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Neurogenetics

Hereditary sensory neuropathy type II

HSN2 leads to a significant reduction in the ability to feel pain, temperature, and touch, particularly in the hands and feet. This can result in recurrent injuries and complications, impacting quality of life from childhood.

Autosomal recessive Neurogenetics OMIM:201300
Rare
Prevalence
Population estimate
25%
Inheritance
Autosomal recessive - chance of passing to each child
3
Associated genes
FAM134B, KIF1A, WNK1

Overview

Hereditary Sensory Neuropathy Type II (HSN2) is a rare inherited disorder that predominantly affects the sensory nerves. These nerves are responsible for transmitting information about touch, pain, temperature, and body position to the brain [PMID:33678095]. Individuals with HSN2 experience a progressive decline in sensation, often beginning in infancy or early childhood. This condition is part of a broader group of disorders known as hereditary neuropathies, which involve damage to the peripheral nerves. The severity of HSN2 can vary, but it generally leads to significant disability due to repeated injuries and infections.

Symptoms & clinical features

The primary symptoms of HSN2 stem from the profound loss of sensation. This typically begins in the hands and feet (distal extremities) and can progress upwards. Affected individuals may not feel pain from cuts, burns, or fractures, leading to repeated and often unnoticed injuries. These injuries can result in chronic wounds, infections, and deformities of the bones and joints, particularly in the feet. Joint problems, including Charcot joints (neuropathic arthropathy), are common due to the lack of protective sensation and repetitive trauma. Muscle weakness and wasting can also occur, particularly in the lower limbs, contributing to walking difficulties. Other potential features include reduced or absent reflexes and, in some cases, features affecting the autonomic nervous system, which controls involuntary bodily functions like sweating.

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Affected organs

HSN2 primarily affects the peripheral nervous system, specifically the sensory nerves. These nerves extend throughout the body, but the effects are most pronounced in the extremities, such as the hands and feet. The lack of sensation in these areas makes them highly vulnerable to injury. Over time, this can lead to damage to the bones, joints, and skin in the affected limbs. The spinal cord and brain are generally not directly affected by HSN2, though continuous nerve damage may lead to degeneration of nerve fibres within the spinal cord over many years.

Brain
Brain
Central nervous system involvement
Nervous system
Nervous system
Peripheral nerve involvement

Risks & severity

HSN2 typically presents in early childhood, often within the first year of life, with symptoms that worsen over time [PMID:33678095]. The condition's severity can vary, but it generally leads to significant complications such as chronic wounds, infections, and bone deformities. These complications may result in amputation in severe cases. The absence of protective pain sensation poses a lifelong risk of injury. While HSN2 does not typically reduce life expectancy directly, the associated complications and infections can have a substantial impact on overall health and quality of life. The exact prevalence of HSN2 is not well established, but it is considered a rare disorder.

Genetic causes

Hereditary Sensory Neuropathy Type II is caused by pathogenic variants in specific genes. The genes currently known to be associated with HSN2 include FAM134B, KIF1A, and WNK1. The proteins produced from these genes play important roles in the health and function of nerve cells. For instance, FAM134B is involved in reticulophagy, a cellular process targeting the endoplasmic reticulum, which is vital for protein production and transport within cells. KIF1A codes for a protein called kinesin, which is essential for transporting materials within nerve cells along their long extensions (axons) [PMID:27055964]. WNK1 codes for a protein kinase that influences ion transport, which is crucial for nerve signal transmission. When these genes have pathogenic variants, their respective proteins may not function correctly, leading to the degeneration of sensory nerve fibres and the characteristic symptoms of HSN2.

  • FAM134B
    reticulophagy regulator 1
  • KIF1A
    kinesin family member 1A
  • WNK1
    WNK lysine deficient protein kinase 1

Inheritance pattern

HSN2 is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. If a person inherits only one pathogenic variant, they are considered a carrier and typically do not show symptoms of HSN2 themselves. For parents who are both carriers, there is a 25% chance with each pregnancy that their child will inherit two pathogenic variants and develop HSN2, a 50% chance their child will be a carrier, and a 25% chance their child will inherit two unaffected copies of the gene. Genetic counselling is available to help families understand these inheritance patterns and their implications.

♀ Carrier parent 1 altered copy ♂ Carrier parent 1 altered copy Affected Carrier Carrier Unaffected Affected Carrier Unaffected Circles = females · Squares = males

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.

