., 1992; Kimura et al., 1994; Kölker et al., 2003). Atrophy and severe neuronal loss affecting the caudate and putamen are always present. Spongiform change in the white matter has been frequently described.
This disease is over-represented among North American aboriginals (Ojibway-Cree) in a genetic isolate in north-eastern Manitoba and north-western Ontario in central Canada (Haworth et al., 1991). In this population, the carrier frequency is 
1 in 10. Twenty-eight affected children, many the products of consanguineous unions, have been identified since 1970; 21 individuals have suffered an encephalopathical crisis with severe striatal damage (unpublished data). Although the phenotype is severe, the amount of GA and 3-OH-GA in blood and urine tends to be very low (Haworth et al., 1991). All affected individuals are homozygous for a splicing mutation, a G to T transversion at the +5 position of intron 1 in the gene encoding GCDH (IVS-1+5 G>T) (Greenberg et al., 1995; Goodman et al., 1998). This splicing mutation allows for some normal splicing with a transcript of the expected size, as well as a truncated transcript resulting from activation of a cryptic splice site 26 base pairs (bp) upstream in exon 1; the cryptic splicing leads to a frame shift and premature termination.
There are many gaps in the present understanding of the neuropathogenesis of striatal injury in this disorder. Here we describe the neuropathological findings in the brains of five children and one adult with GA-1, all with the same mutation. This is of particular interest because the range of survival times and the availability of frozen tissue for genetic analysis might offer additional insight into pathogenesis of the disorder.
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Material and methods |
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This was a retrospective neuropathological study of six individuals of North American aboriginal background diagnosed with GA-1. All patients in this study were examined and diagnosed by clinical geneticists at the Children's Hospital/Health Sciences Centre in Winnipeg, Canada. There have been 13 known deaths in this cohort between 1978 and 2004; complete autopsies have been performed on six cases. The age of death ranged from 8 months to 40 years. In all cases, the medical records were reviewed in detail. Original brain imaging studies were available for review from only three cases. For each case, histological samples from one or two anonymized control cases with no neurological disease and matched for age and gender were obtained from the autopsy archives. Frozen control tissues were more limited and not as closely comparable. This study was conducted with approval of the University of Monitoba Biomedical Research Ethics Board as well as the Pathology Access Committee for Tissue.
Archived paraffin blocks, glass slides and hospital records were retrieved for all cases. The brains had been reasonably well sampled with 8–20 tissue blocks per brain available for microscopic examination. All slides were examined by one neuropathologist (M.R.D.). Age- and sex-matched controls were identified and similar levels of the striatum were sampled for each case. Sections from striatal blocks were stained with haematoxylin and eosin (H&E). Immunohistochemical staining was performed to detect glial fibrillary acidic protein (GFAP) (polyclonal anti-GFAP; 1/1200 dilution; DakoCytomation (Carpinteria CA, USA), activated microglia (anti-HLA-DR; 1/250 dilution; Dako), lymphocytes (anti-CD3; 1/100 dilution; Dako) and synaptic vesicle protein synaptophysin (1/25 dilution; Dako). Neurons were identified with the use of anti-NeuN (neuronal nuclei) (1/800; Chemicon International). To identify inhibitory interneurons, antibodies to calbindin (1/100 dilution; Chemicon) and 
-aminobutyrate (anti-GABA; 1/125; Chemicon) were used. To identify noradrenergic axons, anti-tyrosine hydroxylase (dilution 1/75; Chemicon) was used. Choline acetyltransferase (ChAT) (anti-ChAT; 1/250 dilution; Chemicon) Chemicon International (Temecula CA, USA) was used to identify large cholinergic neurons. GFAP, human leucocyte antigen-DR (HLA-DR), CD3 and synaptophysin antibodies were detected using the Envision detection system. GABA, ChAT, NeuN and tyrosine hydroxylase antibodies were detected with biotinylated secondary antibodies, streptavidin horseradish peroxidase and 3,3'-diaminobenzidine (DAB). A fluorescent secondary antibody (Cy-3) was used with the calbindin primary antibody. Appropriate negative controls were used in all cases.
