HSAN

• 遺伝性感覚性自律神経性ニューロパチー

関

hereditary sensory and autonomic neuropathy、hereditary sensory neuropathy

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/03/14 14:02:28」(JST)

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[Wiki ja表示]

遺伝性感覚性自律神経性ニューロパチー（いでんせいかんかくせいじりつしんけいせいニューロパチー 英語:hereditary sensory and autonomic neuropathy, HSAN）とは、遺伝的要因により主に神経障害などを含む先天的な疾患群である。通常、略称のHSANで呼ばれることが多い。遺伝性感覚性自律神経失調症ともいう。

概要

HSANの発症の原因は遺伝子の異常であることが突き止められているが、原因遺伝子の特定にまでは至っておらず、根本的な治療方法も今のところ無いのが現状である。また、患者数が少なく認知度も低い。IV型に分類される先天性無痛無汗症は、最初の患者が日本で発見されており、他の型も含めて患者の割合は日本人が最も多い。

各型に共通している症状は痛覚の欠如である。即ち患者は痛みを感じることができないので、対症療法も含めて治療法は確立には至っていない。

分類

• I型（遺伝性感覚根性ニューロパチー）
• II型（先天性感覚根性ニューロパチー）
• III型（家族性自律神経異常症/ライリー・デイ症候群）
• IV型（先天性無痛無汗症）

痛覚・温覚が欠如しており、発汗しない。

• V型

痛覚の欠如および不完全性の無汗症。

関連項目

• 症候学
• ニューロパチー

wiki en

[Wiki en表示]

For the gene HSN2, see HSN2.

Not to be confused with Hereditary motor and sensory neuropathy.

Hereditary sensory and autonomic neuropathy
Classification and external resources
ICD-9-CM	356.2
OMIM	162400 201300 223900 256800 608654
DiseasesDB	32501 32096 11631 32097 32610
MeSH	D009477

Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to describe any of the types of this disease which inhibit sensation.

They are less common than Charcot-Marie-Tooth disease.

Classification

Five 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 25,000.

Type 1

Main article: Hereditary sensory and autonomic neuropathy type I

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.

Rarely, people with hereditary sensory neuropathy type 1 will 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 Charcot-Marie-Tooth type 2B syndrome (HMSN 2B). that is also named as HSAN sub-type 1C.

Type 1 is inherited as an autosomal dominant trait. The disease usually starts during early adolescence or adulthood. The disease is characterized by the loss of pain sensation mainly in the distal parts of the lower limbs such as feet and lower legs. Since the affected individuals cannot feel pain, minor injuries in the painless area may not be immediately recognized and may develop into extensive ulcerations. Once infection occurs, further complications such as progressive destruction of underlying bones may follow and may necessitate amputation. In rare case, the disease is accompanied with nerve deafness and muscle wasting. Autonomic disturbance, if present, appears as anhidrosis, a sweating abnormality. Examinations of the nerve structure and function showed signs of neuronal degeneration such as a marked reduction in the number of myelinated fibers and axonal loss. Sensory neurons lose the ability to transmit signals, while motor neurons has reduced ability to transmit signals.

Genes related to Hereditary sensory and autonomic neuropathy Type 1:

Mutations in the SPTLC1 gene cause hereditary sensory neuropathy type 1. The SPTLC1 gene provides instructions for making one part (subunit) of an enzyme called serine palmitoyltransferase (SPT). The SPT enzyme is involved in making certain fats called sphingolipids. Sphingolipids are important components of cell membranes and play a role in many cell functions.

SPTLC1 gene mutations reduce the amount of SPTLC1 subunit that is produced and result in an SPT enzyme with decreased function. A lack of functional SPT enzyme leads to a decrease in sphingolipid production and a harmful buildup of certain byproducts. Sphingolipids are found in myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. A decrease in sphingolipids disrupts the formation of myelin, causing nerve cells to become less efficient and eventually die. When sphingolipids are not made, an accumulation of toxic byproducts can also lead to nerve cell death. This gradual destruction of nerve cells results in loss of sensation and muscle weakness in people with hereditary sensory neuropathy type 1.

