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Hereditary sensory and autonomic neuropathy type I
HSAN I is a rare, inherited condition that leads to progressive loss of sensation, particularly in the feet and hands, and can also affect involuntary body functions. It typically manifests in adulthood and can significantly impact quality of life.
Overview
Hereditary Sensory and Autonomic Neuropathy Type I (HSAN I) refers to a group of rare, inherited neurological disorders. These conditions primarily affect the peripheral nerves, which are the nerves outside of the brain and spinal cord. Specifically, HSAN I impacts sensory nerves, leading to a reduced ability to feel pain, temperature, and touch, especially in the extremities like the feet and hands. It can also affect autonomic nerves, which control involuntary bodily functions such as blood pressure regulation, sweating, and digestion.
The condition is progressive, meaning symptoms tend to worsen over time. HSAN I generally appears in adolescence or adulthood, making it distinct from some other forms of hereditary neuropathy that might present earlier in life. The exact prevalence of HSAN I is not well established due to its rarity.
Symptoms & clinical features
The main symptoms of HSAN I involve a gradual loss of sensation, most commonly starting in the feet and progressing upwards to the legs and hands. Individuals may notice a reduced ability to feel pain, heat, and cold, which can lead to unnoticed injuries, burns, and infections. These injuries can develop into chronic ulcers, particularly on the feet, which may struggle to heal and can sometimes lead to bone infections or require amputation in severe cases [PMID:19187352].
Besides sensory loss, autonomic nerve involvement can cause a variety of symptoms. These might include reduced sweating (anhidrosis) in affected areas, leading to problems with temperature regulation. Some individuals may experience episodes of low blood pressure when standing up (orthostatic hypotension), digestive issues, or problems with bladder control. Hearing loss, often high-frequency, is also a recognised feature in some forms of HSAN I [PMID:15682498].
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Affected organs
HSAN I predominantly affects the peripheral nervous system, which includes nerves extending from the spinal cord to the rest of the body. The primary impact is on the sensory neurons, especially those in the lower limbs, and to a lesser extent, the upper limbs. The autonomic nervous system, which controls involuntary functions, is also affected, influencing organs like the skin (sweat glands), blood vessels (blood pressure regulation), and sometimes the gastrointestinal tract and bladder.
Over time, the chronic sensory loss can lead to secondary complications affecting the skin, bones, and joints, particularly in the feet. Unnoticed trauma and infections can damage tissues, leading to ulcers and bone infections (osteomyelitis) that can be difficult to treat and may impact mobility. Hearing loss affects the inner ear.
Risks & severity
The severity of HSAN I can vary significantly between individuals, even within the same family. The condition typically has a progressive course, with symptoms gradually worsening over years or decades. Lifelong risks include chronic non-healing ulcers, bone infections, and Charcot joints (severe joint damage due to repeated trauma). These complications, if not carefully managed, can lead to significant disability and sometimes require surgical interventions like amputation.
The age of onset is generally in adolescence or adulthood, typically between the second and fourth decades of life [PMID:19187352]. However, symptoms can sometimes appear earlier or later. While HSAN I is not typically considered life-limiting, complications arising from unrecognised injuries and infections can severely impact quality of life and mobility. Regular monitoring and proactive management are crucial to mitigate these risks.
Genetic causes
HSAN I is a genetically heterogeneous condition, meaning it can be caused by pathogenic variants in several different genes. At present, our reference dataset does not include specific causative genes for HSAN I. However, research suggests that pathogenic changes in genes such as *SPTLC1*, *SPTLC2*, and *ATL1* are commonly associated with different forms of HSAN I. These genes are involved in various cellular processes, including sphingolipid metabolism and membrane trafficking within nerve cells.
When a pathogenic variant occurs in one of these genes, it can disrupt the normal function of nerve cells, particularly the long sensory neurons. This disruption can lead to the degeneration of these nerve fibres, resulting in the characteristic loss of sensation and autonomic dysfunction seen in HSAN I. The precise molecular mechanisms linking these gene changes to nerve damage are a subject of ongoing research.
Inheritance pattern
Hereditary Sensory and Autonomic Neuropathy Type I is inherited in an autosomal dominant pattern. This means that a person needs to inherit only one copy of a pathogenic variant in a causative gene from one parent to develop the condition. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and therefore the condition, regardless of their sex.