Neuron counts were performed on H&E stained sections. This was done because the neurons have a fairly characteristic morphology and because we found the immunostaining to be inconsistent in the autopsy material. Counts were made in the dorsal and ventral regions of both the caudate and putamen at an ocular magnification of 400x. The size of the ocular reticule counting square was 250 µm x 250 µm. The counts consisted of neurons contained within six adjacent focal areas in each of the four regions stated above. Only neurons that could be unambiguously identified based on cytological details were counted. National Institutes of Heath (NIH) image analysis software was used to measure the density of DAB precipitation—as an indicator of the magnitude of immunoreactivity—with antibodies against GFAP, HLA-DR and synaptophysin. Images used for NIH analysis were taken in the dorsal and ventral regions of the caudate and putamen at 10x objective magnification. Two images were obtained from each region; their densities were then averaged to give a better representation of immunoreactivity in each area. Neuron counts and immunohistochemical labelling data were tested for normal distribution. Paired t-tests were then used to compare differences between cases and age-matched controls using StatView 5 Software (SAS; Cary, NC, USA). Regression analysis was used to test for age-dependent effects.
Reverse transcription PCR (RT-PCR) was performed on total RNA isolated from frozen brain tissue stored at –70°C following autopsy of four cases. The method has been previously described for analysis of fibroblasts and lymphoblasts from this cohort (Greenberg et al., 1995). Briefly, following reverse transcription of RNA from homogenized tissue, two overlapping fragments of the complete GCDH cDNA were generated by separate standard PCR reactions. PCR conditions were 2 µl cDNA in 50 µl of 50 pmol of each primer, 200 µM of each dNTP, 5 µl of 10x PCR reaction buffer (Perkin Elmer, Boston, MA, USA) and 1 ml AmpliTaq (8 units) (Applied Biosystems, Foster City CA, USA) for 35 cycles at 95°C/3 min, 95°C for 1 min, 58°C for 1 min, and 72°C for 1 min with a final 10 min cycle at 72°C. Products were analysed on 6% acrylamide minigels with ethidium bromide (10 mg/ml) staining. RT-PCR for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a positive confirmation of mRNA integrity and isolation. Similar analyses were performed on brain tissues obtained from non-age matched patients (because the supply of control material was limited) without known neurological disease and with similar post-mortem delay. All analyses were done blinded.
Analysis of organic acid (GA and 3-OH-GA) concentrations was performed on frozen brain tissue from four GA-1 and three control cases. The samples were shipped by courier on dry ice to Germany. The analyses were performed in a blinded manner. The methods for this analysis are described in detail in previous studies (Schor et al., 2002; Kölker et al., 2003). Again due to limited supply, the controls were not age matched.
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Results |
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The ages of the individuals with GA-1 ranged from 8 months to 40 years. Body weights and heights, GA levels in urine (Seargeant et al., 1992
) and GCDH activity are shown in Table 1. In the youngest four cases, the brains were much larger than expected for age. A description of clinical and neuropathological findings follows in order of ascending age.
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Case 1
This male had six out of seven older siblings also affected by GA-1. He is a member of pedigree B described in the clinical report of this cohort (Haworth et al., 1991
). At full term birth in 1993, he was said to be jittery. A brief seizure occurred at 3 months. Developmental delay, mild hypotonia and head bobbing were noted at 4 months. At 6 months, a CT scan showed slightly enlarged ventricles, temporal fossa fluid collections and mild widening of frontal sulci. The head circumference was on the 99.9 percentile at birth, 2 months and 8 months. At 8 months, he presented with vomiting, diarrhoea, fever and severe dehydration. He became rapidly comatose. A CT scan showed haemorrhage in the right temporoparietal region and he died 3 days later. Autopsy revealed widespread ischaemic neuronal damage in the cerebrum and cerebellum. Haemorrhagic infarction in the right parietal and temporal cerebrum was due to venous sinus thrombosis, apparently a complication of sepsis and dehydration. Mild symmetric dilation of the lateral ventricles accompanied atrophy of the striatum. There was severe loss of medium-sized neurons in the caudate and putamen, with dorsal areas more severely affected than ventral. Immunohistochemical stains demonstrated astrocyte hypertrophy and microglial activation in the striatum. There were rare scattered and a few perivascular clusters of CD3 immunoreactive lymphocytes in the putamen. No white matter vacuoles were identified.
