Edit concept Question Editor Create issue ticket

Hereditary Sensory Neuropathy

Hereditary Sensory Neuropathies

Hereditary sensory neuropathies are a heterogeneous group of genetic disorders characterized by both sensory and autonomic dysfunction.


Presentation

The onset is usually as early as birth and initial symptoms include swallowing difficulties, self-mutilation, and delayed development [1]. Later on, the perception of pain and temperature may be either partially or completely absent, followed by depressed reflexes and autonomic dysfunction presenting with postural hypotension, excessive sweating and gastroesophageal reflux [1]. Frequent fractures, skin and corneal ulceration, intermittent fevers, irritability and behavioral issues (type IV), scoliosis and osteomyelitis after injury are also observed in a significant number of individuals [2] [4], whereas life-threatening recurrent aspirations are characteristic for type III [1].

Turkish
  • State and Murat Gunel, Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population, Neurogenetics, 10.1007/s10048-008-0121-9, 9, 2, (119-125), (2008).[doi.org]
Paroxysmal Cough
  • RESULTS: Three of five siblings presented a similar history of paroxysmal cough (5th decade). About a decade later they experienced numbness and paraesthesia in the feet and in all cases there was evidence of an axonal sensory neuropathy.[ncbi.nlm.nih.gov]
  • Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex).[ncbi.nlm.nih.gov]
Pleural Effusion
  • There are appropriate responses to pleural effusions, esophageal irritation, and menstrual cramping. Corneal and tendon reflexes are hypoactive, and taste appreciation is diminished which is due to absence of lingual fungiform papillae.[doi.org]
Lip Cyanosis
  • 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.[en.wikipedia.org]
Lacrimation
  • Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children, failed to do so in these patients, despite their occasional spontaneous lacrimation.[jpma.org.pk]
  • View Article PubMed Google Scholar Riley CM, Day RL, Greely DMcL, Langford WS: Central autonomic dysfunction with defective lacrimation. Pediatrics. 1949, 3: 468-477.[doi.org]
  • KIF1A SCN9A Mutilations (hands, feet) Acroosteolysis Sensory loss Absent or weak tendon reflexes No myelinated fibers Fewer unmyelinated fibers HSAN3 Congenital AR 223900 ELP1 ( IKBKAP ) Prominent autonomic disturbances (vomiting/poor feeding, defective lacrimation[ncbi.nlm.nih.gov]
  • ., Greely, D. and Langford, W.S. ( 1949 ) Central autonomic dysfunction with defective lacrimation. Pediatrics, 3, 468 –477. 9 Axelrod, F.B., Nachtigal, R. and Dancis, J. ( 1974 ) Familial dysautonomia: diagnosis, pathogenesis and management. Adv.[doi.org]
Blurred Vision
  • They may experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.[en.wikipedia.org]
Long Arm
  • In 1993 the FD gene was localized to the long arm of chromosome 9 (9q31) [ 11 ]. In 2001 the gene was cloned.[doi.org]
Neurogenic Arthropathy
Short Attention Span
  • About one-third of children with familial dysautonomia have learning disabilities, such as a short attention span, that require special education classes.[en.wikipedia.org]
Psychomotor Retardation
Peripheral Neuropathy
  • XPA mutations have been shown to cause peripheral neuropathy, and GAS1 is related to the PMP22 gene, which is critical in the pathogenesis of two other peripheral neuropathies.[ncbi.nlm.nih.gov]
  • Three cases with sensory peripheral neuropathies are reported. Case 1 presented with scoliosis, and cases 2 and 3 presented with abnormal gait.[ncbi.nlm.nih.gov]
  • Abstract Hereditary sensory neuropathy type I (HSN-I) is an autosomal dominant peripheral neuropathy affecting sensory and motor neurons. The disease involves distal sensory loss, distal muscle wasting and weakness, and variable neural deafness.[ncbi.nlm.nih.gov]
  • Types of Peripheral Neuropathy There are several different kinds of peripheral neuropathies that stem from a variety of causes.[webmd.com]
  • Abstract Hereditary sensory neuropathy type I (HSN-I) is an autosomal dominant peripheral neuropathy, involving sensory and motor neurons. The disease involves distal sensory loss, distal muscle wasting and weakness, and variable neural deafness.[ncbi.nlm.nih.gov]
Numbness of the Hand
  • The person may awaken at night with numbness in their hand or discover that when they perform activities like using a hair dryer, the numbness is more noticeable. In time, carpal tunnel injuries can weaken the muscles in the hand.[webmd.com]
  • The first sign of the condition is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold.[ghr.nlm.nih.gov]
  • 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.[en.wikipedia.org]
  • The sensory deficits begin with numbness in the hands and feet. There is some disagreement whether or not this disease is progressive. Regardless, these individuals have a severely reduced sense of pain, temperature, and touch.[medicalbag.com]
  • It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs.[ncbi.nlm.nih.gov]
Aura
  • Thus the concept has been proposed that the crisis may represent a type of autonomic seizure and that nausea may be the aura [ 52 ].[doi.org]
Decerebrate Posturing
  • Seizures with decerebrate posturing can follow breathholding even in children with normal EEG findings. There is pathological and clinical evidence that FD is associated with neurological progression.[doi.org]

Workup

A detailed patient history that reveals similar symptoms within the family or first-degree relatives may be one of the most important parts in the workup, together with a thorough physical examination that can confirm sensory and/or autonomic dysfunction [1]. The initial diagnosis should be made on clinical grounds, as genetic tests are available for only a few subtypes [1] [2]. Intradermal injection of histamine phosphate is a useful diagnostic method and in HSN patients [1]. Normally, a diffuse reaction around a central histamine-induced wheal should be observed, but if HSN is present, a reduced axonal flare manifesting as a narrow areola around the wheal will be seen in virtually all types [1].

