Hereditary sensory and autonomic neuropathy type IE (HSAN IE) is a disorder that affects the nervous system. It is characterized by three main features: hearing loss, a decline of intellectual function (dementia), and a worsening loss of sensation in the feet and legs (peripheral neuropathy).

People with HSAN IE develop hearing loss that is caused by abnormalities in the inner ear (sensorineural hearing loss). The hearing loss, which affects both ears, gets worse over time and usually progresses to moderate or severe deafness between the ages of 20 and 35.

Affected individuals experience dementia typically beginning in their thirties. In some people with HSAN IE, changes in personality, such as irritability, apathy, or lack of impulse control, become apparent before problems with thinking skills.

Peripheral neuropathy is caused by impaired function of nerve cells called sensory neurons, which transmit information about sensations such as pain, temperature, and touch. Loss of sensation in the feet and legs, which usually begins in adolescence or early adulthood in people with HSAN IE and worsens over time, can cause difficulty walking. Affected individuals may not be aware of injuries to their feet, which can lead to complications such as open sores and infections. If these complications are severe, amputation of the affected areas may be required.

Some people with HSAN IE also experience recurrent seizures (epilepsy) and sleep problems. The severity of the signs and symptoms of HSAN IE and their age of onset are variable, even among affected members of the same family.

HSAN IE is caused by mutations in the DNMT1 gene, which 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, to DNA molecules.

DNA methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed (gene silencing), regulating reactions involving proteins and fats (lipids), and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 1 is active in the adult nervous system. Although its specific function is not well understood, the enzyme may help regulate neuron maturation and specialization (differentiation), the ability of neurons to migrate where needed and connect with each other, and neuron survival.

DNMT1 gene mutations that cause HSAN IE affect the enzyme's methylation function, resulting in abnormalities in the maintenance of the neurons that make up the nervous system. However, it is not known how the mutations cause the specific signs and symptoms of HSAN IE.

Normal Function

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, to DNA molecules. In particular, the enzyme helps add methyl groups to DNA building blocks (nucleotides) called cytosines.

DNA methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed (gene silencing), regulating reactions involving proteins and fats (lipids), and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 1 is active in the adult nervous system. Although its specific function is not well understood, the enzyme may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons to move (migrate) and connect with each other, and neuron survival.

Health Conditions Related to Genetic Changes

Autosomal dominant cerebellar ataxia, deafness, and narcolepsy

At least four DNMT1 gene mutations have been identified in people with a nervous system disorder called autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN). Features of this disorder include difficulty coordinating movements (ataxia), hearing loss caused by abnormalities of the inner ear (sensorineural deafness), and excessive daytime sleepiness (narcolepsy). Cognitive decline occurs as the disorder progresses. Numbness, tingling, or pain in the arms and legs (sensory neuropathy) can also occur. Affected individuals usually survive into their forties or fifties.

The DNMT1 gene mutations associated with this disorder affect a region of the DNA methyltransferase 1 enzyme, known as the targeting sequence, that helps direct the methylation process to the correct segments of DNA. As a result of these mutations, methylation is abnormal, which affects the expression of multiple genes. Maintenance of the neurons that make up the nervous system is disrupted, leading to the signs and symptoms of ADCADN.

Hereditary sensory and autonomic neuropathy type IE

At least 10 DNMT1 gene mutations have been identified in people with another nervous system disorder called hereditary sensory and autonomic neuropathy type IE (HSAN IE). As in ADCADN, (described above), people with HSAN IE have sensorineural deafness, sensory neuropathy, cognitive decline, and a shortened lifespan. However, they typically do not have the ataxia or narcolepsy that occurs in ADCADN, and the sensory neuropathy begins earlier in life in people with HSAN IE. Seizures can also occur in this disorder.

DNMT1 gene mutations that cause HSAN IE, like those that cause ADCADN, affect the targeting sequence of the DNA methyltransferase 1 enzyme. However, most of the mutations that cause HSAN IE occur in a part of the gene called exon 20 and affect one end of the enzyme's targeting sequence, while the mutations that cause ADCADN are mostly in a nearby part of the gene called exon 21 and affect the other end of the enzyme's targeting sequence.

As a result of the DNMT1 gene mutations, methylation is abnormal and maintenance of the neurons that make up the nervous system is impaired. However, it is not known how the mutations cause the specific signs and symptoms of HSAN IE, or how mutations affecting the targeting sequence of the DNA methyltransferase 1 enzyme can cause either HSAN IE or ADCADN.

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Cancers

Several normal variations (polymorphisms) in the DNMT1 gene have been associated with an increased risk of cancer, including cancers of the breast and stomach. These variations, which are found in cells throughout the body and can be passed on from parent to child, may affect the activity of the DNA methyltransferase 1 enzyme and its role in gene silencing. Changes in the silencing of particular genes can lead to abnormal cell growth and division and increase the risk of cancer.

In addition, increased activity (overexpression) of the DNMT1 gene has been identified in certain brain cancers called gliomas. The genetic changes involved in this overexpression are somatic, which means that they occur only in the tumor cells and are not inherited. Researchers suggest that overexpression of the DNMT1 gene may result in methylation and silencing of genes called tumor suppressors. When tumor suppressor genes are silenced, cells can grow and divide unchecked, which can lead to cancer.

Other Names for This Gene

• AIM
• CXXC finger protein 9
• CXXC-type zinc finger protein 9
• CXXC9
• DNA (cytosine-5)-methyltransferase 1
• DNA (cytosine-5-)-methyltransferase 1
• DNA methyltransferase HsaI
• DNA MTase HsaI
• DNMT
• DNMT1_HUMAN
• HSN1E
• m.HsaI
• MCMT

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

At least four genes responsible for hereditary sensory neuropathy type 1 (HSN1) have been found:

• HSN1A (the most common form) is associated with mutations in the SPTLC1 gene
• HSN1B, reported in a small number of families, is linked to a specific location on chromosome 3, but the exact gene has not yet been identified
• HSN1C is caused by mutations in the SPTLC2 gene
• HSN1D is caused by mutations in the ATL1 gene (the same gene is associated with early-onset hereditary spastic paraplegia 3A)
• HSN1E is caused by mutations in the DNMT1 gene

The Genetic Testing Registry (GTR) provides information about genetic testing for HSN1A. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Although the genes for some other types of HSN1 have been identified, we are not aware of clinical laboratories that offer genetic testing for them. A genetics professional may be able to help you locate laboratories that offer testing for other types of HSN1.

If the genetic mutation in an affected person has been identified, testing for adult relatives at risk for developing symptoms may be possible. This is called predictive genetic testing. However, this testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in people who currently don't have symptoms.

• meticulous care of the distal limbs, which includes proper fit of shoes, prevention and treatment of callus formation, cleaning and protection of wounds, and avoidance of trauma to the hands and feet
• injury prevention when sensory impairment is significant
• the use of hearing aids and/or assistive communication methods as needed
• sedative or antipsychotic medications to help reduce the restlessness, roaming behavior, delusions, and hallucinations associated with dementia
• psychological support for caregivers

HSAN IE is a rare disorder; its prevalence is unknown. Small numbers of affected families have been identified in populations around the world.