Glutaric aciduria type 1: proton magnetic resonance spectroscopy findings

Glutaric aciduria type 1 is an inborn error of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-coenzyme A dehydrogenase. The disease often appears in infancy with an encephalopathic episode that results in acute basal ganglia and white matter degeneration. The neuroimaging findings in glutaric aciduria type 1 have been well defined. However, the changes in magnetic resonance spectroscopy, a noninvasive tool for identifying the biochemical state of the brain, are scarce in glutaric aciduria type 1. This report presents the magnetic resonance spectroscopy findings in a 19-month-old male with glutaric aciduria type 1. Magnetic resonance spectroscopy of right frontal white matter and right lentiform nuclei revealed decreased N-acetylaspartate/creatine ratio, slightly increased choline/creatine ratio, and increased myoinositol/creatine ratio, compared with the age-matched control patients. We thought that these changes were in accordance with neuroaxonal damage, demyelination, and astrocytosis in these areas. In conclusion, proton magnetic resonance spectroscopy provides a tool for assessing metabolic disturbances and the extent of brain damage noninvasively in glutaric aciduria type 1.     

Glutaric aciduria type I: a neuroimaging diagnosis?

Glutaric aciduria type I is an autosomal recessive disorder of organic acid metabolism secondary to glutaryl-coenzyme A (CoA) dehydrogenase deficiency. We report a previously healthy 17-month-old girl who presented with acute dystonia. Conventional T2-weighted and fluid-attenuated inversion recovery magnetic resonance images of the brain showed hyperintensity in the caudates and putamina bilaterally with subtle involvement of the medial frontal lobes. Diffusion-weighted magnetic resonance images showed striking restricted diffusion in the caudates and putamina consistent with acute necrosis. Single-voxel hydrogen magnetic resonance spectroscopy of the involved areas was normal. The clinical diagnosis of glutaric aciduria type I was confirmed by elevation of 3-hydroxyglutaric and glutaric acids. Diffusion-weighted magnetic resonance imaging is a sensitive indicator of basal ganglia necrosis in glutaric aciduria type I.     

Acute bilateral striatal necrosis with rotavirus gastroenteritis and inborn metabolic predisposition

We present a 9-month-old male with acute rotavirus gastroenteritis who developed an acute encephalopathy with focal seizures and developmental regression. Magnetic resonance imaging showed bilateral striatal necrosis and raised glutarylcarnitine levels on tandem mass spectrometry of a (crisis) blood spot, and chromatography of organic acids revealed increased urinary excretion of dicarboxylic acid. Skin biopsy demonstrated a partial decrease in glutaryl-CoA dehydrogenase activity. The case was not typical for either rotavirus encephalitis/rotavirus-associated encephalopathy or for glutaric aciduria type I. The patient has developmental delay and continues to receive physiotherapy, speech therapy, and local developmental follow-up.     

Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy

The clinical phenotype of multiple acyl-CoA dehydrogenase deficiency in infancy is characterized by recurrent episodes of hypoketotic hypoglycemia and lipid storage myopathy. Brain damage has been described only as a consequence of severe and protracted hypoglycemia. We describe a child who experienced normal physical and psychomotor development until the age of 3 years, who then developed progressive intention tremors, dysarthria, ataxia, and spastic tetraparesis. Episodes of acute metabolic distress were never observed. Magnetic resonance imaging disclosed abnormal signals within the white mater of the brain and cerebellum, suggesting leukodystrophy. Gas chromatography/mass spectrometry analysis revealed abnormally high levels of glutaric acid, dicarboxylic acids, and glycine derivatives in urine. Riboflavin therapy was initiated at 4 years of age, when the patient had already lost control of trunk and head posture. Consistent improvement rapidly occurred after riboflavin supplementation. Glutaric aciduria type II may cause brain damage, in spite of the absence of acute metabolic distress, and should be considered in the differential diagnosis of leukodystrophies.     

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy

Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.     

Glutaric aciduria type 1 presenting with epilepsy

Glutaric aciduria type 1 (GA-1, OMIM 608801) is an autosomal-recessive disorder resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Clinical expression usually involves an acute encephalopathic episode in infancy, followed by the development of severe dystonia–dyskinesia. Other presentations include mild developmental delay, macrocephaly, and subdural haematoma. Seizures may occur with the acute encephalopathy but are unusual in the long term, unless motor or cognitive difficulties are severe. We report a 6-year-old female who was referred with recurrent epileptic seizures that proved difficult to control with first-line anticonvulsants. There was no history of encephalopathy. She had no neurological or developmental abnormalities. The electroencephalogram was profoundly abnormal with slow background and mixed multifocal and generalized spike-and-wave discharges. Seizures deteriorated on valproic acid. Cranial magnetic resonance imaging showed widened Sylvian fissures. Metabolic investigations revealed GA-1. She has improved on a low-protein diet, carnitine, levetiracetam, and lamotrigine. This is the first report of epileptic seizures as the sole presenting feature of GA-1 and it potentially adds to the clinical spectrum of this disorder. Furthermore, the case emphasizes the role of metabolic investigation when first- or second-line treatment of epilepsy is unsuccessful.     