Case 2
Following full term birth in 1977, this male sibling of Case 1 had mild respiratory distress requiring incubation. He is the presumed first GA-1 case of pedigree B described in the clinical report of this cohort (Haworth et al., 1991). At 10 months of age, acute bacterial (E.coli) pneumonia was accompanied by fever and lethargy. Cerebrospinal protein was elevated. Despite antibiotic treatment, the fever continued and 3 weeks later he developed episodes of opisthotonus, limb stiffening and lethargy. A CT scan was reported to show enlarged lateral ventricles and Sylvian fissures. On Phenobarbital, there was a slight improvement of his neurological status. He suffered respiratory arrest following aspiration of vomit 6 weeks after presentation. Autopsy revealed pneumonia. The head circumference was on the 71.9 percentile. The external surface of the brain appeared normal, but the ventricles were mildly enlarged. The caudate and putamen exhibited widespread loss of medium-size neurons with marked astrocytic proliferation, microglial activation and focal dystrophic calcification. Mild diffuse lymphocyte infiltration and rare perivascular cuffing (up to 5 cells thick) was present in the putamen. The tail of the caudate adjacent to the hippocampus appeared normal. Rare vacuoles were seen in the white matter of a single gyrus and vacuoles were fairly abundant in the central tegmental tract of the brainstem, but not elsewhere.
Case 3
This male's parents were known heterozygotes for the GA-1 mutation. He is Case 12 in pedigree C described in the clinical report of this cohort (Haworth et al., 1991). Following full-term birth in 1989, he presented at 7 months of age with developmental delay and relatively sudden onset of dystonia and seizures. A CT scan showed hypointensity of the caudate and putamen, and widening of the Sylvian fissures. He became severely impaired, was treated with Phenobarbital and required placement of a feeding tube. He was placed in a chronic care institution. At 16 months, he developed fever and died suddenly. Autopsy showed acute glottitis and pneumonitis. His head circumference was on the 22 percentile. The external appearance of the brain was unremarkable. The caudate and putamen were atrophic and the lateral ventricles were mildly enlarged. Microscopically, the striatum exhibited loss of medium-size neurons, plump reactive astrocytes, reactive microglia, scattered calcospherites and rare CD3 immunoreactive lymphocytes in the caudate. The tail of the caudate adjacent to the hippocampus appeared normal. There were scattered pyknotic neurons in the cerebral cortex.
Case 4
This male was born at 39 weeks by Caesarean section and was found, on genetic screening in 1999, to have GA-1 (he is Case 3 in Greenberg et al., 2002). His development was delayed slightly. At 5.5 months of age, he developed fever with onset of dystonia and athetoid limb movements as well as seizure activity. A CT scan showed enlarged frontal horns of the lateral ventricles and widened Sylvian fissures, but no generalized atrophy (Fig. 1). Caudate atrophy was worse at 10 months. He was treated with Phenobarbital and topiramate, but failed to thrive and had multiple respiratory infections. At 15 months, he was unable to sit but had some head control and visual interaction. During a febrile illness at 18 months, he stopped breathing. Autopsy revealed laryngitis and dehydration. His head circumference had been on the 52 percentile at birth, 89 percentile at 3 months, 63 percentile at 8 months and was on the 50 percentile at the time of death. The brain exhibited mild widening of temporal and frontal sulci, and pronounced widening of the Sylvian fissures. No histological abnormalities were apparent in the cerebral cortex of the temporal lobe tips or frontal lobes. The caudate nuclei were small, yellowish and firm. There was symmetric lateral ventricle enlargement (Fig. 1). The head of the caudate and the putamen exhibited severe neuronal loss with pronounced reactive astrocytes. Only rare reactive microglia were identified. The tail of the caudate adjacent to the hippocampus appeared normal. The cerebral white matter exhibited no vacuoles, no damaged axons were identified using amyloid precursor protein immunohistochemistry, and no myelin debris could be demonstrated with the Marchi method. Rare vacuoles were present in the central tegmental tract at the level of the midbrain.
