Canavan Disease (CD)

At a glance

A progressive leukodystrophy caused by spongy degeneration of the central nervous system. The clinical triad of hypotonia, macrocephaly, and lack of head control in an infant more than 3 to 5 months old should raise suspicion for this disorder.

Synonyms

Canavan Syndrome; Canavan Sclerosis; Canavan-Van Bogaert-Bertrand Disease; Van Bogaert-Bertrand Syndrome; Van Bogaert-Bertrand Spongy Degeneration Syndrome; Cerebral White Matter Spongy Degeneration; Spongy Degeneration of the Nervous System; Familial Spongy Degeneration; Encephalopathia Spongiotica; Progressive Degenerative Subcortical Encephalopathy; Acetylaspartic Aciduria; Aminoacylase 2 Deficiency; ACY2 Deficiency; Aspartoacylase Deficiency.

History

First described in 1931 by the American neuropathologist Myrtelle Canavan (1879-1953).

Incidence

Although the disorder has been described in all ethnic groups, the highest incidence has been reported in Ashkenazi Jews, in whom it occurs in approximately 1:13,000 live births. Two types of mutations account for approximately 97% of all mutations in these patients, whereas the mutations in the general population are different and more diverse. The most common mutation (in almost 40% of non-Jewish patients) involves codon 305 (A305E), where a missense mutation leads to the substitution of alanine for glutamic acid. In the general population, the birth prevalence is in the range of 1 in 100,000.

Genetic inheritance

Autosomal recessive. The disease is caused by mutations of the aspartoacylase (ASPA) gene, which has been mapped to 17p13.2.

Pathophysiology

ASPA is normally present in white matter glial cells (mainly oligodendrocyte progenitor cells and oligodendrocytes) and responsible for the hydrolysis of N-acetylaspartic acid (NAA) into aspartate and acetate. The ASPA deficiency leads to a buildup of neurotoxic NAA and subsequent deficiency in acetate, which result in dys- and demyelination of the white matter in the internal and external capsule, corpus callosum, subcortical white matter, and posterior fossa.

Diagnosis

Based on the clinical features (the triad of macrocephaly, hypotonia, and decreased/absent head control in an infant is suspicious for neonatal/infantile CD) and the demonstration of significantly elevated NAA levels in urine (currently considered the most reliable method for CD diagnosis), blood, cerebrospinal fluid, and the brain (detected by proton nuclear magnetic resonance spectroscopy). Neuroradiological studies show diffuse and bilateral subcortical white matter degeneration (leukodystrophy) and edema in affected areas. The globus pallidus and thalamus are typically involved, while the putamen and caudate nucleus are spared. Brain histology (not usually required for the diagnosis) reveals unspecific spongiform leukodystrophy with abnormal myelination, and swollen and vacuolated astrocytes. Electron microscopy confirms the swelling of the astrocytes and reveals elongated mitochondria. Cultured skin fibroblasts may show reduced ASPA activity, but this test is considered less reliable.

Clinical aspects

The clinical classification of CD is based on the age at symptoms onset and the ...