Autosomal dominant cerebellar ataxia deafness and narcolepsy

Melberg, Atle; Hetta, Jerker; Dahl, Niklas; Nennesmo, Inger; Bengtsson, Mats; Wibom, Rolf; Grant, C. A.; Gustavson, K.-H.; Lundberg, P. O.

doi:10.1016/0022-510x(95)00228-0

Cited by 41 publications

(27 citation statements)

References 29 publications

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“…Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN, OMIM 604121) is a degenerative disease caused by mutations in the DNA-targeting domain of the maintenance methyltransferase DNMT1 [7–9]. This adult-onset condition (onset in the second to fourth decade) is characterized by hearing loss, narcolepsy/cataplexy, and cerebellar ataxia; there are also reports of sensory neuropathy and psychiatric and behavioural manifestations.…”

Section: Introductionmentioning

confidence: 99%

Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

et al. 2016

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BackgroundDNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the maintenance methyltransferase DNMT1 and assess the DNA methylation profile of these individuals.ResultsWe report a family with six individuals affected with ADCA-DN; specifically, patients first developed hearing loss and ataxia, followed by narcolepsy, and cognitive decline. We identified a heterozygous DNMT1 variant, c.1709C>T [p.Ala570Val] by Sanger sequencing, which had been previously reported as pathogenic for ADCA-DN and segregated with disease in the family. DNA methylation analysis by high-resolution genome-wide DNA methylation array identified a decrease in CpGs with 0–10 % methylation and 80–95 % methylation and a concomitant increase in sites with 10–30 % methylation and >95 % methylation. This pattern suggests an increase in methylation of normally unmethylated regions, such as promoters and CpG islands, as well as further methylation of highly methylated gene bodies and intergenic regions. Furthermore, a regional analysis identified 82 hypermethylated loci with consistent robust differences across ≥5 consecutive probes compared to our large reference cohort.ConclusionsThis report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0254-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

et al. 2016

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“…Furthermore, a mitochondrial dysfunction at the biochemical level was already documented in skeletal muscle of an ADCA-DN patient in Melberg et al (1995). In addition, the alteration of NAD + /NADH-related pathways that emerged from the methylome study on HSN1E (Sun et al, 2014) also reinforces the possibility of mitochondrial dysfunction in the complex pathogenesis of this disorder.…”

Section: Adca-dn and Hsn1e: Defective Methylation Diseases With Mitocmentioning

confidence: 79%

“…Autosomal dominant cerebellar ataxia-deafness and narcolepsy was first described by Melberg et al (1995), but the genetic cause has been identified only recently in Winkelmann et al (2012). ADCA-DN is initially characterized by late-onset NC with or without cataplexy, complicated in later stages of the disease by sensorineural deafness, cerebellar ataxia, and dementia appear (Melberg et al, 1995).…”

Section: Adca-dn and Hsn1e: Defective Methylation Diseases With Mitocmentioning

confidence: 99%

“…ADCA-DN is initially characterized by late-onset NC with or without cataplexy, complicated in later stages of the disease by sensorineural deafness, cerebellar ataxia, and dementia appear (Melberg et al, 1995). Mild polyneuropathy, optic atrophy, epilepsy, psychosis, diabetes mellitus, cardiomyopathy, and progressive cerebral, cerebellar, and brainstem atrophy may also be present (Melberg et al, 1999; Winkelmann et al, 2012; Moghadam et al, 2014).…”

Section: Adca-dn and Hsn1e: Defective Methylation Diseases With Mitocmentioning

confidence: 99%

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Dna Methyltransferase 1 Mutations and Mitochondrial Pathology: Is Mtdna Methylated?

et al. 2015

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Autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5)-methyltransferase 1 (DNMT1). DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy, and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however, mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed?

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“…In a Swedish family with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA‐DN; OMIM 604121), 4 of 5 affected patients had symptoms of narcolepsy 4, 5. The diagnosis of narcolepsy was based on symptoms of excessive daytime sleepiness and cataplexy and was verified by multiple sleep latency test 4.…”

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confidence: 99%