Canavan Syndrome

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 is suspicious for this disorder.

Canavan-Van Bogaert-Bertrand Disease; Canavan Sclerosis; 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; Acetylaspartic Aciduria; Progressive Degenerative Subcortical Encephalopathy; Aminoacylase-2 Deficiency; ACY2 Deficiency; Aspartoacylase Deficiency.

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.

Autosomal recessive. The disease is caused by mutations of the aspartoacylase gene, which has been mapped to 17pter-p13.

Aspartoacylase deficiency leads to a buildup of N-acetylaspartate. This defect results in demyelination of the white matter of the internal and external capsule, corpus callosum, subcortical white matter, and posterior fossa.

It is based on clinical features and the demonstration of significantly elevated N-acetylaspartate levels in urine, blood, cerebrospinal fluid, and the brain (detected by magnetic resonance spectroscopy). Neuroradiologic studies show white matter degeneration in affected areas. Brain histology shows spongy degeneration (unspecific), but is usually not required for the diagnosis. Electron microscopy reveals swelling of the astrocytes and abnormalities of the mitochondria. Cultured skin fibroblasts show reduced aspartoacylase activity.

Three different forms of Canavan disease (CD) have been described (neonatal, infantile, and late-onset form). The infantile form seems to be the most common form, and only the rate of disease progression is highly variable. Onset is usually in early infancy at 2 to 4 months of age with loss of the already acquired milestones, while death occurs most often within the first decade of life (although death by approximately 18 months of age is not uncommon). However, survival into the teens has also been reported, and one patient survived for more than 30 years. Patients initially present with poor head control due to hypotonia or atonia of the neck muscles. Hypotonia soon becomes generalized and changes to spastic diplegia or quadriplegia as the disease progresses, ending in late decerebrate or decorticate posturing. Generalized seizures are common. Ocular features include optic atrophy, nystagmus, and finally blindness. Closure of the anterior fontanelle is delayed, and macrocephaly is a common finding. Patients usually are deaf. Copious oral secretions and gastroesophageal reflux can occur. No effective treatment is available. Therapies are mainly symptomatic (e.g., seizure control, physiotherapy). Gene therapies are currently under investigation.

The patient's seizure control should be assessed and medications altered, if necessary. A chest radiograph is recommended if recurrent or recent aspiration is an issue. Consider premedication with a nonparticulate antacid, H2-antagonist, or proton pump inhibitor. Avoid antidopaminergic medications because they can exacerbate existing extrapyramidal movement disorders. Sedative and anxiolytic premedication and the presence of the primary caregiver during induction of anesthesia may be considered. Anticholinergic drugs (e.g., atropine, glycopyrrolate) can be helpful in reducing oral secretions. Depending on the type of procedure, postoperative mechanical ventilation may be required.

A rapid sequence induction technique is recommended. Given the copious secretions and the gastroesophageal reflux disease, patients should be intubated to protect the airway from aspirations. Principal anesthetic considerations are related to seizure control, prevention of aspiration, and airway complications. Carefully evaluate for generalized hypotonia postoperatively.

Chronic antiseizure therapy may change the elimination of anesthetic and other drugs. Avoid medications that reduce the seizure threshold or interfere with the antiepileptic treatment. Avoid succinylcholine in patients with spastic diplegia or quadriplegia due to the risk of an exaggerated hyperkalemic response.

(An overview table can be found under Leukodystrophies).

Alexander Syndrome: A degenerative and progressive disorder of the nervous system caused by leukodystrophy. Affects mainly males and usually begins at approximately 6 months of age. Symptoms include mental and physical retardation, enlargement of the brain and head, spasticity (arms and legs), and seizures.

Metachromatic Leukodystrophy: An inherited disorder of myelin metabolism with progressive loss of white matter in the central and peripheral nervous system.

Pelizaeus-Merzbacher Syndrome: A very rare slowly progressive dysmyelinating disease affecting in a diffuse pattern the cerebrum, cerebellum, brainstem, and spinal cord. Two types are described: X-linked (infantile form) and autosomal dominant (preadulthood form). Clinical features include stridor, muscle spasticity, and nystagmus. Often fatal in the first year of life because of respiratory complications.

X-Linked Adrenoleukodystrophy (XLA): A disorder characterized by progressive demyelinization of the central nervous system and peripheral adrenal insufficiency.

Schilder Syndrome: A rare, progressive, lethal disease of the central nervous system that affects mostly children and is characterized by adrenal atrophy and diffuse central demyelination. Presents with progressive dementia, spasticity, cortical blindness, deafness, hemiplegia, quadriplegia, ataxia, pyramidal signs, seizures, retrobulbar neuritis, and pseudobulbar palsy. Onset in late childhood. Most patients die within a few months after onset.

Zellweger Syndrome: A disorder characterized by the congenital absence of functioning peroxisomes (cellular structures responsible for elimination of toxic substances) resulting in a cerebrohepatorenal syndrome. The disease affects the brain development, particularly myelination. The most important features include hepatomegaly, polycystic kidney disease, visual disturbances, and high plasma levels of iron and copper. Other features include muscular hypotonia already noticeable at birth, mental retardation, seizures, coagulopathy, and dysphagia with recurrent aspiration. Congenital heart defects have been described. Life expectancy is approximately 6 months.