NORD gratefully acknowledges the HSAN1E Society and Christopher J. Klein, MD, Professor of Neurology, Mayo Clinic, Rochester, MN, for the preparation of this report.
The signs and symptoms of HSAN1E and the age of onset are variable, even within members of the same family. HSAN1E typically runs a 15 to 30 year progressive course.
HSAN1E is an adult-onset disorder with an average onset age of 37 years. All HSAN1E pa-tients have presented with a triad of symptoms: hearing loss, sensory neuropathy, and cogni-tive decline. Bilateral hearing loss is often the first symptom and it continues to get worse over time.
Peripheral neuropathy occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.
The cognitive decline (dementia) often starts with personality changes, poor decision making, memory loss, irritability, impulsivity, apathy, and sleepiness.
Some other symptoms of HSAN1E are seizures, auditory or visual hallucinations, renal fail-ure, and sleep disorders.
HSAN1E is caused by a mutation in the DNMT1 gene. Genes provide instructions for creating proteins that play critical roles to allow the body to function normally. When a deleterious mu-tation occurs within a gene, the protein produced will not function normally, and this can af-fect a specific organ or multiple organs of the body. The disease mechanism of the HSAN1E mutations is still being investigated.
The DNMT1 gene is located on the short (p) arm of chromosome 19p13.2. Chromosomes are located on the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. For example, “chromosomes 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a sin-gle copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that oc-curs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
HSAN1E affects both genders equally. Due to the complexity of disease and relatively lack of awareness of this disease, HSAN1E is often misdiagnosed or undiagnosed, making it difficult to assess its prevalence and incidence in the population.
A diagnosis of HSAN1E may be suspected based on the identification of the three main symptoms, a detailed patient history, and a family history. DNA testing for mutations in the DNMT1 gene is necessary to confirm the diagnosis of HSAN1E.
Clinical Testing and Work-up
Nerve conduction studies (NCS) are a standard test for diagnosing peripheral neuropathy. These studies are tests that measure how well individual nerves can send an electrical signal from the spinal cord to the muscles. NCS can determine nerve damage and destruction.
A complete hearing test should be done as well as testing for cognitive function which often shows up in later stage. Individuals who test positive for HSN1E should continue with regular check-ups for hearing tests and clinical testing for dementia.
The treatment of HSAN1E is management of symptoms. Treatment may require a team of specialists including a neurologist, audiologist, and podiatrist.
Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critical. Ulcera-tion of the feet of individuals with HSAN1E is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.
Affected individuals should receive instruction on proper care of their feet, including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.
Shooting pains may be treated with medications commonly used for peripheral neuropathies including amitryptiline, carbamazepine, and gabapentin.
Hearing aides are effective for the hearing loss. As the hearing loss progresses, stronger hearing aids are prescribed.
Sedatives or antipsychotic drugs are often prescribed for the symptoms that are associated with dementia (i.e., roaming behavior, extreme restlessness, delusions, and hallucinations).
As HSAN1E progresses, partners and caregivers may need help from support groups.
Genetic counseling is recommended for individuals with HSAN1 and their family members.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials conducted in Europe, contact:
Baets J, Duan X, Wu Y,et al. Defects of mutant DNMT1 are linked to a spectrum of neurologi-cal disorders. Brain. 2015;138(4):845-861. doi:10.1093/brain/awv010. https://www.ncbi.nlm.nih.gov/pubmed/25678562
Hurley D. Wide Variety of Neurological Disorders Linked to Mutations of Epigenetic Regula-tor. Neurology Today. 2015;15(11):1-19. doi:10.1097/01.nt.0000466928.31108.c4.
Klein CJ, Bird T, Ertekin-Taner N, et al. DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss. Neurology 2013 Feb 26;80(9):824-8. doi: 10.1212/WNL.0b013e318284076d. Epub 2013 Jan 30. https://www.ncbi.nlm.nih.gov/pubmed/23365052
DNMT1 gene – Genetics Home Reference. U.S National Library of Medicine. https://ghr.nlm.nih.gov/gene/dnmt1 Published November 2012. Accessed February 2, 2017.
Klein CJ. DNMT1-Related Dementia, Deafness, and Sensory Neuropathy – GeneReviews® – NCBI Bookshelf. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/books/n/gene/dnmt1-ddsn/?report=reader Last Revision: May 17, 2012. Accessed February 2, 2017.
Online Mendelian Inheritance in Man. NEUROPATHY, HEREDITARY SENSORY. Available at: http://omim.org/entry/614116 Last Update: 10/21/2016. Accessed February 2, 2017.
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