About hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)

What is hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

The hereditary sensory neuropathies (HSN) include 4-6 similar but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. The classification of these diseases is complicated, and sometimes a source of disagreement among the experts.

Hereditary sensory neuropathy type IV (HSN4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. The sensory loss is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. Sweating is almost completely absent with this disorder. Mental retardation is usually present.

The disorder is inherited as an autosomal recessive trait. The gene involved is located on chromosome 1.

HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex, or blood vessel (vasomotor) functions.

What are the symptoms for hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

Infants cannot or have a markedly decreased ability to sweat (anhidrosis). Sweating is the body’s way of cooling itself and maintaining proper body temperature. The inability to sweat can cause recurrent episodes of Fever including extremely high fevers that result in a significant elevation of body temperature (hyperpyrexia). When someone has a significantly increased body temperature it is known as hyperthermia and this can be the initial sign of the disorder. The inability to sweat can affect the entire body, but the trunk and arms are mostly affected. Seizures are sometimes associated with Fever episodes. The skin may become abnormally thickened and callused with an exaggeration of normal skin lines (lichenification). There may be areas of hair loss of the scalp (hypotrichosis) and malformation of the fingernails and toenails.

Affected infants fail to feel Pain in response to stimuli that normally should produce Pain such as failing to respond to routine injections that are part of pediatric immunizations. Pain is essential to protect people from injury and to alert the body of injury. Because of the inability to feel pain, affected infants and children may suffer repeated injuries and may demonstrate behaviors that cause injury to themselves (self-mutilation) including biting one’s tongue, lips and the lining of the inside of the mouth (buccal mucosa). Affected infants often develop ulcers on their tongues from repeatedly biting their tongues. When the primary teeth first erupt, affected children often bite their fingertips or toes; in severe cases, they can chew or bite off the tips of their fingers or toes.

Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel Pain in the affected area. Because of the loss of sensation, affected individuals may be unaware of injury. For example, affected individuals may develop chronic skin erosions, ulcers (open sores), or Blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), and spontaneous, repeated fractures. Repeated trauma to joints results in progressive inflammation, damage, and deformity of the affected joints (Charcot joint or neuropathic arthropathy). The large, weight-bearing joints are especially prone to this complication.

Children with HSAN IV may show delays in attaining developmental milestones (developmental delays) and Learning disabilities are common. Intellectual disability has been reported in some cases, but the severity of this finding has varied widely and some children are only mildly affected. Behavioral problems including irritability, hyperactivity, an inability to control one’s emotions (emotional lability), and episodes of anger or rage have also been reported.

Diminished muscle tone (hypotonia) may be present at birth or during infancy. Hypotonia, also known as a “floppy baby,” may cause affected infants to be abnormally limp. Although Hypotonia is common at birth, strength and tone improves with age.

Some individuals experience postural hypotension, a condition in which there is a drop in blood pressure upon a change in body position such as upon standing. Sometimes, postural hypotension is accompanied by a faster than normal heart rate (compensatory tachycardia), in which the body attempts to compensate for the decreased blood pressure.

Eye abnormalities may develop, specifically neurotrophic keratitis, a condition characterized by damage to the corneas of the eyes. The cornea is the transparent membrane that covers the front of the eyes. Affected individuals can develop Lesions (ulcerations) on the cornea; these Lesions can cause corneal scarring. Infection can also occur.

What are the causes for hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

HSAN IV is caused by mutations in the neurotrophic tyrosine kinase receptor type I (NTRK1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

The NTRK1 gene creates (encodes) neurotrophic tyrosine receptor type 1, a protein that is found on the surface of certain cells, especially nerve cells (neurons) that transmit pain, temperature, and touch sensations. Another protein known as nerve growth factor (NGF) binds to the NTRK1 receptor, which allows nerve signals that are essential for the growth and survival of the cell to be transmitted into the cell. Mutations in the NTRK1 gene result in faulty or deficient neurotrophic tyrosine receptor type 1, which prevents the binding of NGF and, consequently, the transmission of nerve signals. Ultimately, the affected neurons die prematurely. The symptoms of HSAN IV result from this premature destruction of sensory nerve cells.

HSAN IV is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

What are the treatments for hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

Various orthopedic measures may be necessary to treat abnormalities affecting the bones and joints including surgery or the use of braces or orthopedic devices.

Various dental procedures may be used to treat individuals. Smoothing over or grinding down the sharp edges of teeth, prophylactic use of crowns, the use of a night-guard and other orthodontic treatments may be considered. Extracting teeth to prevent self-mutilation has also been done.

Treatment of neurotrophic keratitis can include a procedure in which the eyelids are sewn together to narrow the opening (tarsorrhaphy), plastic surgery to repair the cornea (keratoplasty), replacement of part or all of an affected cornea with healthy corneal tissue from a donor (scleral corneal graft), and special contact lenses that protect the cornea (scleral bandage lens). These contact lenses create a space between the front of the cornea and the back of the lenses that fills with a sterile saline solution.

Behavioral issues tend to improve with age. These issues have been treated with behavior modification techniques along with anti-psychotic medications or attention deficit hyperactivity disorder medications.

Regular, daily inspection for unrecognized or unrealized injury is important as well.

Genetic counseling is recommended for affected individuals and their families.

What are the risk factors for hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

HSAN IV affects males and females in equal numbers. Several hundred cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Many patients have been reported in Japan and the frequency of the disorder is higher in the Japanese and Israeli-Bedouin populations due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. Regions with a high rate of consanguinity also show a higher prevalence. Onset of the disorder is at birth.

Is there a cure/medications for hereditary sensory and autonomic neuropathy iv (hsn iv, hsan iv)?

Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, dental specialists, orthopedists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan for an affect child’s treatment. Psychosocial support for the entire family is essential as well.

Affected individuals may be treated with acetaminophen or ibuprofen when fevers are present. Direct cooling in a bath or with a blanket designed to lower body temperature (cooling blanket) may also be used.

 

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