Acute metabolic crisis induced by vaccination in seven Chinese patients

Seven Chinese patients (5 males and 2 females) with vaccination-induced acute metabolic crisis were reported. Only one male with 21-hydroxylase deficiency had been diagnosed before vaccination. In the remaining six patients, the preexisting diagnoses were not confirmed before the vaccination. Acute metabolic crisis occurred in seven patients between 3 and 12 hours after the administration of Japanese encephalitis, diphtheria, and tetanus toxoids and acellular pertussis, hepatitis B, or measles vaccines. Patients 1 and 2 displayed acute adrenal insufficiencies at the ages of 5 years and 3 months, respectively. Patient 3 had presented with mild motor retardation previously. Patients 4 to 7 were previously healthy, but suffered from fever, seizures, coma, acidosis, and hypoglycemia after being vaccinated. Glutaric aciduria type 1 was evident in case 4. Leigh syndromes were present in Patients 5, 6, and 7. They all died from respiratory failure before 2 years of age. Symmetric foci, cystic cavitations with neuronal loss, and vascular proliferation were observed by postmortem examination. Among the seven patients, although the vaccines were not the primary cause of the acute metabolic crisis, the severe acute episodes occurred coincidentally.     

Glutaric aciduria types I and II

Glutaric aciduria type I is an autosomal recessive disorder resulting from a deficiency of glutaryl-CoA dehydrogenase. This leads to an accumulation of glutaric and 3-hydroxyglutaric acids and secondary carnitine deficiency. The symptomatology is discussed, especially those resulting from lesions in the basal ganglia, and the encephalopathic episodes which are often precipitated by infections. The variability of the clinical presentation is stressed. The most serious complications are collections of fluid and blood in the middle fossae, the bleeding resulting from rupture of bridging veins. The prognosis does not seem to be related to the extent of the enzyme deficiency. The diagnosis is confirmed by identifying the abnormal acids in the urine and the deficiency of the enzyme in cultured fibroblasts. The differential diagnosis is reviewed: from other biochemical disorders and from other cerebral lesions. Treatment is by special diet and carnitine supplementation. The dystonia can prove difficult to treat, and surgery may be needed to remove the collections of fluid and blood. Glutaric aciduria type II is caused by a deficiency of either electron transport flavoprotein or of electron transport flavoprotein oxoreductase. The symptoms can be mild or severe. The former may only occur in times of stress, and the latter include congenital anomalies, especially of the kidneys and heart. The pathology of these are discussed. The demonstration of organic acids in the urine and the results of muscle and liver biopsies confirm the diagnosis, and treatment with a special diet and supplementation with carnitine and riboflavine is effective.     

Hand tremor and orofacial dyskinesia: Clinical manifestations of glutaric aciduria type I in a young girl

A 16‐year‐old girl with a history of postural hand tremor was investigated. Magnetic resonance imaging, biochemical, enzymatic, and molecular studies demonstrated glutaric aciduria type I (GA1). Now, at 19 years of age, focal dystonia and oral dyskinesia are also present. This is the first reported case of GA1 with such clinical phenotype. © 2003 Movement Disorder Society     

Hemiconvulsion-hemiplegia-epilepsy syndrome as a presenting feature of L-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria was diagnosed in a 9-month-old female infant after a complex febrile convulsion with subsequent transient left-sided hemiplegia. The symptoms were consistent with acute hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance imaging (MRI) of the brain revealed distinct white-matter abnormalities in the bifrontal and bioccipital periventricular area and increased signal intensity in the lenticular, caudate, and dentate nuclei, consistent with L-2-hydroxyglutaric aciduria. Increased concentrations of L-2-hydroxyglutaric acid were detected in the urine, plasma, and cerebrospinal fluid. The patient was homozyous for the p.Lys81Glu (c.241A>G) missense mutation in the L-2-HGA gene, confirming the diagnosis of L-2-hydroxyglutaric aciduria. Acute hemiconvulsion-hemiplegia-epilepsy syndrome has not been reported as a presenting feature in L-2-hydroxyglutaric aciduria. In patients with prolonged or complicated febrile seizures such as hemiconvulsion-hemiplegia-epilepsy syndrome, L-2-hydroxyglutaric aciduria should be included in the differential diagnosis, especially in children with concomitant macrocephaly.     

