Hereditary Sensory and Autonomic Neuropathy Type 1E

 Hereditary Sensory and Autonomic Neuropathy Type 1E

OVERVIEW

Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a rare genetic disorder. It is considered an adult-onset disorder with symptoms usually starting to occur in the 20-30’s. Although HSAN1E is considered to be a subtype of HSAN, a group of genetic disorders most-ly affecting the sensory and autonomic neurons of the peripheral nervous system, the central nervous system is also severely affected in HSAN1E patients, especially in the later stage of the disease. HSAN1E patients usually have three main symptoms, hearing loss, sensory neu-ropathy, and cognitive decline (dementia), and many have other various symptoms such as sleep disorders and epilepsy. The symptoms are progressive, worsening with age. At this time, there are no available treatments other than management for each specific symptom, (i.e., hearing aids for the hearing loss) and there is currently no cure for HSAN1E. Based on a re-cent study, the average life span of HSAN1E patients is approximately 50 years. HSAN1E is an autosomal dominant genetic disorder caused by a mutation in the DNMT1 gene.

SYMPTOMS

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.

CAUSES

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.

AFFECTED POPULATIONS

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.

DISORDERS WITH SIMILAR SYMPTOMS

DNMT1 gene mutations have also found to cause autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN). ADCA-DN patients share the same triad of core symp-toms, hearing loss, sensory neuropathy and cognitive decline, and also have adult onset. Progressive cerebellar ataxia and narcolepsy are other common features.

Hereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and predominantly affect the sensory nerves, which frequently leads to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body pro-cesses. Specific symptoms can vary widely from one person to another. HSN1 occurs due to mutations in specific genes and is inherited as an autosomal dominant trait. There are several subtypes of HSN1 designated A through E, each one associated with a different gene. (For more information on this disorder, choose “HSN1” as your search term in the Rare Disease Database.)

DIAGNOSIS

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.

STANDARD THERAPIES

Treatment

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.

Type of Doctor Department : Neurology