Type 2, Congenital sensory neuropathy

Hereditary sensory and autonomic neuropathy type II (HSAN2) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN2. In some affected people, the condition may also cause mild abnormalities of the autonomic nervous system, which controls involuntary body functions such as heart rate, digestion, and breathing. The signs and symptoms of HSAN2 typically begin in infancy or early childhood.

The first sign of HSAN2 is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. People with HSAN2 often develop open sores (ulcers) on their hands and feet. 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 lead to amputation of the affected area. Unintentional self-injury is common in people with HSAN2, typically by biting the tongue, lips, or fingers. These injuries may lead to spontaneous amputation of the affected areas. Affected individuals often have injuries and fractures in their hands, feet, limbs, and joints that go untreated because of the inability to feel pain. Repeated injury can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed.

The effects of HSAN2 on the autonomic nervous system are more variable. Some infants with HSAN2 have trouble sucking, which makes it difficult for them to eat. People with HSAN2 may experience episodes in which breathing slows or stops for short periods (apnea); digestive problems such as the backflow of stomach acids into the esophagus (gastroesophageal reflux); or slow eye blink or gag reflexes. Affected individuals may also have weak deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.

Some people with HSAN2 lose a type of taste bud on the tip of the tongue called lingual fungiform papillae and have a diminished sense of taste.

Type 2, congenital sensory neuropathy (also historically known as Morvan's disease), 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 FAM134B gene. 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 FAM134B gene. These mutations may lead to an abnormally short and nonfunctional protein. The FAM134B 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 FAM134B 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

Main article: 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

Main article: 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.

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. 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.

Management of Hereditary sensory and autonomic neuropathy Type 4:

Treatment of manifestations: Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. For anhidrosis: Monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. For insensitivity to pain: Modify as much as reasonable a child’s activities to prevent injuries. Inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. Methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of a mouth guard. Skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for dry eyes, prevention of corneal infection, and daily observation of the ocular surface. Interventions for behavioral, developmental, and motor delays as well as educational and social support for school-age children and adolescents are recommended.

Prevention of secondary complications: Regular dental examinations and restriction of sweets to prevent dental caries; early treatment of dental caries and periodontal disease to prevent osteomyelitis of the mandible. During and following surgical procedures, potential complications to identify and manage promptly include hyper- or hypothermia and inadequate sedation, which may trigger unexpected movement and result in secondary injuries.

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 (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations 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, also manifests with congenital insensitivity to pain & anhidrosis. There is a selective absence of small myelinated fibers differentiating it from Type IV (CIPA).

Genes related to Hereditary sensory and autonomic neuropathy Type 5:

Mutations in the NGF gene cause HSAN5. The NGF gene provides instructions for making a protein called nerve growth factor beta (NGFβ) that is important in the development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by attaching (binding) to its receptors, which are found on the surface of neurons. Binding of the NGFβ protein to its receptor transmits signals to the cell to grow and to mature and take on specialized functions (differentiate). This binding also blocks signals in the cell that initiate the process of self-destruction (apoptosis). Additionally, NGFβ signaling plays a role in pain sensation. Mutation of the NGF gene leads to the production of a protein that cannot bind to the receptor and does not transmit signals properly. Without the proper signaling, sensory neurons die and pain sensation is altered, resulting in the inability of people with HSAN5 to feel pain.

Associated genes

Type	Sub-type	Gene	Locus
HSAN 1	1A	SPTLC1	9q22.1-q22.3
	1B	unknown (OMIM 608088)	3p24–p22
	1C (= CMT2B, HMSN IIB)	RAB7A	3q21
	1D	unknown	unknown
	1E	DNMT1 (OMIM 614116)	19p13.2
HSAN 2		HSN2	12p13.33
HSAN 3 (Familial dysautonomia)		IKBKAP	9q31
HSAN 4 (CIPA)		NTRK1	1q21-q22
HSAN5		NGFβ	1p13.1
		NTRK1

External links

• GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory and Autonomic Neuropathy IV
• GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory Neuropathy Type I
• GeneReviews/NIH/NCBI/UW entry on Hereditary Sensory and Autonomic Neuropathy Type II

References

UpToDate Contents

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• 1. 遺伝性感覚自律神経ニューロパチー hereditary sensory and autonomic neuropathies
• 2. 遺伝性ニューロパチーの概要 overview of hereditary neuropathies
• 3. シャルコーマリートゥース病などの一次性の遺伝性運動感覚性ニューロパチー hereditary primary motor sensory neuropathies including charcot marie tooth disease
• 4. 新生児における筋緊張低下を引き起こす末梢神経および筋肉の障害に関する概要 overview of peripheral nerve and muscle disorders causing hypotonia in the newborn
• 5. 小児における不明熱：病因 fever of unknown origin in children etiology

English Journal

• The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.

