LAUSR

Dear Sirs, DNA methyltransferase 1 (DNMT1) is essential for many cellular functions including transcription regulation, cell differentiation, gene imprinting, and genome stability [1–3]. Mutations in the target sequence (TS) domain ofDNMT1 gene (chromosome 19p13.2) are responsible for two overlapping, adult-onset, and autosomal dominant neurodegenerative disorders, in particular hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) [1, 3]. Indeed, HSAN1E and ADCA-DN share much more clinical features than once thought, and Baets et al. have proposed a unified terminology, namely DNMT1 complex disorder [3]. All the known pathogenic mutations causal for HSAN1E and ADCA-DN are located in the middle part of N-terminus end (exon 20) or Cterminus end (exon 21) of the TS domain [1, 3]. A 22-year-old Portuguese patient presented with progressive bilateral perceptive hearing loss and sensory loss below the knees with ulceration in the feet at the age of 17. Muscle strength was normal and weight was stable. There were no cognitive, psychiatric, and/or behavioural changes, hypersomnolence, parasomnia, narcolepsy/catalepsy, myoclonic seizures, and/or autonomic symptoms. His medical and familial history was unremarkable. He was the only child from non-consanguineous and healthy parents. At the age of 18, neurological examination disclosed a bilateral sensorineural hearing loss pattern, analgesia and tactile anaesthesia of the halluces, hypoalgesia and tactile hypoesthesia below the knees, and loss of position and vibration sense in the halluces. Muscle strength and reflexes were normal. Higher mental functions were also normal. There were no clinical signs of optic atrophy and/or lymphedema. Nerve conduction studies were consistent with a length-dependent pure sensory axonal neuropathy. Sudoscan assessment was normal. Blood tests were unremarkable, including blood cell counting, sedimentation rate, cryoglobulins, and autoimmunity screening (anti-nuclear, anti-double-stranded DNA, ANA screening, lupus anti-coagulant, anti-cardiolipin, anti-β2-glycoprotein-I, and anti-neutrophil cytoplasmic antibodies). Serology for HIV 1/2, hepatitis B/C, and Lyme and syphilis (VDRL and TPHA) was negative. Audiometry studies revealed moderate-to-severe bilateral sensorineural hearing loss between the frequencies of 1000 and 4000 Hz. Direct sanger sequencing of HSAN1A, namely SPTLC1 gene, was negative. A custom panel of 74 genes involved in inherited peripheral neuropathies was captured and sequenced on a MiSeq sequencer. Next-generation sequencing allowed the identification of a novel heterozygous pathogenic mutation c.1700T>C (p.Leu567Pro) in exon 21 of DNMT1 gene. The nucleotide change was not previously reported in the literature or Exome Sequencing Project, 1000 Genomes Project, and Exome Aggregation Consortium databases. It hits a highly conserved amino acid residue across species and causes an amino acid substitution predicted deleterious by in silico analysis techniques (bioinformatics). Segregation analysis could not be performed, since genomic DNA samples from his parents were not available. During a follow-up period of 4 years, additional cerebellar signs were observed in both upper and lower extremities, bilaterally. Brain MRI revealed cerebellar atrophy involving both vermis and hemispheres, and also a mild diffuse cortical brain atrophy (Fig. 1). Conventional neuropsychological assessment was normal. * Miguel Oliveira Santos [email protected]