37.1 Clinical Features
and Laboratory Investigations Glutaric aciduria type 1 is an autosomal recessive metabolic disorder with highly variable clinical symptomatology. The disease usually presents with an acute encephalitis-like encephalopathy in infancy or childhood after a normal initial development. In most cases the first episode occurs between the ages of 6 and 18 months. Frequently, the only abnormality preceding the first episode is a developing macro- cephaly. The macrocephaly may already be present at birth. The encephalopathic episode is usually trig- gered by an infectious illness or vaccination. The episode is characterized by hypotonia, loss of head control, spasticity, dystonia, rigidity, orofacial dyski- nesia, grimacing, seizures, opisthotonic posturing, lowering of consciousness, and coma. Recovery is slow and often incomplete. There is usually a preser- vation of intellect. After the first crisis, neurological signs may remain static for a long time, suggesting a diagnosis of postencephalitic damage. More often, the subsequent course of disease is slowly progressive with episodes of acute deterioration, often associated with an infection. Patients frequently have a tendency to sweat profusely. There may be episodes of un- explained fever. Ocular abnormalities are frequent, including intraretinal hemorrhages, cataract, gaze palsy, strabismus, ametropia, and pigmentary retino- pathy. If untreated, death usually occurs in the first decade, in the course of an episode of acute deteriora- tion during an infection or in the course of a Reye syndrome-like episode. In other patients the course of disease is more chronically progressive with retarded development during the first year of life. Subsequent- ly, hypotonia, dystonia, athetoid involuntary move- ments, and spasticity develop gradually over the years with loss of motor skills. The progressive dystonia is disabling and leads to a loss of walking and writing abilities. Also, articulate speech may become progres- sively difficult and may be lost altogether. Mental capabilities are intact or relatively preserved. Some patients are stable for several years, suggesting a diag- nosis of athetoid cerebral palsy. Occasional patients present as adults with signs of a progressive en- cephalopathy. Some patients remain asymptomatic, and asymptomatic adults have occasionally been found during screening of families known to be affected. Thus, there is a large phenotypic variation
within families. With early treatment the prognosis of the patients improves and most or all of the neurolog- ical damage can be prevented. Acute deterioration after instigation of treatment is rare.
In glutaric aciduria type 1, excessive urinary excre- tion of glutaric acid, glutaconic acid, and 3-hydroxy- glutaric acid suggests the diagnosis. The defect in me- tabolization of glutaryl-CoA leads to accumulation of this substance in body fluids, partly esterified with carnitine and excreted as glutarylcarnitine. Carnitine deficiency can be the result of this excessive urinary carnitine excretion. Lysine, hydroxylysine, and tryp- tophan, precursors of glutaryl-CoA, are not elevated in urine or body fluids. During episodes of clinical de- compensation, metabolic acidosis, ketosis, hyperam- monemia, and elevation of serum transaminases may be found. Occasionally hypoglycemia occurs in an acute episode. The diagnosis of glutaric aciduria type 1 may be difficult to establish. Enhanced urinary ex- cretion of the metabolites mentioned may be inter- mittent and only detectable during episodes of meta- bolic derangement. In some cases the urine concen- tration of glutaric acid, glutaconic acid, and 3-hydroxy- glutaric acid may even remain normal during episodes of clinical decompensation. In most (but not all) of these patients a decrease in plasma carnitine levels and an increase in urinary glutarylcarnitine levels can be found, indicative of glutaric aciduria. In some patients only elevated levels of glutaric acid can be found in CSF. A definite diagnosis can be estab- lished by assay of glutaryl-CoA dehydrogenase in leukocytes and fibroblasts and by means of DNA analysis. Asymptomatic siblings of patients with glu- taric aciduria type 1 should always be investigated and, if diagnosed with the same disease, treated. Pre- natal diagnosis can be performed by enzyme assess- ment in chorionic villi or cultured amniotic cells and by DNA-based tests.
