Canavan disease, also known as spongiform degeneration of white matter (not to be confused with Creutzfeldt-Jakob Disease) or aspartoacylase deficiency, is a leukodystrophy clinically characterized by megalencephaly, severe mental and neurological deficits, and blindness.
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Epidemiology
Canavan disease is prevalent in the Ashkenazi Jewish community 1. The carrier frequency among the Ashkenazi ranges from 1:37 to 1:57, with a corresponding prevalence of 1 in 6000-14,000 in this high-risk group1. In the general population, the prevalence is 1 in 100,000 11.
Clinical features
There are a wide range of clinical features. Generally, there is a progression from lethargy and hypotonia, to macrocephaly (due to underlying megalencephaly) and spasticity, to blindness and seizures, to decerebrate posturing and eventual death 2. In the vast majority of patients, clinical onset is in infancy with death before 5 years of age, and often before 18 months, but juvenile-onset forms of the disease have also been reported 2. Juvenile-onset forms may have speech difficulty, mild intellectual impairment and suffer neurological regression 11.
Pathology
It is an autosomal recessive disorder due to a gene mutation on the short arm of chromosome 17 leading to deficiency of N-acetylaspartoacylase, a key enzyme in myelin synthesis, with resultant accumulation of N-acetylaspartate (NAA) in the brain, cerebrospinal fluid, plasma, and urine 3,4. Although its effects are widespread, it has a predilection for subcortical U-fibers and Alzheimer type II astrocytes in the gray matter 3,5.
Markers
Increased levels of NAA in the urine may be detected 11.
Radiographic features
In Canavan disease the neuroimaging findings are diagnostic of the condition 11.
CT
The edematous sponginess of the white matter causes a characteristically low radiographic attenuation on CT so that it stands out from the relatively unaffected gray matter 4. Megalencephaly may also be also noted depending on the clinical stage 4.
MRI
MRI confirms the megalencephalic appearance and provides more detail of the white matter disease, which is typically diffuse, bilateral, and involving the subcortical U-fibers 4-8,11:
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T1: areas of low signal
mainly within subcortical white matter
generally with sparing of the corpus callosum, caudate nucleus, putamen and internal capsule
as the condition progresses atrophy of the periventricular white matter may be seen with associated ventriculomegaly
globi pallidi and thalami are usually affected as well
T2/FLAIR: findings as above except for areas of high signal in the affected white matter
DWI: restricted diffusion within the diseased white matter
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MR spectroscopy: markedly elevated NAA and NAA:creatine ratio are pathognomonic for the condition 11.
this can be remembered using the mnemonic CaNAAvan
There is no enhancement of affected regions on either CT or MRI 5-8.
Treatment and prognosis
The condition is fatal with death resulting at 2-5 years and treatment is generally supportive 4. No effective treatment is yet available 4. However, genetic therapies are being trialled and seem to reduce the level of NAA within the brain 11.
History and etymology
It was first described by Myrtelle Canavan (1879-1953), an American neuropathologist, in her 1931 seminal paper 9,10.
Differential diagnosis
Consider other dysmyelinating diseases such as:
Alexander disease: anterior dominance, diffuse late in disease course, normal NAA on MRS
Pelizaeus-Merzbacher disease: associated with cerebellar atrophy, has a tigroid pattern of hyperintensity, spares subcortical U-fibers
adrenoleukodystrophy: spares subcortical U-fibers, has a characteristic occipitoparietal periventricular white matter distribution
metachromatic leukodystrophy: spares subcortical U-fibers, has a characteristic “butterfly” pattern
megalencephalic leukoencephalopathy with subcortical cysts: involvement of subcortical U-fibers, sparing of basal ganglia and thalami, associated subcortical cysts (tipically in the anterior temporal lobes)