Resources

Journal of Peripheral Nerve System, September 2016, doi:10.1111/jns.12178
This study details the case of a man who was repeatedly misdiagnosed before ultimately taking a genetic test that confirmed a mutation in the DNMT1 gene and led to the diagnoses of HSAN1E and ADCA-DN. A 20-year-old man experienced sensory symptoms and recurring pain from reflex spasms in his feet, starting at age 8. Misdiagnosed with various disorders and unsuccessfully treated with medications, he was eventually diagnosed with primary generalized epilepsy. However, the anti-seizure medications did not alleviate his symptoms. Healed ulcerations on his fingers led to the diagnosis of common variable immune deficiency (CVID). Thermography led to the diagnosis of Raynaud’s phenomenon; a rheumatologist diagnosed him with systemic sclerosis spectrum disorder; and endocrinological testing led to the diagnosis of low testosterone and Addison’s disease. By the age of 24, the patient had faced depression, auditory issues, muscle atonia, chronic constipation, and required self-catheterization. Genetic testing revealed a novel mutation in the DNMT1 gene and a diagnosis of HSAN1E and ADCA-DN. [Read full article]

Neurological Sciences, February 2024, https://pubmed.ncbi.nlm.nih.gov/37828385/
This paper details the first confirmed case of ADCA-DN in Spain. The patient reached 46 years old without major cognitive or physical impairments, highlighting the variable expression of this genetic condition. At the age of 46 years old, she was referred to the neurology outpatient unit due to difficulties in walking. Her family history revealed that her mother suffered from narcolepsy, deafness, and needed a wheelchair by the age of 60. Her mother passed away at 68 without a definitive diagnosis. The patient also reported a tendency to fall asleep unexpectedly and episodes of flat affect (speaking without emotion) without losing consciousness. Extensive testing was conducted. Blood tests, electroneurograms, and polysomnography yielded normal results. However, 3 MRI brain scan taken in 3 different years showed generalized brain atrophy, most prominently in the cerebellum—the part of the brain responsible for coordination, balance, and fine motor control. Notably, the atrophy was non-specific and non-progressive. Narcolepsy and other genetic neurological disorders causing motor incoordination were ruled out. Ultimately, a targeted genetic test identified mutations in DMNT1, confirming a diagnosis of ADCA-DN. [Read full article]

BMC Neurology, October 2018, doi:10.1186/s12883-018-1177-2
This study identified a new genetic variant in DMNT1, which is the gene associated with HSAN1E. A 38-year-old female Chinese patient was found to have a rare condition called HSAN1E, but her progression of symptoms was atypical. Her first symptoms appeared in her 30s and included trouble walking and sensory neuropathy. This was followed by hearing loss in her 40s. Researchers used genetic testing to discover a new genetic variant on the exon of DMNT1, expanding the spectrum of DNMT1 disorders [Read full article]

JAMA Otolaryngology, 2016, doi:10.1001/jamaoto.2015.3137
This case report described a woman who began experiencing early-onset gradual hearing loss in her mid-40s, with no family history of similar issues or overexposure to loud noises. Medical tests ruled out common causes of nerve damage, such as vitamin deficiencies, diabetes, alcoholism, and paraneoplastic and immune-mediated causes. A visit with an otolaryngologist showed that her hearing tests showed a distinctive hearing loss pattern, which raised consideration of potential ear lesions or diseases. Three years later, both the right and left ear showed similar hearing loss, which indicated that this early-onset hearing loss could be a genetic condition. A genetic test revealed that she had a mutation in the DNMT1 gene, confirming that she had Hereditary Sensory and Autonomic Neuropathy type 1E (HSAN1E). [Read full article]

Neurological Sciences, December 2019, doi:10.1007/s10072-019-04179-6
This article describes a rare genetic disorder involving the DNMT1 gene, which is crucial for many cell functions like controlling gene expression as well as DNA stability. Changes/mutations in this gene can cause two similar conditions: HSAN1E (Hereditary Sensory and Autonomic Neuropathy type 1E) and ADCA-DN (a disorder causing coordination problems, hearing loss, and sleep issues). These disorders share many symptoms, so some doctors group them under “DNMT1 complex disorder.”

This case study focuses on a 22-year-old patient from Portugal who had hearing loss and a loss of sensation below his knees starting at age 17. He did not show any cognitive or mental changes, but tests revealed sensory nerve damage. Further genetic testing identified a new mutation in his DNMT1 gene that had not been reported before. Over four years, his symptoms worsened, and MRI scans showed shrinkage in the cerebellum and mild brain atrophy (loss or death of tissue).

