DNMT1-complex disorder caused by a novel mutation associated with an overlapping phenotype of autosomal-dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) and hereditary sensory neuropathy with dementia and hearing loss (HSN1E)

Abstract

Dear Sir, Autosomal dominant cerebellar ataxias (ADCA) are a group of heterogeneous clinical conditions characterized by frequent association of progressive ataxia with a plethora of different neurological symptoms. They can underlie a broad genetic background with a large group of ADCA causing loci still to be determined. We have recently identified a novel mutation within the DNMT1 gene, in an Italian individual presenting with a complicated neurological condition dominated by cerebellar ataxia. The index patient (Fig. 1a), now 65 years old, presented in his early fifties with slowly progressive hearing impairment, ataxia, and dysarthria. Initial neurologic examination documented the presence of severe gait disturbances and deep sensations impairment. The brain MRI displayed vermian cerebellar atrophy and mild cortical atrophy (Fig. 2). During follow-up visits, the patient manifested a progressive decline of some frontal lobe functions (executive functions, phonemic fluency, and planning) associated with psychosis, urinary urgency, a sensory-motor mixed axonal-demyelinating polyneuropathy with a distal predominance, and lower limbs lymphedema. Patient also reported sleep problems and excessive daytime sleepiness associated with electroencephalographic evidence of bilateral slow activity. Within the last year of follow-up, three undefined syncopal episodes were reported, possibly attributable to cataplexy attacks. Visual disturbance associated with bilateral optic atrophy was also detected. Family history revealed that his mother, deceased at 85 years, had developed in her adulthood a complex syndrome characterized by a diffuse axonal polyneuropathy, deafness, ataxia, and severe cognitive decline with psychosis. Severe hearing impairment in the maternal grandmother and uncle was also reported. Index patient’s father and a younger brother were unaffected (Fig. 1a). We performed clinical exome sequencing (TruSight One Sequencing Panel, Illumina) on our proband. Sequencing data analysis, under the hypothesis of an autosomal dominant disease, led to the identification of a novel heterozygous variant in exon 21 of DNMT1 (NM_001130823.2:c.1794C > T; NP_001124295.1:p.Arg598Trp; Fig. 1b). The nucleotide change was absent in the healthy brother (aged 61) and not reported in the GnomAD database. It hits a conserved amino acid residue (Fig. 1c) and causes an amino acid substitution predicted deleterious by most commonly used variant predictor bioinformatics tools (Table 1). DNMT1 is a key DNA methyltransferase with essential roles in methylation pattern maintenance during chromosome replication and repair. This protein is composed of a catalytic Cterminal region and a regulatory N-terminal region. All diseasecausing mutations reported to date fall within exons 20 and 21, which encode a small domain of the N-terminal region, called replication foci targeting sequence (Fig. 1d), essential for enzymatic dimerization and binding to DNA hemimethylated CpG sites [1]. Heterozygous mutations in DNMT1 have been associated with two autosomal dominant pathological phenotypes, namely hereditary sensory neuropathy with dementia and hearing loss (HSN1E; OMIM#614116); and cerebellar ataxia, * Alessia Catania [email protected]