Canavan disease: A white matter disorder

Abstract

Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as the loss of myelin, results in axonal dysfunction and hence a disruption of information processing between brain regions. The major feature of leukodystrophies is the lack of proper myelin formation during early development or the onset of myelin loss late in life. These early childhood WM diseases are described as hypomyelination or dysmyelination arising from a primary block in normal myelin synthesis because of a genetic mutation expressed in oligodendrocytes, or failure in myelination secondary to neuronal or astroglial dysfunctions (van der Knaap 2001 Dev. Med. Child Neurol. 43:705-712). Here, we describe the pathophysiological parameters of Canavan disease (CD), caused by genetic mutations of the aspartoacylase (ASPA) gene, a metabolic enzyme restricted in the central nervous system (CNS) to oligodendrocytes. CD presents pathophysiological dysfunctions similar to diseases caused by myelin gene mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk viable) mutant mice. These single gene mutations have pleiotropic effects, whereby the alteration of one myelin gene expression disrupts functional expression of other oligodendrocyte genes with an outcome of hypomyelination/dysmyelination. Among all of the known leukodystrophies, CD is the first disorder, which was approved and tested for the adeno-associated virus vector (AAV)-ASPA gene therapy (Leone et al. 2000 Ann. Neurol. 48:27-38; Janson et al. 2001 Trends Neurosci. 24:706-712) without much success following the first two attempts. ASPA gene delivery attempts in animal models have shown a lowering of N-acetyl L-aspartate and a change in motor functions, while sponginess of the WM, a characteristic of CD remained unchanged (Matalon et al. 2003 Mol. Ther. 7 (5, Part 1):580-587; McPhee et al. 2005 Brain Res. Mol. Brain Res. 135:112-121) even with better viral serotype and delivery of the gene during early phase of development (Klugmann et al. 2005 Mol. Ther. 11:745-753). While different approaches are being sought for the success of gene therapy, there are pivotal developmental questions to address regarding the specific regions of the CNS and cell lineages that become the target for the onset and progression of CD symptoms from early to late stages of development.

Non-genetic therapeutic approaches to Canavan disease

“…suggests that CD mutations might have broader deregulating impacts on the developing CNS (Kumar et al, 2006).…”

“…One of them, the "Ac-lipid-myelin" hypothesis (Table 1) proposes that deficiency in NAA-derived Ac impedes myelin lipid synthesis (Baslow and Guilfoyle, 2013;Hagenfeldt et al, 1987). Although the 1 for more details on the apparent oligodendrocyte number increase in the areas of dysmyelination, the phenotype of the astrocytic (Alzheimer Type 2) populations and the vacuole formation, readers are referred to the review article of Kumar et al (2006). incorporation of acetyl moieties from NAA into myelin lipids has been observed (D'Adamo and Yatsu, 1966), it is believed to be involved in -but not being essential to -myelination, due to documentation of rare cases of CD where ASPA does not function yet myelination proceeds as normal (Janson et al, 2006a;Velinov et al, 2008).…”

“…Canavan disease (CD) is a rare leukodystrophy characterized by diffuse spongiform white matter degeneration, dysmyelination and intramyelinic oedema with consequent impairment of psychomotor development and early death (Hoshino and Kubota, 2014;Kumar et al, 2006;Matalon and Michals-Matalon, 1999a). Globus and Strauss (1928) were the first to recognise the spongy deteriorative effects of the disease, although the first clinical description was provided by Myrtelle Canavan (Canavan, 1931).…”

“…Macroscopically, the brain usually appears to be heavier than expected, and bears a soft, gelatinous white matter. Microscopically, CD patients' brains are characterized by: (i) splits in the myelin lamellae and (ii) astrocytic swelling (evident both in the perikaryon and the processes) accompanied by elongated mitochondria (Adornato et al, 1972;Kumar et al, 2006;Matalon and Michals-Matalon, 1999b;Surendran et al, 2003) 1 .…”

Advances in MR Imaging of Leukodystrophies

“…Children with Canavan disease present with an enlarged head ("megalencephaly"), but show less behavioral changes than other leukodystrophies of infancy. (13,14). Their MRI shows diffuse involvement of white matter including the subcortical U fibers (15).…”