Eight different clinical entities have been described under
hereditary sensory and autonomic
neuropathies – all characterized by progressive loss of function that predominantly affects the
peripheral sensory nerves. Their incidence has been estimated to be about 1 in 250,000.
Type 1 Hereditary sensory
neuropathy type 1 is a condition characterized by nerve abnormalities in the legs and feet (
peripheral neuropathy). Many people with this condition have tingling, weakness, and a reduced ability to feel pain and sense hot and cold. Some affected individuals do not lose sensation, but instead feel shooting pains in their legs and feet. As the
disorder progresses, the sensory abnormalities can affect the hands, arms, shoulders, and
abdomen. Affected individuals may also experience muscle wasting and weakness as they get older, but this varies widely within
families. Affected individuals typically get open sores (
ulcers) on their
feet or
hands or infections of the soft tissue of the fingertips (whitlows) that are slow to heal. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may require amputation of the surrounding area. Albeit rarely, people with hereditary sensory neuropathy type 1 may develop hearing loss caused by abnormalities of the inner ear (
sensorineural hearing loss). The signs and symptoms of hereditary sensory neuropathy type 1 typically appear during a person's teens or twenties. While the features of this disorder tend to worsen over time, affected individuals have a normal life expectancy if signs and symptoms are properly treated. Type 1 is the most common form among the 5 types of HSAN. Its historical names include
mal perforant du pied, ulcero-mutilating neuropathy, hereditary perforating ulcers, familial trophoneurosis, familial
syringomyelia, hereditary sensory radicular neuropathy, among others. This type includes a popular disease called
Charcot-Marie-Tooth type 2B syndrome (HMSN 2B), which is also referred to as HSAN sub-type 1C.), is characterized by onset of symptoms in early infancy or childhood. Upper & lower extremities are affected with chronic ulcerations and multiple injuries to fingers and feet. Pain sensation is affected predominantly and deep tendon reflexes are reduced.
Autoamputation of the distal phalanges is common and so is
neuropathic joint degeneration. The
NCV shows reduced or absent sensory nerve action potentials and nerve
biopsy shows total loss of
myelinated fibers and reduced numbers of unmyelinated fibers. It is inherited as an
autosomal recessive condition.
Genes related to Hereditary sensory and autonomic neuropathy Type 2 There are two types of HSAN2, called HSAN2A and HSAN2B, each caused by mutations in a different gene. HSAN2A is caused by mutations in the
WNK1 gene, and HSAN2B is caused by mutations in the RETREG1 gene (
FAM134B). Although two different genes are involved, the signs and symptoms of HSAN2A and HSAN2B are the same. The WNK1 gene provides instructions for making multiple versions (
isoforms) of the WNK1 protein. HSAN2A is caused by mutations that affect a particular isoform called the WNK1/HSN2 protein. This protein is found in the cells of the nervous system, including nerve cells that transmit the sensations of pain, temperature, and touch (
sensory neurons). The mutations involved in HSAN2A result in an abnormally short WNK1/HSN2 protein. Although the function of this protein is unknown, it is likely that the abnormally short version cannot function properly. People with HSAN2A have a reduction in the number of sensory neurons; however, the role that WNK1/HSN2 mutations play in that loss is unclear. HSAN2B is caused by mutations in the RETREG1 gene. These mutations may lead to an abnormally short and nonfunctional protein. The RETREG1 protein is found in sensory and autonomic neurons. It is involved in the survival of neurons, particularly those that transmit pain signals, which are called
nociceptive neurons. When the RETREG1 protein is nonfunctional, neurons die by a process of self-destruction called apoptosis. The loss of neurons leads to the inability to feel pain, temperature, and touch sensations and to the impairment of the
autonomic nervous system seen in people with HSAN2.
Type 3, Familial dysautonomia Familial dysautonomia is a
genetic disorder that affects the development and survival of certain
nerve cells. The disorder disturbs cells in the
autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the
sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is also called hereditary sensory and autonomic neuropathy, type III. Problems related to this disorder first appear during infancy. Early signs and symptoms include poor muscle tone (
hypotonia), feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia may hold their breath for prolonged periods of time, which may cause a bluish appearance of the skin or lips (
cyanosis) or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay. Additional signs and symptoms in school-age children include bed wetting, episodes of vomiting, reduced sensitivity to temperature changes and pain, poor balance, abnormal curvature of the spine (
scoliosis), poor bone quality and increased risk of bone fractures, and kidney and heart problems. Affected individuals also have poor regulation of blood pressure. They may experience a sharp drop in blood pressure upon standing (
orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting incidents. About one-third of children with familial dysautonomia have learning disabilities, such as a short attention span, that require special education classes. By adulthood, affected individuals often have increasing difficulties with balance and walking unaided. Other problems that may appear in adolescence or early adulthood include lung damage due to repeated infections, impaired kidney function, and worsening vision due to the shrinking size (
atrophy) of optic nerves, which carry information from the eyes to the brain. Type 3, familial dysautonomia (FD) or
Riley-Day syndrome, is an autosomal recessive disorder seen predominantly in
Jews of
eastern European descent. Patients present with
sensory and
autonomic disturbances. Newborns have absent or weak suck reflex, hypotonia and hypothermia. Delayed physical development, poor temperature and motor incoordination are seen in early childhood. Other features include reduced or absent tears, depressed deep tendon reflexes, absent
corneal reflex, postural
hypotension and relative indifference to pain. Scoliosis is frequent. Intelligence remains normal. Many patients die in infancy and childhood. Lack of flare with intradermal
histamine is seen.
