Introduction

What is chediak-higashi syndrome (CHS)? 

Chediak-Higashi Syndrome is a rare genetic disorder. It is characterised by easy bruising, oculocutaneous albinism (reduced pigment in the skin and eyes), and recurrent pyogenic infections.¹ The gene responsible for this syndrome is the LYST gene, where a mutation in this gene affects the movement of proteins within the cells.² When this gene is mutated, transport steps fail, which in turn causes oversized lysosomes. As proteins can’t reach the places they are needed, immune dysfunction occurs, resulting in nerve damage and brain cell changes. Immune cells, such as white blood cells or natural killer cells, cannot destroy harmful viruses and bacteria effectively. Whereas in nerve and brain cells, communication is disrupted, leading to damage building up over time, and consequently, peripheral neuropathy and cognitive decline.

Peripheral neuropathy 

What does peripheral neuropathy mean?

Peripheral neuropathy occurs when nerves outside of the brain and spinal cord are damaged.³ This includes sensory nerves, motor nerves and autonomic nerves. These nerves transmit electrical signals that control sensation, movement and coordination. If these nerves are impaired, the electrical impulses can be slowed, or they may not reach their destination. This can lead to various symptoms.

Symptoms in CHS

In both children and young adults with Chediak-Higashi Syndrome, peripheral neuropathy occurs gradually. Early signs of this condition include: stumbling or unsteady walking, difficulty with fine motor tasks such as writing and tingling or numbness in the feet and hands. Many symptoms tend to progress and become more pronounced in adulthood. The symptoms include: muscle weakness in the arms and legs.⁴ Loss of reflexes, impaired balance and coordination, and ataxia.⁵ These changes can make life extremely difficult, and may reduce independence and require adaptive strategies, such as physical therapy and mobility aids.

Why does it happen

The defective LYST gene in Chediak-Higashi Syndrome affects Schwann cells. These cells play a crucial role in nerve development and are best known for insulating and providing nutrients to axons⁶ found in neurons. Without healthy Schwann cells, the myelin, which is the protective coating of the nerves,⁷  breaks down. This is significant as healthy myelin ensures that electrical signals travel both accurately and rapidly along the nerve fibres. The disruption leads to the blocking of signals, which causes symptoms such as muscle weakness. The axons (nerve fibres) can also degenerate due to cellular stress. This is due to the malfunctioning lysosomes. This combined effect leads to both demyelination and axon damage of the peripheral nerves, which means they cannot effectively communicate with sensory organs or muscles. This, therefore, leads to all the symptoms mentioned above.

Management of peripheral neuropathy in CHS:

There is no current cure for peripheral neuropathy in CHS; therefore, treatment focuses on the management of symptoms. Due to nerve damage being progressive, early intervention is crucial in slowing down functional decline. 

Supportive therapies

Supportive therapies are one of the most beneficial ways to manage peripheral neuropathy in CHS. Physical therapy focuses on maintaining muscle strength, improving mobility and reducing the risk of falls through providing equipment such as canes or walkers. It manages neurological deficits such as spasticity and impaired coordination. Occupational therapy can also help through the use of specialised tools or adaptive techniques. This can help with fine motor difficulties, such as writing or getting dressed, that occur in CHS. Both these therapies are considered the backbone of treatment for CHS.⁸

Pain management 

As peripheral neuropathy in CHS can cause tingling or burning sensations or even stabbing pains, management is essential. These sensations can often interfere with sleep, everyday activities and mobility. In order to manage neuropathic pain, a combination of both pharmacological and non-pharmacological approaches is needed.

To manage pain pharmacologically, specialists can prescribe various medications. For example, anticonvulsants such as gabapentin or pregabalin can be used. These medications stabilise nerve activity and reduce abnormal firing. They change the way in which nerves send messages to your brain,⁹ thus reducing pain. Topical creams such as lidocaine or capsaicin can also provide localized relief. These topicals help pain management by blocking the signals from the nerve endings.

Non-pharmacological treatments to manage any pain are used to complement medications. These include warm baths / hot compresses to soothe muscles and improve blood flow, as well as a gentle massage or stretching to help relax tense muscles. 

Cognitive decline 

What is cognitive decline?

Cognitive decline is a gradual loss of thinking, memory and learning abilities.¹⁰ The gradual deterioration of these abilities can affect everyday functioning. In CHS, cognitive decline most commonly develops over a period of months or years, instead of appearing suddenly. Changes can be subtle, such as forgetting recent events or taking longer to learn new tasks. As time progresses, cognitive decline can be more noticeable. Problems can include: not being able to pay attention, difficulty with decision-making or adapting to unknown situations. These symptoms can impact academic performance, social interactions and everyday life. 