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Case 5
This female born by forceps delivery at 37 weeks gestation, in 1983, had generalized hypotonia in infancy. She is Case 1 in pedigree A described in the clinical report of this cohort (Haworth et al., 1991
). At 6 months of age, she developed seizures and choreoathetoid movements. Thereafter she developed severe spastic quadriparesis. She was unable to walk and developed severe scoliosis. A CT scan at 5 years showed enlarged frontal horns and slightly wide Sylvian fissures. She died of acute pneumonia at age 7 years. Her head circumference had been on the 25 percentile at birth, 52 percentile at 6 months, 3 percentile at 19 months and 25 percentile at the time of death. Her brain exhibited mild gyral flattening, slightly enlarged ventricles and severe striatal atrophy. The caudate and putamen had a near complete loss of medium size neurons (Fig. 2) and some GFAP immunoreactive astrocytes; the nucleus accumbens was spared. Scattered hypertrophic astrocytes and very rare HLA-DR immunoreactive microglia were present in the internal capsule—although there were no vacuoles. There were small foci of spongiform change in the frontal and insular cortex.
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Case 6
This male born at 40 weeks gestation, in 1953, was apparently slow to breathe. He had three siblings that died in infancy from pneumonia. He is Case 14 in pedigree E described in the clinical report of this cohort (Haworth et al., 1991
). At 12 months of age, he developed a high fever and was admitted to hospital with dystonia. At 6 years, he was documented to have severe flexor spasticity of the arms and legs, choreoathetoid movements and oral dyskinesia. Seizures were reported only early in life. He resided in a nursing care facility for his entire life. At no time was brain imaging conducted and head circumference information was not available. He required many hospitalizations for aspiration pneumonia. On one such admission at age 40 years, the treatment was complicated by pseudomembranous colitis from which he died. His brain had a normal external appearance. The frontal horns of the lateral ventricles were moderately enlarged. There was marked atrophy of the caudate and putamen with neuronal loss and abundant corpora amylacea. There was no significant immunoreactivity for GFAP or HLA-DR. The anterior nucleus accumbens was spared. The white matter of the cerebrum and brainstem was well myelinated and no vacuoles were identified. Subtle chronic astrogliosis, demonstrable with modified phosphotungstic acid haematoxylin (PTAH) stain, was evident in the inferior olivary nuclei but there was no obvious neuron loss. Very rare empty basket cells were present in the cerebellum, suggestive of mild Purkinje cell loss. Frontal cortex tissue was examined in all cases, none provided evidence of obvious cell loss or reactive changes.
Comparative analysis
Quantitative comparison of the striatum in GA 1 cases and controls showed statistically significant (P < 0.05) loss of medium sized neurons in the dorsal caudate, ventral caudate, dorsal putamen and ventral putamen (Fig. 3). The dorsal regions of the caudate and putamen were more severely affected, although this was not statistically significant. There was no age-dependent trend (Fig. 4) in the quantity of neurons in the GA-1 cases, suggesting that maximal neuron loss had occurred within 2 months of onset of symptoms, which was the time of death after encephalopathical crisis in Case 1. Large neurons, which are normally much less abundant than the medium-sized neurons, were significantly fewer in the ventral putamen of the GA1 patients with similar trends in all areas of the striatum (Fig. 5). Immunostaining for GFAP (Figs 6 and 7) demonstrated the presence of reactive astrocytes in all areas of the striatum, with a tendency to greater staining in the dorsal striatum. Analysis of reactive microglial activation (Fig. 8) demonstrated significant HLA-DR immunoreactivity in only the three youngest cases and mild infiltrate in the fourth case, suggesting that it only persists a few months after the acute episode. Overall, the differences approached statistical significance (P = 0.0725 and 0.0699, respectively; paired t-test versus age-matched controls) only in the dorsal and ventral putamen.