Adult-onset glutaric aciduria type I: rare presentation of a treatable disorder

neurogenetics - Glutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid...     

Glutaric acid moderately compromises energy metabolism in rat brain

Glutaric acidemia type I is an inherited metabolic disorder biochemically characterized by tissue accumulation of predominantly glutaric acid (GA). Affected patients present frontotemporal hypotrophy, as well as caudate and putamen injury following acute encephalopathic crises. Considering that the underlying mechanisms of basal ganglia damage in this disorder are poorly known, in the present study we tested the effects of glutaric acid (0.2–5 mM) on critical enzyme activities of energy metabolism, namely the respiratory chain complexes I–IV, succinate dehydrogenase and creatine kinase in midbrain of developing rats. Glutaric acid significantly inhibited creatine kinase activity (up to 26%) even at the lowest dose used in the assays (0.2 mM). We also observed that CK inhibition was prevented by pre-incubation of the homogenates with reduced glutathione, suggesting that the inhibitory effect of GA was possibly mediated by oxidation of essential thiol groups of the enzyme. In addition, the activities of the respiratory chain complex I–III and of succinate dehydrogenase were also significantly inhibited by 20 and 30%, respectively, at the highest glutaric acid concentration tested (5 mM). In contrast, complexes II–III and IV activities of the electron transport chain were not affected by the acid. The effect of glutaric acid on the rate of oxygen consumption in intact mitochondria from the rat cerebrum was also investigated. Glutaric acid (1 mM) significantly lowered the respiratory control ratio (state III/state IV) up to 40% in the presence of the respiratory substrates glutamate/malate or succinate. Moreover, state IV respiration linked to NAD and FAD substrates was significantly increased in GA-treated mitochondria while state III was significantly diminished. The results indicate that the major metabolite accumulating in glutaric acidemia type I moderately compromises brain energy metabolism in vitro.     

Basal ganglia lesions in a patient with 3-hydroxyisobutyric aciduria

3-hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. We report the case of a 7-year-old boy with 3HiB-uria who has suffered more than 20 ketoacidotic episodes since the age of 15 months. In the most recent ketoacidotic episode, which was particularly severe, he developed mild dystonia and choreoathetosis. Magnetic resonance imaging (MRI) revealed bilateral swelling and signal abnormalities of the putamina and heads of the caudate nuclei. The abnormal movements showed a gradual improvement over several months, in correlation with neuroradiological findings. 3HiB-uria should be recognized as one of the group of branched chain organic acidemias that can produce lesions in the basal ganglia.     

Nonpoliovirus poliomyelitis simulating Guillain-Barré syndrome

BACKGROUND: Paralytic poliomyelitis due to the wild-type poliovirus has been eradicated in the United States because of effective immunization programs. In the postvaccination era, most cases are caused by other RNA viruses, such as coxsackievirus or echovirus. The condition usually begins with a fever and upper respiratory tract or gastrointestinal tract symptoms that progress to a "paralytic" phase characterized by limb weakness, areflexia, and, occasionally, respiratory failure that superficially resemble Guillain-Barré syndrome. OBJECTIVE: To describe 2 patients with nonpoliovirus poliomyelitis and highlight the findings on magnetic resonance imaging of the spinal cord to distinguish these cases from variants of Guillain-Barré syndrome. DESIGN AND SETTING: Case series from an academic medical center. PATIENTS: Following a viral illness, the patients, aged 35 and 50 years, had painless, progressive, asymmetrical weakness in the arms followed by respiratory failure in one patient, and generalized limb weakness in the other patient, reaching a nadir in 1 week. Both patients had fevers but no signs of meningitis at onset. Tendon reflexes were absent or reduced in affected regions. The cerebrospinal fluid findings were as follows: mononuclear leukocyte counts of 100 000 cells/mm(3) and 700 000 cells/mm(3), respectively, and the protein level was above 10 g/dL in both patients. Compound muscle action potential amplitudes were reduced in some nerves with active denervation in clinically affected muscles, and F-responses were absent but there were no other demyelinating features. Magnetic resonance imaging showed discrete T2-weighted signal changes of the ventral horns of the spinal cord, and one had elevated coxsackievirus titers in the serum. There was little recovery and significant atrophy in weak muscles after 3 years. CONCLUSIONS: The poliomyelitis syndrome still occurs in adults in developed countries. It has superficial similarities to a motor axonal variant of Guillain-Barré syndrome but can be distinguished by clinical, cerebrospinal fluid, and, perhaps specifically, magnetic resonance imaging characteristics.     

