NORD gratefully acknowledges Mary M. Reilly MD, Professor of Clinical Neurology and Consultant Neurologist, Head of Division of Clinical Neurology, Institute of Neurology, MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, London, for assistance in the preparation of this report.
Hereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those 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 processes. 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.
The hereditary sensory neuropathies (HSNs), also known as the hereditary sensory and autonomic neuropathies, include at least six similar, but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes. The classification of the HSNs is complicated, and the experts do not always agree on it. Furthermore, HSNs are classified more broadly as peripheral neuropathies or disorders of the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system. NORD’s Rare Disease Database has separate reports on HSN2, HSN3 (which is related to, or identical with familial dysautonomia), and HSN4.
The symptoms of HSNs are highly variable, even among members of the same family. HSNs of various types usually involve many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.
Although researchers have been able to establish HSNs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis for all subtypes although the main features of each subtype are well described. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. It is also important to note that more than 50% of the causative genes have yet to be identified for the HSNs so many patients will receive a diagnosis of HSN without a specific genetic cause being identified.
The symptoms described below are common to individuals with HSN1A the best known form of HSN. Some symptoms such as progressive distal sensory loss are characteristic of all forms of HSN. Certain symptoms are associated with specific subtypes. HSN1A and HSN1C and a form of Charcot-Marie-Tooth, CMT2B, are all very similar but patients with HSN1A and HSN1C have more neuropathic pain and patients with CMT2B have less pain but more motor involvement at an early stage of the disease. Individuals with HSN1B often do not have foot ulcers, but may experience gastroesophageal reflux and cough in adulthood. HSN1D is caused by a gene, ATL1, which more commonly causes a central nervous system disease called hereditary spastic paraparesis (HSP) and those patients who get HSN1D often have central nervous system signs such as brisk reflexes. HSN1E is a late onset, fatal disease with a mean age of onset of 37 years and average survival age of 53 years. It presents with a triad of symptoms: hearing loss, sensory neuropathy, and cognitive decline (dementia).
Sensory loss of the distal portions of the legs is the characteristic finding of HSNs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and legs and hands and feet. Onset can be anywhere from the teen-aged years to the sixth decade.
The characteristic finding of HSNs is loss of sensation in the lower portions of the arms and legs, especially the hands and feet. The feet are nearly always involved first as these are further from the center of the body than the hands. 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 develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. Patients frequently do not realize they have injured themselves until they see the damage as they often do not feel such damage occurring e.g. putting their feet against a heater. 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), bone loss (osteonecrosis), spontaneous fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy). Severe cases may eventually require amputation.
Although sensory loss and numbness is the characteristic feature of HSNs, some affected individuals may develop sensory symptoms such as burning or tingling sensations in the hands or feet. Some individuals may experience spontaneous shooting pains in the feet, legs, hands or shoulders.
Some affected individuals may have deformities of the feet such as highly arched feet (pes cavus), flat feet (pes planus), or hammertoes. Recurrent fungal or bacterial infections of the toenails (onchymocosis or paronychia) may also occur.
Muscle weakness and muscle wasting can occur in some cases, although these findings are highly variable. In rare cases, muscle weakness in the hands and feet can be the initial sign of HSN. Muscle weakness usually begins in the lower legs and then the lower arms. Progress is usually slow, but in severe cases, muscle weakness can progress to affect the proximal portions of the arms and legs. Proximal refers to those areas that are nearer to the center of the body such as the upper portions of the arms and legs. Muscle weakness can cause weak ankles and eventually progress to difficulty walking (gait disturbances). Some older affected individuals (e.g. those in their 60s or 70s) may eventually require a wheelchair.
Sensorineural hearing loss, which is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain, has rarely been associated with HSN1A. Onset of hearing loss is usually in middle to late adulthood.
Some individuals may develop sweating abnormalities such as excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis) or lack of sweating (anhidrosis). The hands and feet are most often affected. Less often, additional autonomic findings may occur such as low blood pressure (hypotension). All of these symptoms are extremely rare with HSN1 and are more common with some of the other forms of HSN.
HSN1A is caused by a mutation in the SPTLC1 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.
Investigators have determined that the SPTLC1 gene is located on the long arm (q) of chromosome 9 (9q22.31). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 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 sub-divided into many bands that are numbered. For example, “chromosome 9q22.31” refers to band 22.13 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The gene that causes HSN1B is unknown, but believed to be located on chromosome 3p24-p22. HSN1C is caused by mutations in the SPTLC2 gene, located on chromosome 14q24. SPTLC2 is a very similar gene to SPTLC1 which is why patients with HSN1A and HSN1C are very similar. HSN1D is caused by mutations in the ATL1 gene, located on chromosome 14q. HSN1E is caused by mutations in the DNMT1 gene, located on chromosome 19p13.
Mutations associated with HSN1 are usually inherited as autosomal dominant disorders (where a trait is transmitted from either an affected mother or father to their child). In very rare cases, a mutation occurs sporadically as a new mutation without a previously family history (de novo mutation).
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. Dominant genetic disorders occur when only a single 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 occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
HSN1 affects males and females in equal numbers. The exact incidence and prevalence is unknown. The prevalence is estimated to be approximately 2 in 1,000,000 people in the general population. HSN1 frequently goes undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of HSN1 is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Characteristic symptoms along with a family history consistent with autosomal dominant inheritance are also indicative of HSN1.
Clinical Testing and Workup
Electromyography (EMG) and nerve conduction studies may be abnormal. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. Nerve conduction studies measure the speed of conduction of an electrical impulse through a nerve and can reveal nerve damage.
Surgical removal and microscopic examination (biopsy) of affected nerve fibers may be used to aid in the diagnosis of HSN1 by revealing characteristic changes to nerve tissue but this now rarely needed as genetic testing is widely available and is usually only used if other causes (other than HSN1) are suspected.
Molecular genetic testing can confirm a diagnosis in some people. Molecular genetic testing can detect mutations in specific genes known to cause HSN1, but is available only as a diagnostic service at specialized laboratories.
The treatment of HSNs is directed toward the specific symptoms that are apparent in each individual. Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSN is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore the 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.
Additional treatment is symptomatic and supportive. Shooting pains may be treated with medications commonly used for peripheral neuropathies including amitryptiline, carbamazepine, and gabapentin. Damaged joints can be treated by arthrodesis, a reconstructive surgical procedure to repair and fuse a joint. Weakened ankles can be treated with orthodontics, but special care (e.g. sleeves, etc.) may be necessary to prevent skin abrasion.
Genetic counseling may be of benefit for affected individuals and their families.
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