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Published on: March 11, 2020
Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency
Kevin A Strauss1, Jelena Lazovic, Max Wintermark
1Clinic for Special Children, 535 Bunker Hill Road, Strasburg, PA 17579, USA. kstrauss@clinicforspecialchildren.org
Insights
Glutaryl-CoA dehydrogenase deficiency (GA1) can cause permanent disability in Amish infants. Early intravenous fluid and dextrose therapy during illness in the first two years of life significantly protected against brain injury.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Genetics
Background:
- Glutaryl-CoA dehydrogenase deficiency (GA1) is a genetic disorder.
- Early diagnosis is crucial, yet one-third of affected infants develop permanent disabling striatal lesions.
- The Amish population has a high prevalence of GA1 due to a specific GCDH mutation.
Purpose of the Study:
- To investigate the mechanisms of striatal degeneration in Amish GA1 patients.
- To identify potential neuroprotective interventions for GA1.
- To characterize the imaging findings and clinical presentations of striatal injury in GA1.
Main Methods:
- Retrospective study of neuroimaging (MRI, PET) in 25 Amish GA1 patients.
- Analysis of clinical data, including motor development and illness history.
- Correlation of imaging findings with clinical outcomes and interventions.
Main Results:
- Asymptomatic infants showed altered gray matter metabolism and blood volume, suggesting predisposition to injury.
- 36% of patients developed striatal lesions, presenting with sudden motor regression or insidious motor delay.
- Acute striatal necrosis followed a three-stage progression: cytotoxic edema, reduced perfusion, and atrophy.
- Intravenous fluid and dextrose therapy for illnesses in early childhood was strongly neuroprotective (OR=0.04).
Conclusions:
- Both acute and insidious striatal injuries in GA1 may share common mechanisms, differing mainly in timing.
- Early-onset brain injury in GA1 can occur prenatally or perinatally, with delayed clinical manifestation.
- Prompt intravenous fluid and dextrose administration is a critical neuroprotective strategy for GA1 patients.
Abstract:
Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency (GA1) develop striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, we retrospectively studied imaging results from 25 Amish GA1 patients homozygous for 1296C>T mutations in GCDH. Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout gray matter, which may signify a predisposition to brain injury. Nine children (36%) developed striatal lesions: three had sudden motor regression during infancy whereas six had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of three stages: (1) an acute stage, within 24 h of motor regression, characterized by cytotoxic oedema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; (2) a sub-acute stage, 4-5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic oedema; and (3) a chronic stage of striatal atrophy. Apparent diffusion coefficient maps revealed that at least two of the six patients with insidious motor delay suffered striatal injuries before or shortly after birth, followed by latent periods of several months before disability was apparent. Thus, acute and insidious presentations may occur by similar mechanisms, and differ only with regard to the timing of injury. Intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in this cohort (odds ratio for brain injury = 0.04, 95% confidence interval = 0.01-0.34; P < 0.001).