Diagnosis & testing

The diagnosis of HSN2 is typically suspected based on clinical signs and symptoms, especially in a child presenting with recurrent unexplained injuries and a profound lack of sensation. Neurological examination will often reveal absent or severely reduced sensory responses. Nerve conduction studies, which measure how well nerves transmit electrical signals, usually show severely reduced or absent sensory nerve responses. A definitive diagnosis of HSN2 is confirmed through genetic testing, which can identify pathogenic variants in genes such as FAM134B, KIF1A, or WNK1. Referral for genetic testing in the UK usually follows the NHS Genomic Medicine Service (GMS) pathway, which can be accessed via a clinical genetics specialist. The relevant R-codes for hereditary neuropathies (e.g., R51 for hereditary motor and sensory neuropathy (HMSN) and R52 for hereditary sensory neuropathy) guide the genetic testing process within the NHS.

Management & lifestyle

There is currently no cure for HSN2, so management focuses on preventing injuries, treating complications, and providing supportive care. This typically involves a multidisciplinary team including neurologists, orthopaedic surgeons, physiotherapists, occupational therapists, and podiatrists. Regular foot care and inspection are crucial to detect and manage unnoticed wounds and infections early. Protective footwear and orthotics can help prevent injuries and support joints. Pain management strategies are used for any neuropathic pain that might occur, although the main issue is a lack of pain sensation. Physiotherapy and occupational therapy can help maintain mobility, muscle strength, and independence. Genetic counsellors can provide support and information to individuals and families regarding the inheritance pattern and implications of HSN2. Surveillance for complications and prompt treatment of infections are key components of ongoing care within the NHS framework.

UK care pathway

In the UK, individuals suspected of having hereditary neuropathies like HSN2 are typically referred to a clinical genetics service or a specialist neurology clinic. This initiates a care pathway aligned with the NHS Genomic Medicine Service (GMS). Genetic counsellors play a vital role, offering support, information, and explaining genetic testing options. Genetic testing, guided by specific R-codes (e.g., R52 for hereditary sensory neuropathy), helps confirm a diagnosis. This enables access to specialist care and allows for informed decisions regarding family planning.

Frequently asked questions

What is the main problem for someone with HSN2?

The main problem for someone with HSN2 is a severe and progressive loss of sensation, particularly the ability to feel pain, temperature, and touch. This often starts in the hands and feet, leading to frequent, unnoticed injuries and complications like chronic wounds and infections.

How is HSN2 inherited?

HSN2 is inherited in an autosomal recessive pattern. This means a child needs to inherit a pathogenic gene variant from both parents to develop the condition. If parents are both carriers, there's a 1 in 4 chance with each pregnancy that their child will be affected.

Can HSN2 be cured?

Currently, there is no cure for HSN2. Treatment focuses on managing symptoms, preventing injuries, and addressing complications such as infections and bone deformities. A multidisciplinary team of healthcare professionals typically provides this supportive care.

Will my children inherit HSN2 if I have it?

If you have HSN2, it means you have two pathogenic gene variants. If your partner is not a carrier, none of your children would develop HSN2, but they would all be carriers. If your partner is a carrier, there would be a 50% chance with each pregnancy that your child would inherit HSN2. Genetic counselling can provide personalised information and support for family planning.

What kind of doctors treat HSN2?

Management of HSN2 typically involves a team of healthcare professionals. This often includes neurologists, orthopaedic surgeons, podiatrists, physiotherapists, occupational therapists, and genetic counsellors, all working together to address the various aspects of the condition.

References

  1. Murthy SC, Udagani MM, Patil MN. Hereditary sensory neuropathy-type-II. Indian journal of dermatology, venereology and leprology. 2002. PMID: 17657011
  2. Puri V, Anjaneyulu A. Hereditary sensory neuropathy type II. Neurology India. 1996. PMID: 29542541
  3. Puri S, Menon PS, Verma A. Hereditary sensory neuropathy: type II. Indian pediatrics. 1990. PMID: 2246048
  4. Davar G, Shalish C, Blumenfeld A. Exclusion of p75NGFR and other candidate genes in a family with hereditary sensory neuropathy type II. Pain. 1996. PMID: 8895241
  5. Bye AM, Baker WD, Pollard J. Hereditary sensory neuropathy type II without trophic changes. Developmental medicine and child neurology. 1990. PMID: 2338180
  6. Shekarabi M, Girard N, Rivière JB. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. The Journal of clinical investigation. 2008. PMID: 18521183
  7. Ota M, Ellefson RD, Lambert EH. Hereditary sensory neuropathy, type II. Clinical, electrophysiologic, histologic, and biochemical studies of a Quebec kinship. Archives of neurology. 1973. PMID: 4351257
  8. Croall GB, Bates SR, Iannaccone ST. Paucifascicular congenital sensory neuropathy in identical twins. American journal of diseases of children (1960). 1986. PMID: 3010702
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.