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Loss of GABA and calbindin immunoreactivity confirmed that the population of medium sized neurons is decreased in GA-1 (data not shown). The relative absence of NeuN labelling confirmed that neurons were lost and not simply atrophic. Qualitative inspection of ChAT and tyrosine hydroxylase immunoreactivity in large cholinergic and dopaminergic neurons indicated little, if any, difference between GA-1 cases and controls (data not shown). Synaptophysin immunoreactivity in striatum was not significantly different between cases and controls (data not shown), indicating the preservation of input axons to the striatum.
The presence of GAPDH amplification product in both GA-1 cases and controls indicated the presence of undegraded mRNA despite long post-mortem delays to autopsy and the lengthy interval between autopsies and molecular study. However, there was limited frozen tissue stored and striatal tissue was not recoverable. Thus, proper quantification of the relative proportion of normal and mutant GCDH transcripts was not possible. Nonetheless, we observed abundant mutant and normal sized GCDH transcripts in the frontal cortex of Cases 3 and 5 (the most abundant frozen tissue available) (Fig. 9). A similar pattern has been seen in fibroblasts and lymphoblasts of affected patients (Greenberg et al., 1995).
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Organic acid analysis demonstrated marked elevations of GA and 3-OH-GA compared with controls. There was no evidence of striatal specificity or age dependency. There was a slight elevation of GA in one control brain, which likely can be considered a non-specific change related to agonal events (Table 2).
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Discussion |
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The neuropathological changes associated with GA-1 described here in six individuals are essentially similar to those previously described in 10 affected children of other ethnic backgrounds ranging in age from 10 months to 15 years (Goodman et al., 1977
; Leibel et al., 1980; Bennett et al., 1986; Chow et al., 1988; Bergman et al., 1989; Soffer et al., 1992; Kimura et al., 1994; Kölker et al., 2003). Atrophy involving the striatum is consistently described, with sparing of the caudate in one case (Kimura et al., 1994). We observed sparing of the nucleus accumbens and tail of the caudate nucleus. In seven out of ten previously published cases, spongiform change of the white matter was observed. An additional autopsy by Kölker and colleagues (unpublished) on a female aged 3 years and 3 months, with disease onset at 15 months, demonstrated severe neuron loss and gliosis in the basal nuclei, widespread moderate neuron loss in the cerebral cortex, brainstem (including substantia nigra) and cerebellum and diffuse spongiform changes in white matter. There was minimal spongiform white matter change in the cases described here and it was largely confined to the brainstem. Whether this reflects a cohort difference or simply a timing difference is not clear. We did not find clear evidence of axon damage or demyelination in any case, the exception being subtle microglial activation in the internal capsule of Case 5. This suggests that the white matter changes could represent a fluid shift into myelin rather than a destructive change. The anatomical restriction in these cases cannot readily be explained. Imaging studies suggest that white matter alterations are rare in the Amish cohort (Strauss et al., 2003). However, in a boy with GCDH deficiency presenting at 15 years age without major neurological abnormality, magnetic resonance spectroscopy suggested increased myelin turnover in conjunction with a reduction of neuronal integrity (Bodamer et al., 2004). In contrast, a 19-month old child studied by the same technique exhibited changes suggestive of neuroaxonal damage and demyelination (Kurul et al., 2004). Obviously, the only way to truly understand such studies is to perform them on individuals who shortly thereafter undergo autopsy.
We have previously reported both normally spliced and deleted cDNA in fibroblasts and lymphoblasts of our affected patients (Greenberg et al., 1995) and we now observe similar findings in brain tissue. Thus, there does not appear to be a direct correlation between the presence of wild type GCDH transcript in the regions of the brains available for study and clinical outcome. Unfortunately, cDNA could not be prepared from the regions of the basal nuclei to assess expression in these vulnerable areas of the brain. Nonetheless, it seems reasonable to assume that GCDH intron 1 splicing is probably comparable in these areas of the brain. Our results suggest that splicing alone is probably not the sole determinant of clinical outcome. It is possible that, in the target regions, aberrantly spliced mRNA is unstable or is prematurely degraded; other genetic factors influencing higher order RNA structure or RNA protein interactions are likely to affect the final clinical outcome.