37.2 Pathology
External examination of the brain may reveal cerebral atrophy with an open operculum. Ventricular en- largement is often noted. Most commonly noted parenchymal abnormalities involve the putamen and head of the caudate nucleus, less often the globus pal- lidus. Changes tend to be more marked in patients who die after several years than in infants. The lesions
Glutaric Aciduria Type 1
Chapter 37
are characterized by loss of neurons associated with gliosis. The cortex is well preserved.
Marked spongiform changes are seen in the hemi- spheric white matter in some patients. It is the periventricular white matter that is particularly in- volved, whereas the subcortical U fibers are spared. In addition, optic nerves, corpus callosum, internal cap- sule, deep cerebellar white matter, and long tracts of the brain stem may be involved.Vacuolation is caused by myelin splitting and intramyelinic vacuole forma- tion. In electron microscopy splitting is seen to occur along the intraperiod line. Mild spongiform changes due to myelin splitting may be seen in gray matter structures rich in myelin, such as the thalamus, globus pallidus, and brain stem reticular formation.
37.3 Pathogenetic Considerations
Glutaric aciduria type 1 is caused by deficiency of glu- taryl-CoA dehydrogenase. Glutaryl-CoA, a catabolite of lysine, hydroxylysine, and tryptophan is dehydro- genated to glutaconyl-CoA and subsequently decar- boxylated to crotonyl-CoA, both steps being catalyzed by a single enzyme, glutaryl-CoA dehydrogenase. The enzyme is active in mitochondria as a homotetramer.
In glutaric aciduria type 1 this mitochondrial enzyme is lacking. A single case of peroxisomal glutaryl-CoA dehydrogenase deficiency has been described (Ben- nett et al. 1991). Mitochondrial glutaryl-CoA dehy- drogenase is a flavin adenine dinucleotide (FAD)-re- quiring enzyme. Deficiency of this enzyme activity has been reported in glutaric aciduria type 1 and in multiple acyl-CoA dehydrogenase deficiency, also called glutaric aciduria type 2.
The gene encoding glutaryl-CoA dehydrogenase, GCDH, is located on chromosome 19p13.2. Many dif- ferent mutations have been identified in glutaric aciduria type 1. There is no apparent correlation between genotype and phenotype. There is also a marked clinical variability among individuals who are homozygous for the same mutation. This suggests the existence of unrelated, genetically polymorphic protective mechanisms. Clinical variability may also be related to the flexibility of associated enzyme sys- tems such as those involved in g-aminobutyric acid (GABA) or glutamate metabolism. Additionally, envi- ronmental factors may be important in determining the severity of the phenotype.
The cause of striatal dysfunction and necrosis in glutaric aciduria has only been partially elucidated. A number of factors may contribute to the damage. Ex- citotoxicity of accumulating substances may be an important factor and involve activation of N-methyl-
D
-aspartate (NMDA) receptors, of which glutamate is the normal activator.Both glutaric acid and 3-hydroxy- glutaric acid exhibit structural similarities to gluta-
mate. Both glutaric acid and 3-hydroxyglutaric acid are toxic to neurons in culture, and this neurotoxic ef- fect can be prevented by preincubation with NMDA receptor blockers. In addition, glutaric acid, glutacon- ic acid, and 3-hydroxyglutaric acid are competitive in- hibitors of glutamic acid decarboxylase, the enzyme involved in biosynthesis of GABA, an inhibitory neu- rotransmitter. Biochemical analysis of the brains of a few patients demonstrated elevated levels of glutaric acid in the frontal cortex and basal ganglia, very low glutamic acid decarboxylase activity, and very low concentrations of GABA in the caudate nucleus and putamen. Low CSF GABA levels have also been found.
However, the low GABA is not necessarily related to inhibition of glutamic acid decarboxylase, but may also be the result of destruction or dysfunction of GABA-ergic neurons. Quinolinic acid, an intermedi- ate in the metabolism of tryptophan and lysine, and a potent neurotoxin, may contribute to the neuronal damage in glutaric aciduria.
Even less is known about the pathogenesis of myelin splitting and vacuolation. Myelin splitting is probably caused by toxic effects of accumulating sub- stances.
