Marked elevation in the brain concentration of N‐acetyl‐L‐aspartate (NAA) is a characteristic feature of Canavan disease, a vacuolar leukodystrophy resulting from deficiency of the oligodendroglial NAA‐cleaving enzyme aspartoacylase. We now demonstrate that inhibiting NAA synthesis by intracisternal administration of a locked nucleic acid antisense oligonucleotide to young‐adult aspartoacylase‐deficient mice reverses their pre‐existing ataxia and diminishes cerebellar and thalamic vacuolation and Purkinje cell dendritic atrophy. Ann Neurol 2020;87:480–485

Plantar fibromatosis (Ledderhose disease) is a rare, benign, hyperproliferative fibrous tissue disorder resulting in the formation of nodules along the plantar fascia. This condition can be locally aggressive, and often results in pain, functional disability, and decreased quality of life. Diagnosis is primarily clinical, but MRI and ultrasound are useful confirmatory adjuncts. Given the benign nature of this condition, treatment has historically involved symptomatic management. A multitude of conservative treatment strategies supported by varying levels of evidence have been described mostly in small-scale trials. These therapies include steroid injections, verapamil, radiation therapy, extracorporeal shock wave therapy, tamoxifen, and collagenase. When conservative measures fail, surgical removal of fibromas and adjacent plantar fascia is often done, although recurrence is common. This review aims to provide a broad overview of the clinical features of this disease as well as the current treatment strategies being employed in the management of this condition.

The cuprizone induced animal model of demyelination is characterized by demyelination in many regions of the brain with high levels of demyelination in the corpus callosum as well as changes in neuronal function by 4-6 weeks of exposure. The model is used as a tool to study demyelination and subsequent degeneration as well as therapeutic interventions on these effects. Historically, the cuprizone model has been shown to contain no alterations to blood-brain barrier integrity, a key feature in many diseases that affect the central nervous system. Cuprizone is generally administered for 4-6 weeks to obtain maximal demyelination and degeneration. However, emerging evidence has shown that the effects of cuprizone on the brain may occur earlier than measurable gross demyelination. This study sought to investigate changes to blood-brain barrier permeability early in cuprizone administration. Results showed an increase in blood-brain barrier permeability and changes in tight junction protein expression as early as 3 days after beginning cuprizone treatment. These changes preceded glial morphological activation and demyelination known to occur during cuprizone administration. Increases in mast cell presence and activity were measured alongside the increased permeability implicating mast cells as a potential source for the blood-brain barrier disruption. These results provide further evidence of blood-brain barrier alterations in the cuprizone model and a target of therapeutic intervention in the prevention of cuprizoneinduced pathology. Understanding how mast cells become activated under cuprizone and if they contribute to blood-brain barrier alterations may give further insight into how and when the blood-brain barrier is affected in CNS diseases. In summary, cuprizone administration causes an increase in blood-brain barrier permeability and this permeability coincides with mast cell activation.

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Canavan disease is caused by ASPA mutations that diminish brain aspartoacylase activity, and it is characterized by excessive brain storage of the aspartoacylase substrate, N‐acetyl‐l‐aspartate (NAA), and by astroglial and intramyelinic vacuolation. Astroglia and the arachnoid mater express sodium‐dependent dicarboxylate transporter (NaDC3), encoded by SLC13A3, a sodium‐coupled transporter for NAA and other dicarboxylates. Constitutive Slc13a3 deletion in aspartoacylase‐deficient Canavan disease mice prevents brain NAA overaccumulation, ataxia, and brain vacuolation. ANN NEUROL 2021;90:845–850