It was emphasized that HSAN1E is a very rare condition, with only 18 families worldwide identified with the disorder. It typically starts with hearing loss in the late teens or early twenties, followed by nerve damage and sometimes skin ulcers. Most people with HSAN1E also develop cognitive and behavioral changes by their 40s or 50s. Other possible symptoms include hallucinations, sleep issues, and seizures. More studies are needed to understand this disorder fully and help develop better treatments. [Read full article]

Neurological Sciences, February 2023, doi:10.1007/s10072-023-06652-9
This paper follows a 33-year-old Greek woman with HSAN1E. The condition caused sensory loss, preventing her from feeling pain when she was injured, but she did have occasional sharp pains along her nerves, starting in her feet. For example, she fractured her toe without realizing it. She also suffered from mild memory issues, trouble sleeping, and sometimes acted out her dreams. Her personal and family medical history had no other major issues. Upon evaluation by the physicians, they found a general lack of reflexes and significant loss of sensation to pinpricks and vibrations, especially in her legs. She also had some high-frequency hearing loss. Nerve tests showed weak sensory responses in her arms, which disappeared entirely two years later. In her legs, there was mild, ongoing nerve damage. Blood tests and other investigations, including MRI, did not show anything unusual. Genetic tests didn’t find any mutations, but a custom panel, focused on nerve diseases, found a mutation on exon 21 of the DNMT1 gene. These findings, along with her symptoms, add to our understanding of this rare disorder. [Read full article]

eNeurologicalSci, 2020, doi:10.1016/j.ensci.2020.100271
The patient is a 43-year-old woman who started experiencing bilateral hearing loss at 31, and developed tremors on both hands at 34. By 38, she started having difficulty walking due to an ataxic gait. At the age of 41, a horizontal head tremor began. She has a new mutation in the DNMT1 gene. Interestingly, tests revealed optic atrophy (damage or loss of the nerves that send visual information to the brain). The ankle jerk reflex was absent, and her gait was wide stanced. MRI showed widespread cortical atrophy. Based on the laboratory findings, the patient’s hormonal profile revealed abnormally low levels of FSH and LH, similar to what is found with hypogonadism. Whole exome sequencing identified a heterozygous missense mutation in DNMT1, which is the responsible gene for autosomal dominant cerebellar ataxia, deafness, and narcolepsy. Her mother and youngest sister did not carry the same mutation in the DNMT1 gene. [Read full article]

Clinical Epigenetics, 2016, 8:91
DNA 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. [Read full article]

Neurol Genet, 2020.
To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder. [Read full article]

Brain, 2015.
We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. [Read full article]

Genetics Home Reference, 2014.
The DNMT1 gene provides instructions for making an enzyme called DNA methyltransferase 1. This enzyme is involved in DNA methylation, which is the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms (methylation), to DNA molecules. [Read full article]

Epigenetics, 2014.
DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. [Read full article]

OMIM, 2014.
Hereditary sensory neuropathy type 1E is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early‑onset dementia (summary by Klein et al., 2011). [Read full article]

NCBI Bookshelf, 2013.
DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) is a degenerative disorder of the central and peripheral nervous systems characterized by sensory impairment of the distal lower extremities, loss of sweating (sudomotor function) on the distal aspects of the upper and lower limbs, sensorineural hearing loss, and dementia. Affected persons are normal in their youth but begin to manifest progressive sensory neuropathy and moderate to severe progressive sensorineural deafness by age 20 to 35 years. [Read full article]

American Academy of Neurology, 2013.
Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20-21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. [Read full article]

Genetics Home Reference, 2012.
Hereditary sensory and autonomic neuropathy type 1E (HSAN 1E) is a disorder that affects the nervous system. Affected individuals have a gradual loss of intellectual function (dementia), typically beginning in their thirties. In some people with this disorder, changes in personality become apparent before problems with thinking skills. [Read full article]

HHS, 2011.
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy (HSAN1) with dementia and hearing loss. [Read full article]

Prevention Genetics, 2012.
Hereditary sensory neuropaihy type 1E (HSN1E, OMIM 614116) was first described in a multi-generation American family with adult-onset distal sensory impairment and subsequent progressive memory and sensorineural hearing loss. Onset of dementia occurred between the second and fourth decades of life and death occurred in the fifth and sixth decades of life. [Read full article]

Genetic Information Nondiscrimination Act, 2008.
Title II of the Genetic Information Nondiscrimination Act of 2008 (GINA), which prohibits genetic information discrimination in employment, took effect on November 21, 2009. [Read full article]