If a parent has HSAN I, they can pass the condition on to their children. If a person does not inherit the pathogenic variant, they will not develop the condition and cannot pass it on to their own children. Genetic counselling is available for families affected by HSAN I to discuss inheritance patterns, risks to other family members, and reproductive options.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of HSAN I typically involves a combination of clinical evaluation, neurological examination, and specific diagnostic tests. A neurologist will assess symptoms such as sensory loss, foot ulcers, and any signs of autonomic dysfunction. Nerve conduction studies and electromyography (NCS/EMG) can help confirm peripheral nerve involvement and distinguish HSAN I from other neuropathies.
Confirmation of HSAN I often requires genetic testing. Patients suspected of having HSAN I can be referred to a clinical genetics service in the UK, often via their GP or a specialist neurologist. Genetic testing is typically carried out under an NHS Genomic Medicine Service (GMS) pathway, which may involve R-codes such as R403 (Peripheral neuropathy, inherited) or R416 (Ataxia and hereditary spastic paraplegia). A genetic counsellor can provide support and information throughout the diagnostic process.
Management & lifestyle
The management of HSAN I focuses on symptom relief, preventing complications, and improving quality of life, as there is currently no cure. A multidisciplinary team approach, including neurologists, podiatrists, pain specialists, and physiotherapists, is often recommended. Key aspects of management include meticulous foot care to prevent and manage ulcers, regular inspections for injuries, and protective footwear.
Pain management strategies may be employed for neuropathic pain. Management of autonomic symptoms, such as orthostatic hypotension, may involve lifestyle modifications or medication. Physiotherapy and occupational therapy can help maintain mobility and independence. Regular follow-up appointments with specialists are essential for monitoring disease progression and addressing new symptoms or complications. Genetic counsellors can provide ongoing support for affected individuals and their families.
UK care pathway
In the UK, individuals suspected of having hereditary neuropathies like HSAN I can access care through the NHS Genomic Medicine Service (GMS). Referral to a regional clinical genetics service is typically made by a GP or specialist, such as a neurologist. Genetic counsellors play a vital role in explaining the condition, discussing inheritance, and supporting families through genetic testing. Diagnostic testing for inherited neuropathies often falls under specific NHS R-codes within the GMS National Genomic Test Directory, such as R403 for inherited peripheral neuropathies.
Frequently asked questions
What is the difference between sensory and autonomic nerves?
Sensory nerves are responsible for transmitting information about touch, pain, temperature, and position from the body to the brain. Autonomic nerves control involuntary bodily functions such as heart rate, digestion, breathing, and sweating, which you don't consciously control.
Will my children inherit HSAN I if I have it?
HSAN I is inherited in an autosomal dominant pattern. This means there is a 50% chance that each child you have will inherit the pathogenic gene variant and therefore the condition. Genetic counselling can provide more detailed information specific to your family.
Can HSAN I be cured?
Currently, there is no cure for HSAN I. Management focuses on treating symptoms, preventing complications, and improving quality of life. This includes careful foot care, pain management, and addressing any autonomic symptoms.
Why is foot care so important for people with HSAN I?
Foot care is crucial because the loss of sensation in the feet means injuries, cuts, or sores may go unnoticed. These can then become infected and difficult to heal, potentially leading to serious complications like bone infections or requiring amputation if not managed properly.
Where can I get support for HSAN I in the UK?
In the UK, you can receive support through your NHS clinical genetics service, which can provide genetic counselling. Patient support groups and charities focused on rare neurological conditions or neuropathies may also offer valuable resources and community support.
References
- Houlden H, Blake J, Reilly MM. Hereditary sensory neuropathies. Current opinion in neurology. 2004. PMID: 15367861
- Stögbauer F, Young P, Kuhlenbäumer G. Autosomal dominant burning feet syndrome. Journal of neurology, neurosurgery, and psychiatry. 1999. PMID: 10369826
- Chen Q, Xiao Y, Chai P. ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy. Current biology : CB. 2019. PMID: 30773365
- Ren J, Saied EM, Zhong A. Tsc3 regulates SPT amino acid choice in Saccharomyces cerevisiae by promoting alanine in the sphingolipid pathway. Journal of lipid research. 2018. PMID: 30154231
- Houlden H, King R, Blake J. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain : a journal of neurology. 2006. PMID: 16364956
- Bi H, Gao Y, Yao S. Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese. Neuropathology : official journal of the Japanese Society of Neuropathology. 2007. PMID: 18018475
- Suh BC, Hong YB, Nakhro K. Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Molecular medicine reports. 2014. PMID: 24247255
- Rotthier A, Auer-Grumbach M, Janssens K. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. American journal of human genetics. 2010. PMID: 20920666