Biochemically, the most intriguing result of our study is the discrepancy between high concentrations of GA and 3-OH-GA in brain and low concentrations in urine and plasma (Haworth et al., 1991). The concentrations are much higher than in one previously described patient who was treated with a lysine-restricted diet (Kölker et al., 2003). However, GA concentrations are comparable with those found in a post-mortem examination of another published case (Goodman et al., 1977) and in a frontal cortex biopsy of an untreated adult who excreted high levels of GA (S. Kölker, unpublished data). We failed to confirm the prior observation that concentrations of GA and 3-OH-GA are highest in the striatum (Kölker et al., 2003). The high gradient of organic acids towards the brain and the low permeability of the blood–brain barrier for dicarboxylic acids in general (Hoffmann et al., 1993) support the notion that organic acids are probably generated in the brain. However, this has not yet been explicitly proven for GA or 3-OH-GA, and requires detailed further investigation, including permeability studies of the blood–brain barrier and blood–CSF barrier. Unfortunately, we do not have data concerning CSF concentrations of GA and 3-OH-GA in this cohort of patients (Haworth et al., 1991; Greenberg et al., 2002).
Despite genetic homogeneity and a wide range in duration of survival following encephalopathical crisis, all cases had near complete loss of medium neurons from the striatum, with the exception of the nucleus accumbens and tail of the caudate. This likely occurs within, at most, a few weeks of the first encephalopathical crisis. It is important to emphasize the apparent lack of progression over the lifespan because this observation supports the idea that a single severe insult during infancy creates the bulk of striatal injury. The three individuals that died soonest after the encephalopathical crisis (Cases 1, 2 and 3) had small collections of lymphocytes in the cerebrum. This is not a common incidental finding in childhood death; it might simply reflect a septic state rather than a specific component of GA-1 brain damage or it could be interpreted as evidence that mild encephalitis can precipitate the striatal destruction. Reactive microglia, which can accompany neuron loss or encephalitis, also dissipated within 6 months of the encephalopathical crisis. Because the neurotoxic effect of 3-ON-GA per se is weak (Freudenberg et al., 2004; Lund et al., 2004), it has been suggested that additional amplifying mechanisms are necessary to initiate neuronal damage. Among these, induction of nitric oxide, synthase and indoleamine 2,3-oxygenase by inflammatory cytokines have been considered as relevant, increasing the formation of nitric oxide and quinolinic acid, respectively. The occurrence of infections in early life may provide the trigger for a cascade of injurious events. Reactive astrocytes, which are activated acutely perhaps as a protective response (Porciuncula et al., 2004), persist many years post injury.
Quantification of large cholinergic neurons has never been performed in cases of GA-1; these cells have been reported as unaffected. If this population of neurons was undamaged, one would demonstrate an increased density in atrophied striatum whose medium neurons had been lost. Our results indicate that there is a significant loss of large neurons from some regions of the striatum. They receive glutamatergic input from the thalamus that is mediated by NMDA, AMPA and mGluR receptors (Haber and Gdowski, 2004) and therefore should be vulnerable. Quinolinic acid has been shown to damage cholinergic neurons (Rossato et al., 2002; Guidetti and Schwarcz, 2003; Kumar, 2004). The observed dorso-ventral gradient of neuron loss might be explained in different ways. First, the neuron characteristics as well as the afferent and efferent connections to the striatum exhibit dorso-ventral and rostro-caudal differences (Haber and Gdowski, 2004), which are likely to influence vulnerability. Secondly, blood flow through lenticulostriate arteries could, in the face of the excitotoxic stress/hyperactivity, be diverted away from the dorsal regions leading to a additive hypoxic/ischaemic injury.
