Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings.

Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1), acute (striatal necrosis) stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients.

Introduction

Glutaric aciduria type 1 is an autosomal recessive disease with typical imaging features. Incidence is 1 in 40,000 live births; but can be as high as 1 in 300 in certain inbred populations. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. To the best of our knowledge, MR imaging of different stages of striatal necrosis in siblings has not been described previously. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients.

Case Report

Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. The younger (1-year-old) child presented with regression of achieved milestones after an acute encephalopathy episode associated with a respiratory infection. The elder (6-year-old) child had similar neurological problems since infancy; he had undergone VP shunting for “subdural collections,” with no clinical improvement.

Imaging of elder child showed a VP shunt [Figures 1a and b] that had been inserted to drain “subdural effusion,” widened sylvian fissures [Figures 1b, d–f], dilated CSF space anterior to temporal lobes [Figure 1a], loss of volume in striatum with a small area of T2 hyperintensity in putamen [Figure 1d], and diffusion restriction [Figures 1e and 1f].

Figure 1

CT scans. (a) Dilated CSF space anterior to temporal lobes; a VP shunt tube noted outside skull (white arrow). (b) Widened sylvian fissure; a VP shunt tube inside (black arrow) and outside (white arrow) skull. (c-f) MRI. (c) T2W image showing dilated CSF space anterior to temporal lobes (white arrow). (d) T2 hyperintensity in putamen. (e) Diffusion image showing hyperintensity in putamen. (f) The ADC map showing hypointensity in putamen. Widened sylvian fissures are seen in d-f images

Imaging of younger child showed widened sylvian fissures [Figure 2a], dilated CSF space anterior to temporal lobes [Figure 2c], T2 hyperintensities in the dentate nucleus [Figure 2b], pons [Figures 2b and 2c], periventricular white matter [Figures 2c–e], caudate nucleus [Figures 2d and 2e], lentiform nucleus [Figures 2d and 2e]. Caudate nucleus and lentiform nucleus showed extensive hyperintensity on diffusion images.

Figure 2

(a) Widened sylvian fissures on CT scan. (b-d) MRI showing T2 hyperintensities. (b) Dentate nucleus (arrow) and pons (arrowhead), (c) periventricular whitematter (arrow) and pons (arrowhead), and (d and e) caudate nucleus (black arrowhead), lentiform nucleus (arrow), and periventricular white matter (white arrowhead). (f) Caudate nucleus (arrowhead) and lentiform nucleus (arrow) hyperintensity on diffusion images. Also seen is dilated CSF space anterior to temporal lobes in (c)

Imaging features are classical of glutaric aciduria type 1, acute (striatal necrosis) stage in younger sibling and chronic stage in older sibling. Urine screening for aminoaciduria was negative in both children.

Discussion

Type 1 glutaric aciduria is an autosomal recessive disease with genetic heterogeneity (caused by many mutations) and phenotypic variability (severe and mild forms of the disease may be seen even in the same family). High incidence is seen in the Palestinian, Amish, Greek, and Canadian Indian populations, reflecting the historical tradition of marriages within extended kindreds.

Deficiency of glutaryl CoA dehydrogenase enzyme leads to elevation of glutaric acid and 3-OH glutaric acid. Dystonia and psychomotor regression are the predominant symptoms. The symptoms appear after an asymptomatic period during the first months of life. It may present chronically and insidiously or acutely as metabolic encephalopathy during a banal infectious condition or vaccination. Microencephalic macrocephaly at birth is the earliest sign of GA1. Rarely, adult onset glutaric aciduria type I presenting with leukoencephalopathy has been reported. Treatment with carnitine, protein restriction, and early approach of the hypermetabolism conditions has been shown to be effective in decreasing the encephalopathy episodes in the first years of life.

