Introduction

Lesch-Nyhan Syndrome is a rare enzyme deficiency disorder that primarily affects males.^1,²

The enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT), helps remove protein waste before it turns into uric acid in the body, which can be harmful in excess.¹

A mutation in the gene responsible for producing HPRT leads to a deficiency or complete lack of the enzyme, resulting in Lesch-Nyhan Syndrome.¹^,3

Lesch-Nyhan Syndrome is an inherited disorder, which means parents can pass the gene responsible for it to their children, although the gene has to be present in both parents.²

As a syndrome, it means it manifests with various symptoms and signs that consistently occur together. 

The key symptoms² of the condition are:

• High levels of uric acid in the blood (a substance that can cause problems like gout)
• Delays in a child’s development, such as learning to speak, walk, or interact later than usual
• Uncontrolled body movements
• Behaviours where the person harms themselves, like biting or hitting themselves (self-mutilation)

Among other disorders that occur as a result of this condition, in this article, we are going to focus on the movement disorders and the diagnostic and therapeutic challenges.

Movement disorders in Lesch-Nyhan Syndrome 

Movement disorders are a part of the neurological symptoms of this condition and a major characteristic.

The symptoms usually begin during the first few years of life² and the most common ones are:³

• Dystonia 
• Choreoathetosis
• Ballismus 
• Spasticity

Dystonia 

This is the most common movement disorder.²

It is an uncontrolled twisting movement of the arms and legs.

It occurs as a result of too much muscle activity in both agonist and antagonist muscles at the same time during voluntary movement, causing the body to twist or hold awkward positions for a while. 

According to a study, slower movements, also known as chorea, usually occur on the face, neck, trunk, and limb muscles and can be triggered by stress, excitement, or attempted actions.⁴

The twisting and stiff movements in the arms make it hard for the patient to carry out everyday activities like feeding, holding objects, or grabbing things. 

Problems with the legs make it difficult or impossible to walk or stand, so patients usually need help or have to use a wheelchair all the time.³

There can also be jerky movements or tightness in their jaw and tongue when talking or eating.³

Ballismus 

It is uncontrolled movements that are quick and occur in a throwing-like manner of the arms or legs.⁴The arms are mostly affected, and sometimes, the legs.³

They usually occur only when the child is agitated or excited, or when something is close enough to the child, leading to increased muscle tone and exaggerated reflexes. For example, if someone puts a toy or a cup near the child, the arm might suddenly fling toward it.

Choreoathetosis

This is a purposeless movement, such as flexing or bending the fingers, shrugging the shoulders, or making unusual faces that are repetitive.

They are involuntary, non-regular vary in time and where they occur.³

Spasticity 

Spasticity is when muscles become unusually tight or stiff, making it hard to move a part of the body. 

The more attempts a patient makes to move a part of the body, the greater the resistance the patient encounters.

This stiffness usually gets worse when trying to straighten the joint (extension) compared to bending it (flexion).³

Most of the movement disorders in Lesch-Nyhan Syndrome (LND) are caused by issues in a part of the brain called the basal ganglia, which helps control and coordinate body movements.⁴

Diagnosis and Diagnostic Challenges in Lesch-Nyhan Syndrome

Diagnosing LNS poses significant challenges due to symptom overlap with that of other conditions, under-recognition of motor signs overshadowed by behavioural symptoms and limitations in imaging and neurophysiological assessments. 

Overlap with Other Movement Disorders

The motor manifestations of LNS often resemble those seen in other neurological disorders, leading to potential misdiagnosis. 

For instance, the dystonic movements in LNS can be mistaken for cerebral palsy (CP), especially in early childhood when hypotonia and developmental delays are common.³

Choreoathetosis in LNS mimics other movement disorders such as Huntington's disease or other basal ganglia disorders.⁴  

Under-recognition due to behavioural symptoms overshadowing motor signs

Behavioural symptoms, especially self-injurious behaviour (SIB), are very defining features of LNS and often dominate the clinical picture.

It can mask underlying motor abnormalities, leading to under-recognition and delayed diagnosis. 

The severity of self-injurious behaviour in Lesch-Nyhan Syndrome patients often leads clinicians to focus primarily on behavioural management, hence leading to neglect of assessment and treatment of motor dysfunction.⁵ 

Also, the behavioural symptoms can interfere with neurological examinations, making it difficult to assess motor function properly. 

