Introduction  

Hereditary neuralgic amyotrophy (HNA) is a rare genetic disorder involving the peripheral nervous system. It is characterised by episodes of pain, marked muscle weakness, and atrophy, most prominently in the shoulders and arms. HNA is typically associated with mutations in the SEPT9 gene, although mutations in SEPSECS and NEDD4 have also been associated. These genes are essential for proper nerve development and function, and their disruption leads to impaired signalling pathways and nerve degeneration.

HNA tends to have an acute onset of symptoms, normally attributed to exertion or viral infections. Clinical diagnosis can be challenging, as the symptoms closely resemble those of other neuropathies. Current management focuses on symptom relief, including pain control and physical therapy.

This article reviews the genetic aspects of HNA, clinical manifestations, and focuses on the role of early diagnosis and supportive care to enhance patient outcomes.  

Causes of hereditary neuralgic amyotrophy

Genetic basis

Hereditary neuralgic amyotrophy is primarily caused by mutations in the SEPT9 gene on chromosome 17q25. This gene encodes septin 9, a cytoskeletal GTP-binding protein involved in cell division, vesicle trafficking, and maintenance of cell shape. 

Role of septin 9 in nerve function

In peripheral nerves, septin 9 contributes to the structural integrity of axons and Schwann cells, which are vital for nerve repair and regeneration.¹ Mutations in SEPT9 disrupt these cellular functions, particularly affecting the brachial plexus, the network of nerves that transmits motor and sensory signals from the spinal cord to the limbs.

Inheritance pattern

HNA follows an autosomal dominant inheritance pattern, meaning a single copy of the mutated gene from either parent can cause the disorder.²  It is noted for incomplete penetrance and variable expressivity; not all individuals with the mutation exhibit symptoms, and the severity varies significantly among those affected.

Inflammatory mechanism

Acute inflammatory brachial plexopathies are a hallmark of HNA.³ These are immune-mediated, involving focal demyelination and nerve inflammation typically following physical stress, trauma, or infections. The pathology leads to transient or permanent injury of the nerve fibres known as axonopathy, which clinically presents as sharp agonising pain that commences together with weakness and atrophy of the muscles in the shoulder and arm.

Symptoms and clinical presentation

Pain

HNA typically presents with sudden, intense pain in the shoulder or upper arm, often radiating along the limb.⁴ Pain is usually severe enough to limit movement and may persist for days or weeks. 

Muscle weakness and atrophy

Muscle weakness typically follows the acute pain phase, particularly affecting the shoulder girdle and upper arm muscles innervated by the brachial plexus. This weakness, if not addressed, may progress to muscle atrophy, whereby muscles shrink due to disuse and appear smaller and weaker on the arm or shoulder.

Recurrent and variable episodes

Recurrent episodes are a hallmark of HNA, though their frequency, duration, and severity vary greatly among individuals. Some individuals experience only a few episodes in their lifetime, while others suffer repeated, debilitating attacks. Each episode can involve different nerves or muscle groups, leading to fluctuating patterns of weakness and atrophy.^5,6

Sensory involvement

In addition to weakness and pain, HNA patients may experience sensory loss, including numbness, tingling, or reduced ability to feel temperature or touch in affected limbs. Sensory involvement is always less pronounced compared with motor symptoms but does equally impair function. 

Involvement beyond the upper limbs

In more severe cases, HNA may involve the facial or respiratory muscles. Facial paralysis may occur, and if the phrenic nerve (which controls the diaphragm) is affected, patients may experience breathing difficulties.

Age of onset and triggers

The age of onset of HNA is typically childhood or early adult years, between ages 3 and 20, although symptoms may appear at any time. Episodes are often precipitated by physical stress, infections (more commonly viral), or surgery, as well as emotional stress. These stressors can sometimes enhance the inflammation response that causes nerve damage and malfunction.

Diagnosis 

Clinical history and physical examination

To a great extent, the diagnosis of HNA depends on clinical history and examination of the patient. The hallmark of the disease is awareness of the pattern of recurrent episodes of acute pain and muscle weakness, which typically occur in the shoulder and arm. 