There are other conditions with overlapping neuropathological features including familial infantile striatal necrosis (Straussberg et al., 2002), Huntington disease (Portera-Cailliau et al., 1995), neuroacanthosis and Wilson disease (Nelson, 1995), most of which have a gradual progressive course. The presentation of the acute encephalopathical crisis in GA1 resembles that of a ‘metabolic stroke’ (i.e. acute neuronal damage induced by toxic agents), in contrast to vascular occlusion or hypoxia/ischaemia as in peripartum neonatal encephalopathy (Johnston, 2001). The result is a rapid selective loss of vulnerable neurons rather than an infarct. Our results support the prior assertion that GA-1 preferentially targets striatal medium-spiny neurons, whereas cholinergic neurons are affected to a lesser extent. The mechanisms underlying this particular vulnerability have been the subject of much debate and have been well investigated in models for adult neurodegenerative disorders (Bates, 2003) and for a few paediatric neurological disorders (hypoxia ischemia in the term infant, bilirubin encephalopathy); they may well share final overlapping pathways. Several variables should be considered in a hypothesis to explain the selective striatal damage. A neuro-anatomical basis might play a role. The striatum receives strong glutamatergic corticostriatal and thalamostriatal input as well as dopaminergic input (Haber and Gdowski, 2004). Within the striatum, GABAergic medium-spiny neurons are more vulnerable than cholinergic aspiny interneurons to energy compromise (Nishino et al., 2000). Specific membrane ion channels, glutamate receptor subtypes and subunits, and intracellular enzymatic activities are involved in the events responsible for differential vulnerabilities to oxygen or glucose deprivation and to glutamate receptor-mediated toxicity (Calabresi et al., 2000). Susceptibility to nitric oxide mediated cell damage also strongly differs among striatal neurons, with medium-spiny neurons being the most vulnerable (Dawson, 1995). Quinolinic acid production via shunting through the kynurenine pathway was postulated to play a role in GA-1 some years ago (Heyes, 1987) and has been reiterated as a mechanism through which intercurrent infection could precipitate damage (Varadkar and Surtees, 2004). Recent pathophysiological models for GA-1 refer to many of the above mentioned aspects, hypothesizing a role for accumulating organic acids acting via direct or indirect overactivation of glutamatergic receptors (in particular NMDAr) resulting in increased influx of calcium and increased generation of reactive oxygen species (Kölker et al., 2004a,b). Notably, concentrations of 3-OH-GA in the present post-mortem CNS investigations are at the same level as the lowest concentrations of 3-OH-GA that cause neuronal damage in vitro (Kölker et al., 2004a). Alternate mechanisms have been also considered. Strauss and Morton (2003) speculated on alternative mechanisms of organic acids, such as damage to the microvasculature with modulation of blood–brain barrier permeability, alteration of astrocyte function (Frizzo et al., 2004; Muhlhausen et al., 2004). Integrity of the blood–brain barrier and functional status of astrocytes cannot be assessed by our methods; there is no morphological evidence for changes in the vasculature.
The timing of injury needs to be considered; most children who suffer an encephalopathical crisis do so by 1 year of age and rarely if ever after 5 years (Goodman and Frerman, 2001; Strauss et al., 2003). Some of the vulnerability might be explained on the basis of postnatal developmental changes. Several studies have examined the concentration of glutamatergic receptors in human forebrain using 3H-glutamate and 3H-MK801 binding assays. In the cerebral cortex, the concentration appears to be relatively low in newborns and peaks sometime between 5 months and 1–2 years, thereafter declining. Changes in the modulatory sites of the NMDA receptor can also be demonstrated by pharmacological studies (Kornhuber et al., 1988, 1989; D'Souza et al., 1992; Piggott et al., 1992; Slater et al., 1993; Chahal et al., 1998). The quantity of aspartate binding sites also peaks at around 5 months postnatal in the cortex; this peak in glutamatergic synapses could be related to plasticity (Slater et al., 1992). Fewer studies have directly examined the human striatum; the quantity of glutamate binding sites is roughly similar in putamen and frontal cortex (Kornhuber et al., 1988) and the concentrations of glutamate and aspartate increase rapidly during the first postnatal year (Kornhuber et al., 1993). Studies in the postnatal rat during the first month of life, an age that roughly corresponds to human infancy, have defined at the molecular level the shifts that occur in NMDA receptor subtypes (Monyer et al., 1994; Portera-Cailliau et al., 1996; Gurd et al., 2002). Particular NMDA receptor subtypes may make neurons especially vulnerable in infancy (McQuillen and Ferriero, 2004). Additionally and in relation to the infectious aspect discussed above, the onset of a vulnerable period could reflect the loss of passive immunity after which damage is initiated by exposure to, presumably ubiquitous, infectious agents.