Patients can even be uncooperative or exhibit behaviours that hinder standard motor assessments.

Limitations of Imaging and Neurophysiological Tests

Neuroimaging and neuropsychological examinations are a crucial part in evaluating neurological disorders; however, their use in diagnosing Lesch-Nyhan syndrome is limited.  

Standard imaging techniques such as MRI and CT scans often yield non-specific findings in LNS patients.³ 

Routine imaging studies frequently appear normal or show only mild cerebral atrophy, which is not distinctive for LNS.

Quantitative MRI shows reductions in basal ganglia volume, but these findings require specialised imaging protocols and are not routinely available.³

The misdiagnosis is further complicated by the rarity of LNS, leading to limited clinical familiarity among healthcare providers. 

Therapeutic Challenges in Lesch-Nyhan Syndrome 

The management of LNS is complex, requiring a multifaceted approach that addresses both neurological and behavioural symptoms. This can be a challenging factor, coupled with the exhibition of symptoms of other disorders 

Pharmacological treatments

Dopaminergic Agents

Dopaminergic agents are used in Lesch-Nyhan syndrome due to the disorders associated with basal ganglia dysfunction and dopamine deficiency.³ 

However, their efficacy remains limited. While dopamine replacement therapies offer short-term benefits, they often fail to produce significant long-term improvements in motor function.  

Moreover, these agents may exacerbate behavioural symptoms, including self-injurious behaviour (SIB), making it very important for cautious use.⁶ 

Benzodiazepines, Anticholinergics, and Baclofen

Benzodiazepines, such as diazepam, are commonly used to manage anxiety and muscle spasms in LNS patients. They may provide temporary relief from dystonia but are often limited by sedation and the potential for dependence; hence, their use in the management of this condition is uncertain and unclear.³

Anticholinergic agents, like trihexyphenidyl, are effective in reducing dystonic movements, though their use is frequently constrained by the fact that they must be sedating doses and have also shown some cognitive side effects.³

Baclofen has been used to reduce spasticity and dystonia. Although some patients experience modest benefits, others show minimal response, showing the inconsistency in treatment outcomes.³

S-adenosylmethionine (SAMe) treatment reduces dystonic movements and improves life for patients with Lesch-Nyhan syndrome.

Although more research has to be done to determine the long-term safety and efficacy of SAMe and its appropriate dosage.⁶ 

Botulinum Toxin for Focal Dystonia

Botulinum toxin causes muscle weakness by blocking the release of acetylcholine at the neuromuscular junction. The toxin is effective in treating symptoms of dystonia.⁷ 

However, the benefits are temporary, meaning need for repeated injections, and the response can vary among individuals. 

Surgical Interventions

Deep Brain Stimulation (DBS)

Deep Brain Stimulation (DBS) of the globus pallidus internus (GPi) has been investigated as a treatment modality for refractory dystonia and in LNS. 

It involves the implantation of electrodes that deliver electrical impulses to specific brain regions, modulating neural activity.  

Several case reports and small series have reported improvements in motor function following DBS.⁸ 

However, the outcomes are variable, with some patients experiencing significant benefits and others showing minimal or transient improvements.⁸ 

Unfortunately, deep brain stimulation has risks associated with surgery and potential device-related issues, making it very important to carefully select patients and conduct a comprehensive preoperative assessment.

Behavioural and Supportive Therapies

Occupational and Physical Therapy

Occupational and physical therapies are important components of the multidisciplinary approach to managing LNS. 

These therapies focus on boosting functional capabilities, refining motor skills, and encouraging greater self-reliance.   

Physical therapy focuses on maintaining joint mobility, reducing spasticity, and preventing contractures, while occupational therapy addresses fine motor skills and activities of daily living. 

However, when carrying out these interventions, it is necessary to ensure that the patient's rights are not being infringed upon.

Summary 

Lesch-Nyhan Syndrome (LNS) is a rare, inherited disorder primarily affecting males, caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This deficiency leads to excess uric acid and a range of neurological and behavioural symptoms, notably movement disorders and self-injurious behaviour.

For the movement disorders, symptoms are linked to dysfunction in the basal ganglia, a brain region responsible for movement regulation.

Although there are attempts at diagnosis and treatment, this is always encountered with challenges because of the fact that the condition shows certain symptoms that are present in other disorders.