18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in glutaric aciduria type 1: clinical and MRI correlations

The clinical, PET (positron emission tomography) and MRI (magnetic resonance imaging) findings of brain studies in eight patients, previously diagnosed to have glutaric aciduria type 1, were retrospectively reviewed. The neurological findings typically consisted of variable degrees of dementia and extrapyramidal symptoms (dystonia, choreoathetosis and rigidity). Both MRI and PET showed involvement of the putamina in all the patients. The PET scan demonstrated lesions in the head of the caudate nuclei in all of the patients. Brain atrophy, and in particular the characteristically-enlarged Sylvian fissures, was better demonstrated by MRI. On the other hand, the cerebral cortex and thalamic structures were found to be normal by MRI in all patients, whereas PET scan showed decreased uptake in the cerebral cortex in seven, and in the thalami in three patients. Correlation between imaging and clinical findings was found to be good when both PET scan and MRI findings of the brain were taken into consideration. Therefore, the functional (PET) and structural (MRI) studies of the brain were complementary in the imaging evaluation of glutaric aciduria type 1.     

Magnetic resonance: a noninvasive approach to metabolism, circulation, and morphology in human brain death.

Phosphorus (31P) magnetic resonance spectroscopy and magnetic resonance imaging were used to study the intracellular metabolism, circulation, and morphology in the brains of 3 patients with clinical brain death syndrome due to traumatic brain damage, subarachnoid hemorrhage, and acute occlusive hydrocephalus caused by a colloid cyst. Magnetic resonance spectra were characterized by a complete absence of ATP and were dominated by an intense inorganic phosphate signal. Magnetic resonance imaging revealed a uniform pattern of diffuse brain swelling and tentorial and foraminal herniation. Intracranial blood flow was absent on the magnetic resonance angiography projections. These preliminary findings suggest an important impact of magnetic resonance in the determination of human brain death.     

L-2-hydroxyglutaric aciduria in two siblings

Two Pakistani siblings with L-2-hydroxyglutaric aciduria are reported herein. A 6-year-old male and a 2-year-old female, born to consanguineous parents, had chronic slowly progressive neurodegenerative disorder with insidious onset after infancy. Mental regression and seizures were evident in both patients, whereas cerebellar dysfunction was the main motor handicap in the male and pyramidal symptoms were prominent in the female. Magnetic resonance imaging revealed bilateral symmetrical abnormal signal in the subcortical white matter, internal and external capsules, basal ganglia, and dentate nuclei. The underlying metabolic defect, which is likely inherited in an autosomal recessive mode, remains unknown in this disorder.     

Magnetic resonance spectroscopic characteristics of glutaric aciduria type II

Magnetic resonance spectroscopy (MRS) of a 12-year-old female patient with glutaric aciduria type II was compared with data obtained from four healthy age- and sex-matched volunteers. In the clinically active phase, conventional magnetic resonance imaging showed mild ventricular dilatation. Frontal lobe choline/creatine (Cho/Cr) ratio (1.98) was higher than the ratios reported for the comparison participants (1.64 [SD 0.21]). The N-acetylaspartate/creatine (NAA/Cr) ratio (1.95) was lower than normal limits (2.66 [SD 0.23]). After successful riboflavin treatment and dietary restriction for proteins, the NAA/Cr ratio was within the normal range (2.44) and Cho/Cr ratio was below the normal range (1.15), suggesting riboflavin-responsive multiple acyl-coA dehydrogenase deficiency. An elevated Cho/Cr ratio and decreased NAA/Cr ratio is consistent with a demyelinating process in the active phase of glutaric aciduria type II. MRS helps to monitor the progress of the disease and the efficacy of treatment by revealing changes in NAA/Cr and Cho/Cr ratios.     

Fumaric aciduria: clinical and imaging features

Fumaric aciduria (fumaric acidemia, fumarase deficiency) is a rare inborn error of metabolism caused by deficient activity of fumarate hydratase, one of the constituent enzymes of the Krebs tricarboxylic acid cycle. We describe the clinical and imaging features of this disease arising from a consanguineous pedigree in 8 patients in the southwestern United States. Thirteen patients have been previously described in the medical literature. Our patients presented with an early infantile encephalopathy with profound developmental retardation and hypotonia, and most experienced seizures. Previously unreported characteristics described here include structural brain malformations, dysmorphic facial features, and neonatal polycythemia. Magnetic resonance imaging showed multiple abnormalities, including diffuse polymicrogyria, decreased cerebral white matter, large ventricles, and open opercula. Fumaric aciduria should be included in the differential diagnosis of inborn errors of metabolism that cause cerebral malformations and dysmorphic features. The possibility that inborn errors of energy metabolism may cause structural malformations deserves increased recognition.