The cause of the macrocephaly has not been ade- quately explained. Contributing factors may be the presence of extracerebral fluid collections, hydro- cephalus, and myelin splitting with intramyelinic ac- cumulation of fluid. The pathogenesis of the extrac- erebral fluid collections is unexplained.
37.4 Therapy
During a metabolic crisis, it is essential to correct the
metabolic decompensation as soon as possible to pre-
vent and limit the irreversible brain damage. A high-
calorie glucose infusion (if necessary together with
insulin), intravenous lipids, intravascular volume ex-
pansion, and correction of acidemia and hypo-
glycemia are essential. Chronic treatment consists of
a diet low in protein, in particular low in tryptophan
and lysine, supplemented with carnitine. Carnitine is
used to stimulate the formation and excretion of glu-
tarylcarnitine. Riboflavin is a coenzyme for glutaryl-
CoA dehydrogenase, but cofactor responsiveness is
rare. A trial of riboflavin can be recommended, but
the drug should be stopped if no beneficial biochem-
ical effect is found. After the onset of neurological
problems this treatment protocol leads to no or only
modest improvement, but in most cases further dete-
rioration is halted and subsequent episodes of acute
encephalopathy are prevented. Early treatment has
been shown to be effective in preventing the occur-
rence of most or all problems, and improvement or
resolution of neuroimaging abnormalities can be ob-
served. Some treated patients, however, still show
some deterioration, and unfortunately even a serious encephalopathic episode may occur.
There are some additional therapeutic options. In view of the decreased GABA levels, treatment with a GABA analogue, baclofen, is logical and has produced some symptomatic improvement with a decrease in dystonia. Gamma-vinyl GABA (vigabatrin) causes an irreversible inhibition of GABA transaminase, the first step of GABA catabolism, and in this way leads to increased GABA levels. Decreased dystonia has been noted with vigabatrin therapy. Valproate has been recommended because of its inhibitory action on GABA transaminase. However, valproate is partly ex- creted as valproylcarnitine and may cause further stress to the already compromised carnitine system.
Whether subdural fluid collections should be evac- uated, and whether shunt implantation should be per- formed in cases of ventricular enlargement and pro- gressive macrocephaly, is highly questionable. Reso- lution of these abnormalities, spontaneously or with metabolic treatment, has been documented. If meta- bolic treatment is not started, deterioration may con- tinue despite neurosurgical intervention. A prompt diagnosis of glutaric aciduria type 1 is extremely important in this context. The stress of the subdural hygroma or hematoma itself and the stress of the surgery, combined with a catabolic state in a very ill child, may provoke serious neurological injury.
37.5 Magnetic Resonance Imaging
CT scan of the brain discloses enlarged CSF spaces in most untreated patients with glutaric aciduria type 1, even if asymptomatic. The most often noted are fluid collections over the convexities in the frontoparietal and frontotemporal areas. In some cases the fron- toparietal fluid collections have the appearance of subdural hygromas, usually bilateral, occasionally unilateral. In most cases the fluid collections consist of enlarged subarachnoid spaces, frequently ascribed
to cerebral atrophy, sometimes to communicating hydrocephalus. Considering the presence of absolute or relative macrocephaly, mild enlargement of the ventricular system, and absence of significant cortical damage at autopsy, communicating hydrocephalus may be the most probable explanation. Both in the case of subdural hygroma and in the case of enlarged subarachnoid spaces, these spaces are crossed by bridging veins. As a consequence, patients with glu- taric aciduria type 1 are prone to developing subdur- al hemorrhages after minor head trauma. Especially in the presence of retinal hemorrhages, a misdiagno- sis of nonaccidental head injury and child abuse is readily made. In many patients with glutaric aciduria type 1, the sylvian fissure is wide open, forming a large CSF space anterior to the temporal lobes. Some authors ascribe these CSF collections to the presence of bitemporal arachnoid cysts, but this is rarely in conformity with the configuration of the CSF collec- tions. Usually they are ascribed to either frontal and temporal atrophy or failure of opercularization. The aspect of the incompletely formed frontal and tempo- ral operculum is most consistent with a failure of opercularization. However, in a few patients a normal sylvian fissure has been noted soon after birth,
Chapter 37 Glutaric Aciduria Type 1 296
Fig. 37.1. Boy, 10 months old, with untreated glutaric aciduria type 1.
