Case of the Week

Background:

• Glutaric aciduria type 1 (GA-1) is a rare autosomal recessive neurometabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase, which is involved in the catabolic pathway of the amino acids lysine and tryptophan.
• Enzyme deficiency results in accumulation of glutaric and glutaconic acids, responsible for a brain cytotoxic effect, particularly in the basal ganglia.

Clinical Presentation:

• Most patients are apparently healthy at birth, but present with macrocephaly.
• The clinical course of the disease varies from asymptomatic, for a minority of patients, to a severe disabling movement disorder that usually occurs early in life following an acute encephalopathic crisis in the setting of catabolic situations such as childhood febrile infections.
• The initial crisis, or subsequent crises, can cause striatal degeneration. This striatal injury often results in motor disorder with predominantly dystonic/dyskinetic features.
• Adult-onset presentations differ dramatically from the common early-onset presentations with symptoms that are commonly associated with white matter dysfunction including incontinence, gait abnormalities, inattentiveness, and paraesthesias.

Key Diagnostic Features:

• The imaging features described for GA-1 are a characteristic combination of macrocrania, diffuse cerebral atrophy, widened or “open” Sylvian fissures due to lack of operculation (with temporal lobe hypoplasia), diffuse hemispheric white matter abnormalities, and bilaterally symmetric basal ganglia lesions.
• With progression of disease, diffuse cerebral atrophy, ventriculomegaly, and basal ganglia atrophy become more conspicuous. With further chronicity and enlargement of sulcal spaces, there may be tearing of bridging cortical veins, which can result in recurrent subdural hematomas.
• Subependymal nodules are an uncommon feature of GA-1. These may develop as a natural progression of GA-1 despite early diagnosis and metabolic control, though their clinical significance is yet to be determined.
• Growth of the subependymal nodules with follow-up MRI appears to be slow. Lesion number and size apparently increase with age and might moreover be related to age at diagnosis. The location of lesions is exclusive to the lateral ventricles with a predilection for the roof.

Differential Diagnoses:

• Subependymal hamartomas: seen in patients with tuberous sclerosis. Small subependymal lesions, smaller than 1 cm, demonstrate variable signal on MRI with contrast enhancement and may calcify.
• Subependymal giant cell astrocytoma: benign tumors (WHO grade 1), seen in young patients with tuberous sclerosis. These appear as an intraventricular mass near the foramen of Monro, larger than 1 cm, showing calcifications, heterogeneous MRI signal, and marked contrast enhancement. 
• Subependymal gray matter heterotopia: nodules of gray matter located immediately beneath the ependyma of the lateral ventricles. The nodules follow gray matter on all sequences including on postcontrast sequences.
• Causes of bilateral basal ganglia high T2 intensity: Such as Wilson disease, mitochondrial disease, Huntington disease, hypoxic-ischemic encephalopathy, extrapontine myelinolysis, hepatic encephalopathyhy, and other conditions.

Treatment:

• The therapeutic protocol is based on dietary lysine restriction and carnitine supplementation to minimize the risk of neuronal damage after diagnosis.
• The acute treatment in the encephalopathic crisis follows the basic principles of intoxication due to metabolic disease, which includes the prevention or reversal of the catabolic state through the increase of the caloric rate (or administration of insulin in the case of hyperglycemia); restriction of natural protein for 24 to 48 hours; prevention of carnitine depletion (through supplementa­tion at a dose of 100 mg/kg/day); and corrected hydroelectrolytic disorders.