Severe Canavan Disease

Severe Canavan disease (CD) is a rapidly progressing neurodegenerative disorder characterized by leukodystrophy with macrocephaly, severe developmental delay and hypotonia.

Epidemiology

The disease has been reported worldwide, but is more frequent in Ashkenazi Jewish population. The incidence of the severe form of CD in the non-Jewish population has been estimated at approximately 1:100,000 births. If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500.

Clinical description

Onset of severe CD is in infancy. Patients have hypotonia, head lag, and macrocephaly. Developmental delay is most frequently noticed between the 3rd and 5th months of life: patients fail to achieve independent sitting, ambulation and speech. The head circumference increases after the age of 6 months and is usually above the 90th percentile by one year of age. With age, hypotonia progresses to spasticity, seizures may occur and optic atrophy is apparent. Children are often irritable and exhibit sleep disturbance. Gastro-esophageal reflux leads to feeding difficulties, requiring nasogastric feeding or permanent feeding gastrostomy.

Etiology

CD is caused by mutations in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme, the only enzyme responsible for the deacetylation of N-acetyl-L-aspartic acid (NAA) in the brain. Enzymatic activity is usually totally absent in severe CD. The most frequent mutations found in Ashkenazi Jews are a missense (E285A) and a nonsense (Y231X) mutation (84% and 13.4%, respectively). In the non-Jewish population the mutations are different and more diverse, the most common being the A305E missense mutation.

Diagnostic methods

Diagnosis is suspected based on the clinical findings of hypotonia, macrocephaly and head lag. The urine reveals a very high concentration of NAA. Cerebro-spinal fluid and blood also contain high levels of NAA. Brain CT scan or MRI show diffuse white matter degeneration and leukodystrophy progressing with age. Mutation screening can be performed for molecular diagnosis.

Differential diagnosis

Differential diagnosis includes other neurodegenerative disorders such as Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaric acidemia type 1 (see these terms). Spongy degeneration of the brain can be observed in Leigh syndrome and glycine encephalopathy (see these terms) or other mitochondrial disorders and viral infections.

Antenatal diagnosis

Antenatal diagnosis is feasible by DNA analysis when the proband mutation is known. Preimplantation diagnosis using a single cell mutation analysis is feasible in an at-risk pregnancy. When mutation analysis is not available, determining the concentration of NAA in the amniotic fluid may be used for the diagnosis.

Genetic counseling

CD is an autosomal recessively transmitted disease, recurrence risk is 25%. Carrier molecular genetic testing is available in a clinical setting. Ashkenazi Jewish individuals are tested for the most prevalent mutations. For non-Jewish couples, genotype should be determined using molecular diagnostic techniques.

Management and treatment

There is no curative treatment for severe CD. Management is supportive and relies on feeding assistance, physical therapy to improve the muscular status, antiepileptic drugs and therapies to improve communication skills. Research for gene therapy and enzyme replacement therapy is ongoing.

Prognosis

Prognosis is variable but globally poor. Life expectancy is about one decade, although with advances in medical and nursing care, some patients survive into their adolescence or young adulthood. Morbidity is also severe, with a total dependence for daily living activities.