Hereditary sensory and autonomic neuropathy type 1E

Other Names: Hereditary sensory neuropathy with hearing loss and dementia; Hereditary sensory neuropathy type IE; DNMT1-Related Dementia, Deafness, and Sensory Neuropathy; HSNIE; HSAN1E; Hereditary sensory neuropathy-deafness-dementia syndrome; Hereditary sensory neuropathy-sensorineural hearing loss-dementia syndrome; HSN1E

Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a progressive disorder of the central and peripheral nervous systems. 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).

Epidemiology

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

Cause

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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

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.

Signs and symptoms

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.

Diagnosis

The diagnosis of HSAN I is based on the observation of symptoms described above and is supported by a family history suggesting autosomal dominant inheritance. The diagnosis is also supported by additional tests, such as nerve conduction studies in the lower limbs to confirm a sensory and motor neuropathy. In sporadic cases, acquired neuropathies, such as the diabetic foot syndrome and alcoholic neuropathy, can be excluded by the use of magnetic resonance imaging and by interdisciplinary discussion between neurologists, dermatologists, and orthopedics. The diagnosis of the disease has been revolutionized by the identification of the causative genes. The diagnosis is now based on the detection of the mutations by direct sequencing of the genes. Nevertheless, the accurate phenotyping of patients remains crucial in the diagnosis. For pregnant patients, termination of pregnancy is not recommended.

Treatment

There is currently no effective treatment for any type of hereditary sensory neuropathy. Management of symptoms may include:

• 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

NIH genetic and rare disease info

• NIH info on Hereditary sensory and autonomic neuropathy type 1E

Hereditary sensory and autonomic neuropathy type 1E is a rare disease.

Hereditary sensory and autonomic neuropathy type 1E Resources
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