Clinical signs

Patients are normal at birth and during the first month of life. Axial hypotonia and macrocephaly appear around the 2nd to 4th month in the infantile form, and later in the juvenile form. The worsening of the neurological picture continues, transitioning to spasticity and opisthotonos, loss of contact, sleep disturbances, blindness, convulsions.
Leukodystrophy is shown by brain imaging methods.

Diagnosis

The diagnosis is made by urinary excretion of N-acetylaspartate, which is 50 times more than normal. Histopathology shows spongy degeneration.

Pathophysiology and genetics

Aspartoacylase, an enzyme that converts N-acetylaspartate into aspartate and acetic acid, is deficient: this enzyme is abundant in white matter but can also be measured in cultured fibroblasts. Aspartoacylase is located in oligodendrocytes – these are the cells that synthesize myelin – the gene that codes for this enzyme is located on the short arm of chromosome 13. It has 6 exons that span 29 kb; the protein, a 55 kDa monomer, has 313 amino acids.
Two mutations have been discovered in Aschkenazi Jews (A854G and C693A); they are responsible for 97% of the cases observed in this population. Other mutations unrelated to a founder effect have been observed in other populations.
Prenatal diagnosis is easy by analysing N-acetylaspartate in the amniotic fluid or, if the mutation is known, by searching for it in the chorionic villi.
The pathophysiology is poorly understood: N-acetylaspartate, which accumulates in white matter due to enzymatic deficiency, is specifically synthesized in gray matter neurons in which aspartoacylase has very little activity. The function of N-acetylaspartate in the brain is essential both at the level of the molecular water pump for myelinated neurons and as an acetyl group donor during the synthesis of lipids in myelin. A prevention program in populations at risk is based on the search for heterozygotes by studying the mutations mentioned above.