Congenital Sensory Neuropathy

For the gene HSN2, see HSN2.

Hereditary sensory and autonomic neuropathy
Classification and external resources
ICD-9 OMIM DiseasesDB 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[1] which inhibit sensation.

They are less common than Charcot-Marie-Tooth disease.[2]

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

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.[3] This type includes a popular disease Charcot-Marie-Tooth type 2B syndrome (HMSN 2B).[3] that is also named as HSAN sub-type 1C.

Type 1 is inherited as an autosomal dominant trait which means there is a risk of 50% for subsequent generations to have the disease regardless of their sex. 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. [3]

Type 2, Congenital sensory neuropathy

Type 2, congenital sensory neuropathy (also historically known as Morvan's disease[4]), 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.

Type 3, Familial dysautonomia

Main article: Familial dysautonomia

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. Retarded 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.

Type 4, Congenital insensitivity to pain with anhidrosis

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

Type 5, congenital insensitivity to pain with partial anhidrosis,[4] also manifests with congenital insensitivity to pain & anhidrosis. There is a selective absence of small myelinated fibers differentiating it from Type IV (CIPA).

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[5] 9q22.1-q22.3
1B unknown (OMIM 608088)[3] 3p24–p22
1C
(= CMT2B, HMSN IIB)
RAB7A[3] 3q21
1D unknown[3] unknown
HSAN 2 HSN2[6] 12p13.33
HSAN 3 (Familial dysautonomia) IKBKAP 9q31
HSAN 4 (CIPA) NTRK1 1q21-q22
HSAN5   NGFβ[7][8] 1p13.1
  NTRK1[9]  

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

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