Histopathology of peripheral nerve shows reduced number of
myelinated and non-myelinated
axons. The
catecholamine endings are absent.
Genes related to Hereditary sensory and autonomic neuropathy Type 3 Mutations in the
IKBKAP gene cause familial dysautonomia. The
IKBKAP gene provides instructions for making a protein called IKK complex-associated protein (
IKAP). This protein is found in a variety of cells throughout the body, including
brain cells. Nearly all individuals with familial dysautonomia have two copies of the same IKBKAP gene mutation in each cell. This mutation can disrupt how information in the IKBKAP gene is pieced together to make a blueprint for the production of IKAP protein. As a result of this error, a reduced amount of normal IKAP protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of the protein, and other cells—particularly brain cells—have very little of the protein. Critical activities in brain cells are probably disrupted by reduced amounts or the absence of IKAP protein, leading to the
signs and symptoms of familial dysautonomia.
Type 4, Congenital insensitivity to pain with anhidrosis Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain,
anhidrosis (the inability to sweat), and
intellectual disability. The ability to sense all pain (including
visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and
buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal.
Anhidrosis predisposes to recurrent
febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals;
hyperactivity and emotional lability are common. 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. Intellectual disability is usually present. Type 4, congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive condition and affected infants present with episodes of
hyperthermia unrelated to environmental temperature,
anhidrosis and insensitivity to pain. Palmar skin is thickened and
charcot joints are commonly present.
NCV shows motor and sensory nerve action potentials to be normal. The
histopathology of
peripheral nerve biopsy reveals absent small unmyelinated fibers and
mitochondria are abnormally enlarged.
Type 5, Congenital insensitivity to pain with partial anhidrosis Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the
sensory nerve cells. These cells are impaired in people with HSAN5. The
signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose the ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called
Charcot joints, in which the bones and tissue surrounding joints are destroyed. Type 5, congenital insensitivity to pain with partial anhidrosis, is a severe
autosomal recessive disorder characterized by
neonatal hypotonia,
respiratory and feeding difficulties, lack of
psychomotor development, and autonomic abnormalities including
labile cardiovascular function, lack of
corneal reflexes leading to corneal
scarring,
areflexia, and absent
axonal flare response after
intradermal histamine injection.
Genes related to Hereditary sensory and autonomic neuropathy Type 6 Mutations in the DST (
Dystosin) gene are associated HSAN6. In two separate studies of families with presentations of HSAN6, the DST gene was found to be mutated, in one case with a truncating mutation, and in the other a non-sense or missense mutation. In the latter case, the authors proposed that
homozygous truncating mutations result in a severe form of HSAN6, with
congenital defects and early
lethality, while
heterozygosity for a truncating or missense mutation maintains enough dystosin expression and function to allow a normal
lifespan, albeit with symptoms of HSAN6.
Type 7 Hereditary sensory and autonomic neuropathy type 7 (HSAN7) is an
autosomal dominant genetic condition caused by a
mutation in the gene
SCN11A with symptoms typically appearing at birth or during
infancy. The disorder is characterized by a congenital inability to feel pain, excessive sweating, and significant
gastrointestinal issues due to
intestinal dysmotility. This
pain insensitivity can lead to repeated, severe, and unnoticed injuries, while poor wound healing and
hyperhidrosis are additional common features.
Type 8 Hereditary sensory and autonomic neuropathy type 8 (HSAN8) is an autosomal recessive
genetic disorder caused by a
mutation in the gene
PRDM12, with
signs and symptoms usually appearing at birth or during infancy. Subject with this condition have a complete inability to feel pain and temperature, leading to severe, often unnoticed injuries and
self-mutilation. Other symptoms include decreased sweating (
anhidrosis) and absent
corneal reflexes, which can result in overheating and severe eye injuries. ==Genetics==