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Hereditary motor and sensory neuropathy (HNPP)
HNPP primarily affects the peripheral nerves, which are outside the brain and spinal cord. Individuals with HNPP can experience recurrent, temporary nerve palsies, often triggered by minor pressure or trauma, leading to symptoms like 'foot drop' or wrist weakness.
Overview
Hereditary Neuropathy with Pressure Palsies (HNPP) is a condition that affects the peripheral nervous system. This system includes all the nerves that lie outside the brain and spinal cord, connecting them to the rest of the body. In HNPP, these nerves are unusually susceptible to damage from even minor pressure or trauma, leading to temporary but sometimes severe symptoms [PMID:10377042].
The condition is sometimes referred to as 'tomaculous neuropathy' due to the characteristic sausage-like thickenings (tomacula) of the myelin sheath that can be seen on nerve biopsies [PMID:17963385]. These thickenings are thought to make the nerves more vulnerable to compression and injury. While symptoms are often temporary, they can recur and, in some cases, lead to more persistent issues.
Symptoms & clinical features
The symptoms of HNPP typically involve episodes of nerve dysfunction, known as pressure palsies. These episodes can develop after activities that involve prolonged pressure on a nerve, such as leaning on an elbow, crossing legs, or repetitive movements. Common symptoms during an episode include numbness, tingling sensations (paraesthesia), and muscle weakness in the affected limb or area.
Specific examples of pressure palsies include 'foot drop', which is difficulty lifting the front part of the foot, leading to a dragging foot when walking. Another common presentation is 'wrist drop', where the wrist and fingers cannot be extended. The severity and frequency of these episodes can vary widely among individuals, even within the same family. While many people recover completely from an episode, some may experience residual weakness or sensory loss [PMID:10377042].
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Affected organs
HNPP primarily affects the peripheral nerves, which extend throughout the body to the muscles, skin, and internal organs. The condition specifically impacts the myelin sheath, which is the protective covering around nerve fibres. This myelin allows electrical signals to travel quickly and efficiently along the nerves. When the myelin is damaged, nerve impulses are slowed or blocked. While the brain and spinal cord (central nervous system) are not directly affected by HNPP, the peripheral nerve damage can lead to problems with movement (motor nerves) and sensation (sensory nerves) in the limbs.
Risks & severity
The severity of HNPP symptoms can range significantly, from very mild and infrequent episodes to more frequent and debilitating pressure palsies. Some individuals may experience only subtle symptoms or remain asymptomatic throughout their lives, while others can have recurrent, disabling episodes. The first symptoms often appear during adolescence or early adulthood, but onset can range from early childhood to later in life [PMID:17963385].
While most pressure palsies in HNPP are temporary, some individuals may develop chronic weakness or sensory loss, especially after repeated injury to the same nerve. The condition is generally not life-threatening, but it can significantly impact quality of life due to the unpredictable nature of symptoms and the potential for long-term disability.
Genetic causes
HNPP is caused by pathogenic changes in the PMP22 gene. This gene provides instructions for making a protein called peripheral myelin protein 22. PMP22 is a crucial component of the myelin sheath, which insulates and protects nerve cells in the peripheral nervous system. Healthy myelin allows nerve signals to transmit rapidly and effectively throughout the body.
In most cases of HNPP, the condition results from a deletion of a segment of chromosome 17 that includes the PMP22 gene [PMID:10377042]. This means individuals have only one functional copy of PMP22 instead of the usual two. Having a reduced amount of the PMP22 protein disrupts the normal formation and maintenance of the myelin sheath, making the peripheral nerves fragile and highly susceptible to damage from pressure or trauma.
- PMP22 peripheral myelin protein 22
Inheritance pattern
HNPP is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered PMP22 gene from one parent to develop the condition. Each child of an affected parent has a 50% chance of inheriting the altered gene and therefore developing HNPP.
It is important to remember that even if a person inherits the altered gene, the severity of symptoms can vary greatly. Some individuals may have mild symptoms, while others have more significant issues, even within the same family. Genetic counselling can provide more detailed information about inheritance patterns and risks for family members.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of HNPP is typically suspected based on a person's medical history, particularly recurrent episodes of numbness, weakness, and tingling following minor pressure or trauma. A physical examination may reveal signs of nerve damage, such as muscle weakness or reduced reflexes.
Electrodiagnostic studies, such as nerve conduction studies and electromyography (NCS/EMG), can help to confirm nerve damage and identify characteristics consistent with demyelination. However, the definitive diagnosis of HNPP is made through genetic testing, which looks for the specific deletion or other pathogenic changes in the PMP22 gene. In the UK, genetic testing for HNPP would typically be accessed via the NHS Genomic Medicine Service following referral from a neurologist or clinical geneticist. The relevant R-codes (NHS National Genomic Test Directory codes) would guide testing pathways.
Management & lifestyle
Currently, there is no specific cure for HNPP, so management focuses on preventing nerve damage and alleviating symptoms. This generally involves avoiding activities that put prolonged pressure on nerves. For example, individuals may be advised to avoid prolonged sitting with crossed legs, leaning on elbows, or maintaining certain postures for extended periods.
Protective padding for elbows and knees may be helpful. Physical therapy can play a role in maintaining muscle strength and flexibility, and occupational therapy can help individuals adapt daily activities to prevent nerve compression. Regular follow-up with a neurologist is often recommended to monitor symptoms and adjust management strategies as needed. Genetic counsellors can also provide support and information regarding the genetic aspects of the condition and family planning.
UK care pathway
In the UK, individuals suspected of having HNPP would typically be referred to a neurologist or a clinical genetics service. Clinical geneticists and genetic counsellors are specialists who can provide expert advice, diagnostic testing, and support for genetic conditions. The NHS Genomic Medicine Service offers genomic testing for conditions like HNPP, guided by specific R-codes in the National Genomic Test Directory. This pathway ensures that eligible patients can access appropriate genetic diagnosis and counselling.
Frequently asked questions
What activities should someone with HNPP avoid?
Individuals with HNPP are generally advised to avoid activities that involve prolonged or repetitive pressure on nerves. This includes prolonged sitting with crossed legs, leaning on elbows for extended periods, or wearing tight-fitting casts or restrictive clothing that might compress nerves. Taking regular breaks during activities can also be beneficial.
Is HNPP a progressive condition?
HNPP typically causes recurrent episodes of nerve dysfunction rather than continuous progression. While each episode usually resolves, repeated injuries to the same nerve can sometimes lead to residual weakness or sensory loss. The overall course of the condition varies widely among individuals.
Can HNPP be misdiagnosed?
Yes, HNPP symptoms, particularly temporary numbness or weakness, can sometimes be mistaken for other conditions, such as carpal tunnel syndrome or other types of nerve compression. A detailed medical history, neurological examination, and especially genetic testing are crucial for an accurate diagnosis.
How does HNPP affect family planning?
As HNPP is an autosomal dominant condition, there is a 50% chance for each child of an affected parent to inherit the altered PMP22 gene. Genetic counselling can provide comprehensive information about inheritance risks, reproductive options, and prenatal or pre-implantation genetic diagnosis if desired.
Are there any medications for HNPP?
There are currently no specific medications that directly treat the underlying cause of HNPP. Management focuses on preventing nerve damage and treating symptoms, for instance, with pain relief for discomfort or physical therapy to maintain muscle function. Always discuss any medications with your healthcare provider.