• Nagy V1, Cole T, Van Campenhout C, Khoung TM, Leung C, Vermeiren S, Novatchkova M, Wenzel D, Cikes D, Polyansky AA, Kozieradzki I, Meixner A, Bellefroid EJ, Neely GG, Penninger JM.
• Cell cycle (Georgetown, Tex.).Cell Cycle.2015 Apr 18:0. [Epub ahead of print]
• PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and au
• PMID 25891934

• The shifting paradigm of Charcot-Marie-Tooth disease.

• Echaniz-Laguna A1.
• Revue neurologique.Rev Neurol (Paris).2015 Apr 17. pii: S0035-3787(15)00692-X. doi: 10.1016/j.neurol.2014.12.003. [Epub ahead of print]
• Molecular studies have created a paradigm shift in our perception of Charcot-Marie-Tooth disease (CMT). Indeed, CMT has evolved from the concept of a rather homogeneous hereditary disease exclusively involving peripheral nerves to the concept of a highly heterogeneous clinical and genetic syndrome m
• PMID 25896909

• Mitochondrial dynamics and inherited peripheral nerve diseases.

• Pareyson D1, Saveri P2, Sagnelli A2, Piscosquito G2.
• Neuroscience letters.Neurosci Lett.2015 Apr 3. pii: S0304-3940(15)00272-4. doi: 10.1016/j.neulet.2015.04.001. [Epub ahead of print]
• Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells
• PMID 25847151

Japanese Journal

• 遺伝性運動性・感覚性・自律神経性ニューロパチーの臨床

• 髙嶋 博
• 臨床神経学 54(12), 957-959, 2014
• … とも障害されるhereditary motor and sensory neuropathy（HMSN）またはCharcot-Marie-Tooth病（以下CMT），運動神経のみが障害されるhereditary motor neuropathy（HMN），感覚，自律神経が障害されるhereditary sensory and autonomic neuropathy（HSAN）などに分類される．遺伝性ニューロパチーは，臨床的特徴と遺伝形式で分類されていたが，原因遺伝子の同定も相次ぎ，その整合性がとれなくなっている部分も多い．同じ遺伝子の異常でも臨床的な病型に …
• NAID 130004921173

• Hereditary motor sensory neuropathy (HMSN) の広がり

• 中川 正法
• 臨床神経学 49(11), 950-952, 2009-11-01
• … Hereditary neuropathies are classified into HMSN/Charcot-Marie-Tooth disease (CMT), familial amyloid polyneuropathy (FAP), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). …
• NAID 10026291204

• The external aldimine form of serine palmitoyltransferase : structural, kinetic, and spectroscopic analysis of the wild-type enzyme and HSAN1 mutant mimics

• RAMAN M. C.
• J Biol Chem 284, 17328-17339, 2009
• NAID 80020376206

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リンク元	「hereditary sensory neuropathy」「遺伝性感覚性自律神経性ニューロパチー」
関連記事	「HS」

「hereditary sensory neuropathy」

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遺伝性感覚性ニューロパチー、遺伝性感覚性ニューロパシー、遺伝性感覚ニューロパチー、遺伝性感覚ニューロパシー

関

hereditary sensory and autonomic neuropathy、HSAN

「遺伝性感覚性自律神経性ニューロパチー」

　　[★]

英

hereditary sensory and autonomic neuropathy、HSAN

関

遺伝性感覚性ニューロパチー

「HS」

　　[★]

• ヘパラン硫酸 heparan sulfate heparitin sulfate
• 熱ショック heat shock heat-shock heatshock
• ウマ血清 horse serum
• 遺伝性球状赤血球症 hereditary spherocytosis