The gross brain findings also need to be addressed. The temporal fossa fluid collections have been interpreted by some as an indicator of atrophy. However, at least two patients in this cohort (not described in this report) identified by newborn screening had the abnormality at 1 and 6 weeks age, without significant neurological impairment. This has also been described by others (Neumaier-Probst et al., 2004). The one case where we were able to examine the temporal lobe tip exhibited no obvious abnormalities and there were no insular cortex abnormalities in any case. Therefore, this represents a developmental abnormality, i.e. temporal hypotrophy or arachnoid cyst-like anomaly, rather than atrophy. The absence of generalized subarachnoid space enlargement suggests that this is not a disorder of CSF absorption, as has been suggested previously (Martinez-Lage, 1996). Concerning the macroencephaly and megalencephaly, only two out of six individuals had enlarged heads during infancy, while brain weight deviated substantially from the median only in the three youngest cases (up to 16 months). In a clinical follow-up study of Nordic patients, the head circumference relative to normal values peaks at 6 months of age and tends to normalize thereafter (Kyllerman et al., 2004). Together, the observations suggest that the brain is most enlarged around the time that encephalopathical crises occur. If the organic acids act as osmotic agents, brain enlargement could partly be accounted for largely by water accumulation; however, our observation that concentration of the organic acids is not correlated with age to some extent negates the idea. Alternative mechanisms, such as a role for GA or 3-OH-GA as osmoregulators (in analogy to N-acetylaspartate in aspartoacylase deficiency) have not yet been investigated (Baslow, 2003). Because our data do not indicate that the concentrations decrease with age, ‘normalization’ of head size and brain weight might be accounted for by mild atrophy beyond the striatum, which can be almost impossible to detect histologically.
With the advent of screening among vulnerable populations, GA-1 can now be identified presymptomatically at birth. Current treatments for newborns identified presymptomatically with GA-1 involve dietary modifications and very aggressive treatment of intercurrent infections (Strauss et al., 2003; Naughten et al., 2004). Outcome in some children treated presymptomatically appears to be improved, but acute brain injury and its devastating sequelae still occur in others (Greenberg et al., 2002). Our evidence of a single insult and data indicating that excitatory synapses peak in the first year of life opens up the possibility that presymptomatic detection and the use of neuroprotective agents could be tried to limit brain injury. Anti-inflammatory agents might also be of value. Whether preservation of neurons (e.g. with a pharmaceutical agent) in infancy could allow them to mature into a less vulnerable phenotype is not known. An animal model of GA-1 that mimics the human neuropathology is required to test possible treatment interventions. However, a useful animal model is not yet available (Funk et al., 2004; Koeller et al., 2004). Further comparative clinical studies of individuals with GA1 in this cohort who do not suffer an encephalopathical crisis could provide some insight. For example, if GA levels in the CSF simply correlated with enzyme activity and with clinical severity, a dose-response relationship could be invoked. However, when considering all mutations, there is no simple correlation between genotype and phenotype; there is some evidence that low excretors tend to be more impaired (Christensen et al., 2004). The significance of this finding is not yet known. One might speculate that low urinary excretion of organic acids in some patients reflects high tissue retention. Alternately, accumulating organic acids might influence the expression of relevant proteins, such as neurotransmitter receptors, thereby altering the susceptibility to neuronal damage—analogous to chemical preconditioning (Riepe et al., 1997; Ravati et al., 2001; Kölker et al., 2002). More work and a representative animal model are required to fully understand the pathogenesis of this disorder (Goodman, 2004).
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We wish to thank members of the Winnipeg GA-1 study group and especially Louise Dilling for helping to identify patients. We wish to thank Melissa Caswill for help with review of the records and Sharon Allen, Susan Janeczko, Patrick Feyh and Christy Pylypjuk for technical assistance. This work was funded by grants to M.D., A.P. and C.R.G. from the Garrod Association of Canada and the Manitoba Medical Service Foundation and a grant to S.K. from the German Research Community (DFG KO 2010/2-1). Dr Del Bigio holds the Canada Research Chair in Developmental Neuropathology.
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