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Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome.

The inherited pediatric leukodystrophy Canavan disease is characterized by dysmyelination and severe spongiform degeneration, and is currently refractory to treatment. A definitive understanding of core disease mechanisms is lacking, but pathology is believed to result at least in part compromised fatty acid synthesis during myelination. Recent evidence generated in an animal model suggests that the breakdown of N-acetylaspartate metabolism in CD results in a heightened coupling of fatty acid synthesis to oligodendrocyte oxidative metabolism during the early stages of myelination, thereby causing acute oxidative stress. We present here the results of a dietary intervention designed to support oxidative integrity during developmental myelination in the nur7 mouse model of Canavan disease. Provision of the odd carbon triglyceride triheptanoin to neonatal nur7 mice reduced oxidative stress, promoted long-term oligodendrocyte survival, and increased myelin in the brain. Improvements in oligodendrocyte survival and myelination were associated with a highly significant reduction in spongiform degeneration and improved motor function in triheptanoin treated mice. Initiation of triheptanoin treatment in older animals resulted in markedly more modest effects on these same pathological indices, indicating a window of therapeutic intervention that corresponds with developmental myelination. These results support the targeting of oxidative integrity at early stages of Canavan disease, and provide a foundation for the clinical development of a non-invasive dietary triheptanoin treatment regimen.

Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease.

Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.

Canavan disease (CD) is a genetic degenerative brain disorder associated with mutations of the gene encoding aspartoacylase (ASPA). In humans, the CD syndrome is marked by early onset, hydrocephalus, macroencephaly, psychomotor retardation, and spongiform myelin sheath vacuolization with progressive leukodystrophy. Metabolic hallmarks of the disease include elevated N -acetylaspartate (NAA) levels in brain, plasma and CSF, along with daily excretion of large amounts of NAA and its anabolic metabolite, N -acetylaspartylglutamate (NAAG). Of the observed neuropathies, the most important appears to be the extensive demyelination that interferes with normal neuronal signaling. However, finding the links between the lacks of ASPA activity in oligodendrocytes, the buildup of NAA in white matter (WM) and the mechanisms underlying the edematous spongiform leukodystrophy have remained elusive. In this analytical review we consider what those links might be and propose that in CD, the pathological buildup of NAA in limited WM extracellular fluid (ECF) is responsible for increased ECF osmotic–hydrostatic pressure and initiation of the demyelination process. We also hypothesize that NAA is not directly liberated by neurons in WM as it is in gray matter, and that its source in WM ECF is solely as a product of the catabolism of axon-released NAAG at nodes of Ranvier by astrocyte NAAG peptidase after it has docked with the astrocyte surface metabotropic glutamate receptor 3. This hypothesis ascribes for the first time a possible key role played by astrocytes in CD, linking the lack of ASPA activity in myelinating oligodendrocytes, the pathological buildup of NAA in WM ECF, and the spongiform demyelination process. It also offers new perspectives on the cause of the leukodystrophy in CD, and on possible treatment strategies for this inherited metabolic disease.

N-acetyl-L-aspartate (NAA), an abundant amino acid present in the vertebrate brain, is synthesized and stored primarily in neurons. Its metabolism is also dynamic, with NAA turning over more than once each day by its regulated efflux into extracellular fluid (ECF), cycling between an anabolic L-aspartate acetylating compartment in neurons and a catabolic NAA deacetylating compartment in oligodendrocytes. An inborn error in NAA metabolism results in Canavan disease (CD), a rare and usually fatal early-onset autosomal recessive human central nervous system (CNS) disease, caused by failure of the catabolic metabolism of NAA resulting from a lack of sufficient amidohydrolase II activity in oligodendrocytes. Various hypotheses regarding the metabolism of NAA and its role have been considered, and although NAA may perform several functions in the CNS, an important role of NAA appears to be osmoregulatory. Based on this role, an osmotic-hydrostatic mechanism for the etiology of the CD phenotype is proposed. In CD, the daily addition of 13375 Pascals (0.132 atmospheres or 1.94 lbs per square inch) of hydrostatic pressure to brain ECF, on the brain cell side of brain-barrier epithelial membranes, resulting from the continuous synthesis and efflux of NAA, is considered to be responsible for the syndrome.

N-Acetylaspartic acid accumulates in Canavan Disease, a severe inherited neurometabolic disease clinically characterized by severe mental retardation, hypotonia, macrocephaly and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain poorly understood, in the present study we investigated the in vitro and in vivo effects of N-acetylaspartic acid on the activities of catalase, superoxide dismutase and glutathione peroxidase, as well as on hydrogen peroxide concentration in cerebral cortex of 14-day-old rats. Catalase and glutathione peroxidase activities were significantly inhibited, while hydrogen peroxide concentration was significantly enhanced by N-acetylaspartic acid both in vitro and in vivo. In contrast, superoxide dismutase activity was not altered by N-acetylaspartic acid. Our results clearly show that N-acetylaspartic acid impairs the enzymatic antioxidant defenses in rat brain. This could be involved in the pathophysiological mechanisms responsible for the brain damage observed in patients affected by Canavan Disease.

Canavan in 1931 described spongy degeneration of the brain in a child who was thought to have had Schilder's disease. Since that classic histological description, Canavan disease has become a distinct clinical entity, with the recognition by Van Bogaert and Bertrand that this is an autosomal recessive disease prevalant among children of Jewish extraction. Recent advances in the understanding of the biochemical defect led to an increase in awareness and ease in diagnosis, and indeed the disease is not as rare as initially thought. Exploring the molecular aspects of Canavan disease has led to exciting new developments in carrier detection and prevention of Canavan disease. Work is underway in our laboratory to develop a knock-out mouse for Canavan disease for understanding of the pathophysiology of this disease and formulating gene therapy.