Gliosis
  • The finding of cell loss and gliosis in the thalamus in nuclei that do not subserve these two pathways as well as in the red nuclei, inferiro olivary nuclei, and claustrum suggested that HSN-I with deafness is nosologically related to familial multisystem[ncbi.nlm.nih.gov]
Pleural Effusion
  • There are appropriate responses to pleural effusions, esophageal irritation, and menstrual cramping. Corneal and tendon reflexes are hypoactive, and taste appreciation is diminished which is due to absence of lingual fungiform papillae.[doi.org]

Treatment

Supportive care is the mainstay of therapy, as there is no cure for HSN, regardless of the type. Topical lubricants are used to prevent corneal scarring, GABA agonists, anticholinergics and alpha-adrenergic agonists are used to cope with varying degrees of gastrointestinal dysfunction, hydration and exercise are recommended for long-term preservation of the cardiovascular system and various orthopedic measures in the form of splints and braces are used to reduce the burden of fractures [1] [4].

Prognosis

The quality of life is severely impaired in patients suffering from HSN, especially in the setting of pain and temperature sensation loss. Significant advances were made in the field of supportive care, however, and more patients are able to reach adulthood with current therapeutic options [1].

Etiology

At this moment, seven types of HSN are recognized [1] [3]:

  • Type I, acquired by autosomal dominant patterns of inheritance, is known as hereditary sensory radicular neuropathy. It is caused by progressive degeneration of dorsal root ganglia as a result of mutations in the subunit-1 of serine palmitoyltransferase gene (SPTLC1) on chromosome 9.
  • Type II, congenital sensory neuropathy (CSN) is autosomal recessive and presumably involves mutations of unspecified genes on chromosome 12.
  • Type III, familial dysautonomia (FD), is autosomal recessive as well and stems from mutations in IκB kinase complex-associated protein (IKAP) on chromosome 9.
  • Type IV, congenital insensitivity to pain with anhidrosis (CIPA), is distinguished by mutations in neurotrophic tyrosine kinase receptor type 1 (NTRK1) mutations on chromosome 1, with an autosomal recessive pattern of inheritance.
  • Type V, congenital insensitivity to pain with partial anhidrosis, has a similar pathogenesis as type IV, but the mode of inheritance is still not known.

Congenital autonomic dysfunction with universal pain loss (CAD) and progressive panneuropathy have also been proposed as subtypes of HSN [1].

Epidemiology

Type III is estimated to occur in 1 per 3,600 live births and is exclusively seen in the Eastern European Jewish population, whereas types II and III are very rarely encountered in clinical practice [1]. Family history is considered as the most important risk factor for virtually all types.

Sex distribution
Age distribution

Pathophysiology

Across all types, genetic mutations have shown to impair lipid metabolism, regulation of intracellular vesicular transport, the activity of nerve growth factors and regulators of transcription, eventually leading to neuronal atrophy and degeneration of sensory and autonomic fibers [1] [2].

Prevention

Genetic counseling can be recommended to parents with known family members suffering from HSN.

Summary

Hereditary sensory neuropathy (HSN) is a term encompassing several disorders inherited through either autosomal dominant or recessive patterns [1]. At this moment, seven types have been recognized and classified as HSN subtypes, all distinguished with some form of sensory (disrupted sensation of pain and temperature, hyporeflexia) and/or autonomic (postural hypotension, excessive sweating, gastroesophageal reflux) dysfunction [1], which is why the term hereditary sensory and autonomic neuropathy (HSAN) is often used [1]. Chronic skin ulcers, spontaneous fractures, and neuropathic arthropathy necessitating amputations are constitutive parts of the clinical presentation as well [2]. The diagnosis is primarily made by obtaining a thorough patient history and a detailed physical examination, but a unique feature of almost all types is an abnormally reduced axonal flare after intradermal injection of histamine phosphate [1]. Genetic tests are not readily available and treatment is mainly supportive.

Patient Information

Hereditary sensory neuropathy (HSN) is a disorder characterized by degeneration of neurons that regulate sensory input, such as temperature and pain, and autonomic functions, including blood pressure regulation and activity of the gastrointestinal system. So far, seven types have been described in the literature, with five caused by genetic mutations that are inherited by children from their parents. The clinical presentation starts from birth, with main signs being swallowing difficulties, a reduced sense of pain and temperature perception leading to severe unintentional injuries and fractures, blood pressure changes, skin and corneal ulcerations, but also behavioral changes in the form of irritability and rage. The diagnosis is primarily made based on clinical signs and symptoms, whereas treatment mainly consists of supportive care, as there is no cure for any of the recognized subtypes. Genetic counseling is recommended for parents with a positive family history for HSN, as the condition profoundly impacts the quality of life of patients and their families.

References

Article

  1. Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2:39.
  2. Auer-Grumbach M, Mauko B, Auer-Grumbach P, Pieber TR. Molecular genetics of hereditary sensory neuropathies. Neuromolecular Med. 2006;8(1-2):147-158.
  3. Lee MJ, Stephenson DA, Groves MJ, Sweeney MG, Davis MB, An SF, et al. Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4) gene. Hum Mol Genet. 2003;12(15):1917-1925.
  4. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 20:15