Symptoms in CHS

Cognitive decline can present itself in various ways. As previously mentioned, early symptoms can include subtle symptoms in attention, learning speed and also memory. In particular, children may struggle with various tasks even if they were not difficult before. Children may also find it hard to learn new information or forget instructions given to them. This can severely impact performance in education.¹¹ As Cheniak-Higashi syndrome progresses, more noticeable and pronounced difficulties emerge. This includes difficulty with problem-solving and organising daily activities. Adults often experience significant learning difficulties and memory impairments.  

Why does cognitive decline occur?

The cognitive decline seen in this condition is linked to the mutation of the LYST gene, which impairs the functions of lysosomes in neurons. When the lysosomes cannot function properly, waste products can accumulate within the neurons. This leads to cellular stress and impaired function. It also leads to the eventual death of the neuron. This then affects key brain regions, such as the cerebral cortex and hippocampus, which are responsible for learning, memory and attention.¹² As the defective gene also disrupts intracellular trafficking, the movement of proteins and organelles is disturbed. This accelerates neuronal damage, slowing down communication between neurons, and, therefore, also contributing to difficulties with processing new information and coordinating thought. 

Management of cognitive decline 

Cognitive decline in Chediak-Higashi syndrome is currently irreversible. However, a combination of different supportive strategies can help maintain function despite the progressive nature of the symptoms. Early recognition is essential, as interventions at the start are more effective than when severe symptoms appear. 

Structured routines can provide consistency and reduce cognitive load. This may help with planning daily tasks or activities, remembering tasks, and also reducing potential frustration. To strengthen certain skills, cognitive rehabilitation programs may help. These include memory exercise and attention training. These programs aim to correct any deficits in memory, attention, planning and learning ¹³. All exercises should be tailored to age and cognitive level. 

Educational support is also important, especially for children. Support can be provided in the form of individualised learning plans or simplification of tasks. Furthermore, assistive technologies such as reminders or visual schedules may support performance in academia and also daily functioning. Occupational therapy also helps with cognitive decline, as well as peripheral neuropathy. Therapists can teach organisational strategies (such as visual cues or checklists) and also provide training for daily activities. These include skills such as cooking or dressing as well as managing finances. Through learning these skills and management, feelings of distress can be reduced. An occupational therapist will ensure independence despite the cognitive decline, with the aim of preventing any accidents or feelings of frustration.

Social encouragement can also help maintain thinking skills and reduce cognitive decline. This can be done through engaging with family or friends, as this provides mental stimulation. It can also help preserve memory and attention. Structured group activities or clubs can also encourage communication and emotional expression. This can help reduce feelings of isolation or depression, both of which can often contribute to the worsening of cognitive impairment. Through fostering a stimulating and supportive social environment, quality of life can be improved despite the gradual cognitive decline associated with CHS. 

Diet and lifestyle choices can also support brain functioning, as well as overall well-being. A balanced diet rich in whole greens, proteins and healthy fats can provide essential nutrients, including omega-3 fatty acids and antioxidants that help protect neurons and may help with cognitive decline.¹⁴ Regular physical activity also may enhance neuroplasticity, while adequate sleep (seven to nine hours for adults) supports both memory and attention. Mental stimulation in the form of puzzles or reading can also help maintain cognitive reserves, promoting functional independence and also quality of life. 

FAQs

Why does chediak-higashi cause peripheral neuropathy?

CHS is caused by mutations in the ‘LYST’ gene. This disrupts intracellular trafficking as well as lysosome function, which affects Schwann cells in the nervous system. These cells form a protective myelin layer around peripheral nerves; however, the mutation causes improper myelination and nerve fibre degeneration. This leads to impaired signal transmission, causing peripheral neuropathy and manifesting itself through symptoms such as weakness and numbness. 

What is the hallmark of chediak-higashi syndrome?

The hallmark of Chediak-Higashi Syndrome is the presence of giant cytoplasmic granules in almost all granule-containing cells. These giant granules are abnormal lysosomes. This abnormality leads to characteristic symptoms such as partial albinism, immune system dysfunction and neurological manifestations. 

How does peripheral neuropathy affect your brain?

Peripheral neuropathy happens when damage to nerves outside the brain and spinal cord has occurred. Therefore, it does not directly damage the brain. It may, however, indirectly affect brain function through chronic pain and sensory deficits. 

Can peripheral neuropathy cause confusion?

Peripheral neuropathy rarely causes confusion. However, symptoms associated with peripheral neuropathy, such as sleep disturbances and reduced mobility, may impair concentration and memory. This can therefore manifest as confusion or cognitive decline. 

Summary 

Chediak-Higashi syndrome is a rare genetic disorder caused by mutations in the LYST gene. It is an autosomal recessive condition. Neurological symptoms include peripheral neuropathy as well as cognitive decline. These affect fine motor skills, can cause uncomfortable sensations, difficulty walking, as well as impaired thinking and attention skills. There is no current cure for this condition; however, various strategies and methods can help with independence and management of pain.