Case of the Week
Section Editors: Matylda Machnowska1 and Anvita Pauranik2
1University of Toronto, Toronto, Ontario, Canada
2BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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September 2, 2021
Canavan Disease
- Background:
- Canavan disease is an autosomal recessive disorder that is caused by a deficiency of aspartoacylase (ASPA).
- ASPA, largely expressed in oligodendroglia, hydrolyzes NAA to acetate and aspartate.
- Deficiency of ASPA results in the accumulation of NAA in the brain, from where some of it is excreted in urine.
- Myelin damage is related to profound impairment of water homeostasis resulting in fluid imbalance between intracellular (axon-glial) and extracellular (interlamellar) spaces within myelinated white matter.
- Accumulation of NAA leads to abnormally high osmolar levels in the periaxonal space and vacuolar spongiform destruction of gray matter and existing myelin.
- Clinical Presentation:
- Progressive and fatal disorder affecting the CNS, muscles, and eyes
- Early symptoms in the first weeks to months of life include marked hypotonia with severe head lag. Macrocephaly and seizures may soon develop.
- Symptoms progress to spasticity, intellectual failure, and blindness.
- Death usually occurs in the second year of life.
- Key Diagnostic Features:
- Bilateral symmetric T2 white matter hyperintensity including the cerebellum
- The juxtacortical U-fibers are preferentially affected in the early course of the disease.
- The globi pallidi are nearly always affected, with sparing of the adjacent putamen; thalami are frequently involved, especially in more advanced stages.
- The cerebellar dentate nuclei may be affected.
- ADC values may be reduced in the white matter due to myelin vacuolization, which has been noted as an early marker of Canavan disease in infants.
- MRS reveals elevated levels of NAA peak, a finding that is strongly suggestive.
- Differential Diagnoses:
- Differential diagnoses include other macrocephalic leukodystrophies such as:
-
Alexander disease: Frontal dominance typical; diffuse brain involvement later in disease course; caudate involvement; differing periventricular signal; contrast enhancement; facilitated diffusion; low NAA +/- high myoinositol
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC): Clinical criteria (onset in first year for Canavan, second year for MLC); cerebral deep gray nuclei spared; subcortical cysts; facilitated diffusion; low NAA
- Vanishing white matter disease: Usually later onset; early psychomotor development normal or mildly delayed; white matter restricted diffusion in active disease; gradual development of white matter rarefaction/necrosis vermian atrophy; absent metabolites other than lactate and glucose in affected white matter
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- Differential diagnoses include other macrocephalic leukodystrophies such as:
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Treatment:
-
There is no cure, nor is there a standard course of treatment. Treatment is symptomatic and supportive.
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