The images show extensive bilateral subdural hygromas and frontotempo- ral hypoplasia with an open sylvian fissure. Note that the arachnoid and subdural spaces can be easily distin- guished. Myelination is seriously delayed. The basal ganglia have a slightly abnormal signal intensity.
From Osaka et al. (1993), with permission
Fig. 37.2. A 3-year-old girl with glutaric aciduria type 1, who presented with an acute encephalopathic episode at the age of 1 year. Note the mildly enlarged subarachnoid spaces, the open sylvian fissure, enlarged spaces anterior to the temporal lobe, and mildly dilated lateral ventricles. There are extensive mild signal changes in the periventricular white matter, sparing the corpus callosum and U fibers. Bilateral lesions are present in the putamen, caudate nucleus, globus pallidus, den- tate nucleus, and pontine central tegmental tracts. The puta- men and caudate nucleus are atrophic. Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
䊳
Fig. 37.2.
whereas wide open sylvian fissures are seen several months later, forming an argument for atrophy. De- crease of enlarged CSF spaces has been noted to occur spontaneously and with treatment. In some patients hemispheric white matter hypodensity has been found on CT.
MRI may depict transient subependymal cysts in young and often still presymptomatic infants. MRI also depicts the fluid collections (Figs. 37.1–37.3). In most cases, the aspect of the wide open sylvian fis- sures is not consistent with arachnoid cysts but more probably with hypoplasia of the frontal and temporal operculum (Figs. 37.1–37.3). The enlarged peripheral fluid spaces are the result of enlarged subarachnoid spaces, subdural spaces, or a combination of the two (Figs. 37.1–37.3). Subdural hematomas may also be seen. In some patients the brain has a highly atrophic appearance with greatly enlarged extracerebral fluid spaces (Fig. 37.1).
Bilateral lesions are often seen in central gray mat- ter structures, variably including the putamen, globus pallidus, head of the caudate nucleus, dentate nucleus, and substantia nigra (Figs. 37.1–37.4). The lesions are swollen in the acute stage and subsequently become atrophic. Myelination may be delayed (Fig. 37.1). In some of the patients more prominent white matter abnormalities are seen, most often in combination with striatal lesions or enlarged fluid collections as described above (Figs. 37.2 and 37.4). The white mat- ter abnormalities are extensive, symmetrical, and most marked in the frontal and occipital periventric- ular white matter and in the centrum semiovale. The arcuate fibers and corpus callosum are usually spared (Figs. 37.2 and 37.4). In other patients, more limited white matter abnormalities are seen (Fig. 37.3).
On the whole, the imaging findings are highly vari- able. In some patients no abnormalities are noted at all, whereas in others only or mainly enlarged CSF
Chapter 37 Glutaric Aciduria Type 1 298
Fig. 37.3. A 3-year-old girl with glutaric aciduria type 1, who was diagnosed at the age of 15 months and has been non- compliant with treatment since. There is an open sylvian fis- sure and free space anterior to the temporal lobe. There are small spots of abnormal signal within the deep cerebral white matter. The putamen, globus pallidus, and caudate nucleus
have an abnormal signal and are atrophic. There are signal changes in the central tegmental tracts of the pons. Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
spaces are seen; other cases show a predominance of striatal lesions, while others have a combination of striatal and white matter abnormalities. Most cere- bral abnormalities can be prevented by early treat-
ment. If already present, they tend to improve with treatment, depending partly on the reversibility of the abnormalities found.
Fig. 37.4. A 14-month-old boy with glutaric aciduria type 1.
He was diagnosed at 8 months and responded well to treat- ment.The cerebral white matter is abnormal, partly because of delayed myelination, partly because of white matter damage.
It is easier to distinguish the two using T1-weighted images
(third row). There are bilateral lesions in the putamen, globus pallidus, dentate nucleus, and pontine central tegmental tracts. Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