These episodes are usually precipitated by physical stress, infections, or emotional states, helping differentiate HNA from other neuropathies. A family history of similar episodes with autosomal dominant inheritance supports the diagnosis.

Genetic testing

Diagnosis of HNA is confirmed by genetic testing, particularly the mutation in the SEPT9 gene. This makes a definitive diagnosis between other conditions, and it will also guide family planning due to the 50% risk of inheritance.⁷

Imaging and electrophysiological studies

Imaging techniques, such as MRI or nerve ultrasound, can identify inflammation in the brachial plexus during acute episodes. Electromyography can also help evaluate nerve damage and muscle denervation.⁸

Nerve histology

In rare cases, nerve histology may be performed to identify demyelination and axonal degeneration, particularly if alternative neuropathies need to be excluded.⁹ 

Treatment and management

Management of HNA is multifaceted and is tailored to both the acute phase and long-term care needs of the patient:

Pain management

Pain management in HNA is necessary because the pain during acute episodes is typically extremely severe. In acute episodes, management should include nonsteroidal anti-inflammatory drugs (NSAIDS) for a reduction in inflammation and pain, with aggressive use of corticosteroids to reduce the severity and duration of the illness. Analgesics and other pain relievers may also be prescribed according to the severity of the attack.¹⁰

Immunotherapy

Immunotherapy also holds out the prospect of a therapeutic approach in severe forms of the disease in which inflammation appears to be an important factor. Intravenous immunoglobulin (IVIG) and plasma exchange can modulate the immune response and thus lower the frequency or severity of attacks, although the response is patient-dependent and is usually reserved for those who suffer from frequent debilitating attacks.¹¹

Physical therapy

It is critical to incorporate physical therapy into the rehabilitation process following a primary attack of HNA. Only after acute pain is controlled can physical and occupational therapy help the patient regain strength and achieve good mobility, thereby preventing chronic muscle atrophy. Physical therapy concentrates on strengthening the muscles, improving range of motion, and arranging for the patient to have no or minimal residual deficits in coordination or balance. Early intervention can potentially improve outcomes by allowing patients to recover quickly and by reducing permanent disability.

Long-term management and lifestyle modifications

Long-term management for HNA would involve lifestyle adjustments to decrease the chances of developing the attack. Known triggers must be avoided, like intense exercise, infections, or stress factors. Rest, stress management techniques and keeping oneself in good health enable patients to reduce the frequency of attacks. Regular check-ups with healthcare providers provide continuous monitoring and changing the treatment plans.

Surgical intervention

In some cases, surgical intervention may be necessary if a patient suffers from nerve entrapment and/or significant structural injury from repeated inflammation of the brachial plexus. Surgery can relieve pressure on affected nerves, restore function, and even alleviate pain; it is typically only considered when all of the above treatments have not provided a positive response.¹²

Prognosis

Symptoms of HNA often improve after acute episodes, with partial recovery of strength and pain resolution. However, repeated episodes can result in persistent weakness and chronic muscle atrophy, impairing daily functioning.

HNA significantly impacts quality of life. Recurrent pain, physical limitations, and emotional distress can affect social activities and occupational performance. While some patients enjoy long periods of remission, others face progressive functional decline.¹³

Orthopaedic complications may develop due to muscle imbalance and joint instability, particularly in the shoulder.¹⁴ These can lead to postural issues, joint degeneration, and chronic pain, necessitating ongoing physiotherapy and musculoskeletal care.

Summary

Hereditary neuralgic amyotrophy (HNA) is a rare genetic neuropathy marked by recurrent episodes of severe pain and muscle weakness, most commonly affecting the shoulder and upper limbs. It is usually caused by mutations in the SEPT9 gene and follows an autosomal dominant inheritance pattern. 

Symptoms of HNA are often triggered by stress, infection, or trauma, and can result in lasting muscle atrophy and functional impairment. Diagnosis is confirmed through clinical evaluation and genetic testing. Management focuses on pain control, physical rehabilitation, and preventive strategies. Prognosis varies, with some patients recovering fully and others experiencing persistent deficits.