Introduction

Canavan’s disease is a fatal disease which presents early on in life, with patients typically dying before the age of 10. It is characterised by white matter dysmyelination that appears as spongy degenerations. One of the most noticeable presentations of Canavan’s disease is the inability to pass neuro developmental milestones, abnormally reduced muscular tone, increased head circumference, seizure, and early death. This is an inherited condition showing autosomal recessive inheritance. It is most commonly seen in Ashkenazi Jews, but those with different backgrounds can still get this disease. The disease is thought to be a result of a mutation in the gene that encodes the aspartocylase enzyme. This enzyme is responsible for converting N-acetyl aspartic acid to aspartate and acetate in the human brain. Whilst the exact nature of Canavan’s disease is not known, there are some suggestions implementing myelin breakdown.¹

Molecular discussion of Canavan’s disease

The aspartocylase enzyme has often been associated with Canavan’s disease, with there being a defect in the enzyme observed. N-acetylaspartic acid is a marker used in the diagnosis of the disease as it is released in large quantities in the urine. There are two key aminoacylase, with aminoacylase II being deficient in Canavan’s disease. When the aspartoacylase deficiency was described in the disease, it was suggested that N-acetylaspartic acid plays a key role in the maintenance of white matter in the brain. However, this does still not account for the lack of the hydrolysis of N-acetylaspartic acid causing disruption to white matter.²

Aspartoacylase

We know that Canavan’s disease occurs as a result of a deficiency in the aspartocylase enzyme. Under normal conditions, this enzyme is found in high levels in the white matter and can be linked to myelin tracts. Aspartoacylase is also found in the kidneys and lungs. You cannot assess the levels of this enzyme using a blood test, as it is not found in blood cells. Cultured skin fibroblasts can be used instead. Whilst we find aspartoacylase in the white matter of the brain, its substrate, N-acetylaspartic acid, is only made in the grey matter of the brain, and only found here². 

As Canavan’s disease is caused by the deficiency of the aspartoacylase enzyme, it can be presumed that aspartoacylase in peripheral tissues is used for housekeeping and maintenance. When the level of N-acetylaspartic acid increases, there is swelling in the brain and the white matter is impacted. Due to the disruption to the normal workings of N-acetylaspartic acid, patients experience neurological problems. As the disease progresses,  grey matter becomes involved, shown by grey matter atrophy. Imaging of the brain shows spongy degeneration in the white matter. Electrolytes swell and mitochondria elongate².

Molecular water pump and osmolyte imbalance theory

The brain is a source of metabolic water and uses around 20% of the daily calories consumed. Two of the symptoms of Canavan’s disease are an increase in cerebral spinal fluid pressure and intramyelinic oedema. These are characteristics of fluid imbalance, perhaps implementing a molecular water pump. The theory suggests that N-acetylaspartic acid accumulation could cause an osmotic imbalance in the brain, as it is like taurine (an osmolyte)³. 

Dysmyelination theory

N-acetylaspartic acid derived acetyl groups have been implicated in fatty acid synthesis in rats. Other later studies show N-acetylaspartic acid being transferred from the axon to myelin. This theory suggests that a deficiency of N-acetylaspartic acid derived acetate reduces the generation of certain lipids in Canavan’s disease, which causes dysmyelination. There is also a correlation shown between developmental increases in aspartoacylase activity and myelination. There is further research into this theory, but it is largely based on animal models, so further investigation is needed.

Protein folding and stabilisation theory

. Cells that have active protein secretion pathways are known to be sensitive to disorders from protein misfolding. Oligodendrocyte is an example of these cells.  There is a substrate needed for acetylation and deacetylation of polypeptide chains which are needed to stabilise proteins. When the availability of a substrate called acetyl CoA is reduced, it could have a negative impact on protein folding and stabilization. In mice, the loss of a myelin protein has been shown, alongside a reduction in myelin fibres³. 

Clinical features of Canavan’s disease

When babies with the disease are first born, they appear normal, showing no signs of the disease for the first few months of their life. However, as they progress, they become irritable and have poor head control. Head control is used to assess babies between 3 and 6 months of age. From here onwards, developmental milestones are delayed, and the head size gets progressively larger. The combination of head lag, hypotonia (low muscle tone) and megalencephaly (too large brain) indicated Canavan’s disease.²

The developmental delay is clearer as the child ages, as there is a difference in their motor and verbal skills. They do, however, laugh, smile, roll over and lift their heads. It is uncommon that they begin walking and talking. The low muscle tone can give way to spasticity, sometimes leading to a misdiagnosis with cerebral palsy.²

Treatment

The palliative care measures for those with Canavan’s disease are based on those used for other neurodegenerative diseases. For example, respiratory issues can be treated with suction and cough assist machines and oxygen concentrators. For hypotonia, positioning equipment can be used, as can foam supports, feeder seats and bath chairs.³

In terms of pharmaceutical treatments, early trials tried out acetazolamide to decrease water concentrations and N-acetyl aspartic acid in white matter. Whilst the drug did decrease intracranial pressure, it did not decrease water content or N-acetyl aspartic acid levels. A ketogenic diet was also tried, but these methods did little to reduce oedema. More recently, injections of lipoic acid have been used in animal models. There are encouraging results from these studies, but it is unknown as to whether the same results will be seen in humans.³

Supplementation of acetate in newborns was suggested as the main pathogenesis is postnatal deficiency of aspartoacylase and acetate. When tried, there were improvements in myelin glucocerebroside content and brain vacuolation. There was also a small reversal in motor dysfunction in rats.³

Targeting aspartoacylase deficiency has been difficult as enzyme replacement is hard due to the blood-brain barrier. Some of the surface groups in human aspartocylase were altered to decrease an immune response. However, when used, they did not cause any significant improvements despite them being well tolerated.³

Gene therapy involves the alteration of DNA to reduce disease. Commonly, the mutant gene can be replaced by a functional gene. There was a clinical trial done, where a gene transfer was done in two Canavan’s patients. This study did determine the gene transfer to be safe, but the patients showed different responses, so it was hard to determine if the treatment was successful or not.³

Summary

Canavan’s disease is an inherited degenerative brain disorder likely caused by a deficiency of the aspartoacylase enzyme. As a result, there is an accumulation of N-acetyl aspartic acid in the brain and other parts of the body. It is thought that N-acetyl aspartic acid functions as a water pump. Diagnosis looks for increased levels of N-acetyl aspartic acid in the urine. The disease is characterized by insufficient myelination and spongy degeneration of the brain white matter. As a result, symptoms present in early life and progress through childhood, with patients typically dying before the age of 10. Currently, the disease is incurable, but there are studies looking at gene therapy and enzyme replacement ongoing.