Laboratory diagnosis

Neonatal screening programs for glutaric aciduria type I have been established in some countries with high prevalence using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. Due to risk of missing patients with a mild biochemical phenotype (i.e., low excretors), a binary strategy – using glutarylcarnitine as a primary variable and glutarylcarnitine/acylcarnitine ratios as a secondary variable – to improve the diagnostic sensitivity and specificity of neonatal screening is proposed.

In patients, urinary excretion of glutaric, 3-hydroxyglutaric and glutaconic acids may be elevated. If there is suspicion of glutaric aciduria, glutaryl-coenzyme A dehydrogenase should be measured in skin fibroblasts or interleukin-2-dependent lymphocytes even if glutaric acid is not increased in the urine.

Hyperlactacidemia, hyperlactatorrachia, mitochondrial abnormalities in muscular cells and a deficiency in complexes I and IV of the respiratory chain in isolated mitochondria from muscle have been reported in GA-1.

Imaging findings

Widening of the sylvian fissures, the fluid spaces anterior to the temporal lobes, and the mesencephalic cistern are cardinal signs of GA-1.[1] Abnormal high-signal intensity on T2-weighted images is seen in the basal ganglia, periventricular white matter, dentate nucleus, substantia nigra, and the pontine medial lemniscus. Subdural collections and bilateral multiple caudothalamic cysts are described. MRI, CT perfusion, and transcranial Doppler studies have shown altered perfusion and blood flow velocities.[2]

Subdural hemorrhage with/without retinal hemorrhage due to stretched bridging veins may be an initial sign of glutaric aciduria type 1 and can be a diagnostic pit fall[34] since post-traumatic and nonaccidental causes have to be excluded.

Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Between birth and 18 months of age, with a peak at 14 months, 90% of untreated children with GA1 suffer an acute neurological crisis precipitated by an infectious illness. A depressed consciousness and profound axial hypotonia (behavioral arrest) may be accompanied by seizures or dystonic extremity movements. The relatively abrupt neurological deterioration coincides with swelling, metabolic depression, and necrosis of basal ganglia gray matter, especially the putamina.[5] Adequate treatment reduces the incidence of radiologically and clinically evident basal ganglia injury significantly (from approximately 90–35%).

Acute striatal necrosis can be visualized as focal, usually symmetric, stroke-like signal hyperintensity on T2- and diffusion-weighted magnetic resonance imaging (MRI), bilateral striatal lucency on computed tomography (CT), or a sharp decline of fluorodeoxyglucose uptake imaged by positron emission tomography (PET).[5] Diffusion-weighted MR imaging has been known to show more extensive disease than was apparent either on CT or on the conventional MR images.[6] Over ensuing weeks, circumscribed and near-complete degeneration of the putamina occurs with variable extension to the caudates and pallidi. Neural tissue is replaced by a thin gliotic scar and the resulting dystonia is irreversible, static, and severe.

Three stages of acute striatal necrosis have been described: (1) an acute stage, within 24 hours of motor regression, characterized by cytotoxic edema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; (2) a subacute stage, 4-5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic edema; and (3) a chronic stage of striatal atrophy.[7]

When there is a family history of GA-1, prenatal diagnosis at 11 week's gestation through chorionic villus sampling[8] can be done if the responsible mutation is known. Later in pregnancy, ultrasound[8] and MRI[9] can diagnose GA-1 in suspected cases. Progressive dilatation of the quadrigeminal cisterns associated with macrocephaly, fronto-temporal atrophy and wide space of perisylvian fissure were found in the follow-up scans when parents decided to continue pregnancy in affected cases.

Timely diagnosis and start of therapy (preferably in the presymptomatic phase) are essential for the prevention of irreversible brain damage. Greater awareness of glutaric aciduria among pediatricians, neurologists, neurosurgeons, and radiologists is key to (a) avoiding misdiagnosis as bilateral subdural collections (which may be unnecessarily drained) or nonaccidental injury (which has important sociological and legal implications) (b) early diagnosis so that proper neurological development for affected child can by ensured by early diet modification, and (c) genetic counseling of parents regarding future offspring.