Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry

BACKGROUND AND CLINICAL INFORMATION: Head

Summary: Canavan's disease (Canavan-van Bogaert-Bertrand disease) or spongy degeneration of the brain is an autosomal recessive leukodystrophy due to abnormal aspartoacylase. Clinically characterized by hypotonia, head lag, and macrocephaly without hydrocephalus. Biochemically characterized by aspartoacylase deficiency. Histologically characterized by spongiotic changes in both white matter and gray matter.

Biochemistry: N-acetylaspartic acid is found in high concentration and, after glutamic acid, the second most abundant free amino acid in the brain. Canavan's disease is due to deficiency of N-aspartoacylase that catalyses N-acetylaspartic acid into L-aspartic acid and acetate.

Genetics: autosomal recessive, prevalent among Ashkenazi Jew extraction (carrier rate 1:37). The N-aspartoacylase gene is on chromosome 17p13-ter. The most common mutation is a mis-sense mutation in codon 854 that changes from A to C leading to a change of glutamic acid to alanine (E285A mutation)in the hydrolytic domain causing deficient enzymatic activity. Other mutations include A305E. Clinical course is not related to genetic heterogeneity.

Clinical:

Symptoms usually do not manifest at the time of birth.
Clinical triad of hypotonia, head lag, and macrocephaly without hydrocephalus should suggest Canavan's disease. Babies may have developmental delays. Persistent hypotonia and head lag are important features as well as seizure, mental retardation, and macrocephaly.
There may also be optic atrophy, irritability, sleep disturbance and problems with esophageal disorder and swallowing. Most patients die in the first decade of life.
Canavan's disease, Alexander disease and Aicardi-Goutières syndrome are the three leukodystrophy that typically present with megalencephaly.

Clinical variants (described by Acardi):

Congenital form: the disease is apparent at birth or shortly after birth and rapidly progressive;
Infantile form: most common, the symptoms appear after the first 6 months of life;
Juvenile form: disease manifests after the first 5 years of live, relatively rare.

Diagnosis:

Diagnostic Test: quantitation of acetylaspartic acid in urine and aspartoacylase level (accumulation of abnormally high level of non-functional enzyme) in cultured fibroblasts. Carrier state can be detected by abnormal level of aspartoacylase in fibroblasts cultures. Aspartoacylase is not present in plasma or blood cells. In the past, a brain biopsy showing spongy changes is needed for the diagnosis.
Prenatal diagnosis is difficult due to the low enzymatic activity in normaly cultured chorionic villi.
Detection of carrier: aspartoacylase activity in cultured fibroblasts.

NEUROIMAGING: Head

Generalized white matter degeneration primarily in the cerebral hemispheres with less involvement in the cerebellum and brain stem. Neurologic differential diagnoses may include Alexander's disease and Pelizaeus-Merzbacher disease.

NAA peak: Canavan’s disease is the only metabolic disorder that demonstrates an increase in the NAA peak, providing a specific diagnosis.

GROSS PATHOLOGY: Head

The brain often weighs heavier than normal but brains from patients that survive more than two years may be of normal weight. The external surface is normal but the gray white junction is blurred on sections. The white matter is soft and gelatinous but without cavitation. The cerebellum and brain stem are pale.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Histology:

The white matter is vacuolated, particularly subcortically and there is extensive loss of myelin. Less severe vacuolization may be seen in the cortex.
The deep white matter and supreficial cortex are least vacuolated. The vacuoles measure up to 100 micron and are empty. No neutral fat or macrophages are present.
Cortical neurons are normal but many Alzheimer type II astrocytes are seen in the cortex.
In the cerebellum, Alzheimer's type II astrocytes and vacuolization are seen in the subcortical white matter, and in the molecular and Purkinje cell layers of the cortex.

Other structures frequently involved include the optic nerve, basal ganglia, nuclei of the brain stem, and gray and white matter of the spina cord. Peripheral nerve is normal.

Electron microscopy: Two features are seen in the cortex,

Splits in myelin lamellae, and swellings of the astrocytic perikaryon and processes.
Gigantic abnormal and elongated mitochondria that contain dense filamentous matrix and distorted cristae.

NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu

Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry