Lesch-Nyhan Syndrome

Etiology

Lesch Nyhan syndrome is an X-linked recessive disorder resulting from mutation of the HPRT1 gene, located at a q26-27 position on the long arm of the X chromosome. Though only a single gene is associated with this syndrome, over 600 mutations have been identified, each leading to varying levels of severity of clinical presentations making HPRT enzyme deficiency a spectrum rather than a single disease.[3] Males who receive the defective X chromosome from the carrier mothers manifest the disease. Females are mostly carriers but may develop the disease if the healthy X chromosome undergoes lionization, and the defective X chromosome is expressed phenotypically.

Epidemiology

The estimated prevalence of Lesch Nyhan syndrome is between 1:235,000 and 1:380,000.[4] Studies show that it occurs in relatively equal frequencies in all populations. Although it is an X-linked disorder manifesting mostly in males, a few females with Lesch Nyhan syndrome have been reported.

Pathophysiology

HPRT enzyme catalyzes the conversion of hypoxanthine and guanine into IMP and GMP, respectively, through the purine salvage pathway. This step utilizes PRPP as a cosubstrate. HPRT deficiency causes the accumulation of hypoxanthine and guanine by dual mechanisms, (1) Decreased utilization for purine synthesis, and (2) increased availability of PRPP to be used for the synthesis of IMP by the Denovo pathway, which is then converted to hypoxanthine and eventually into uric acid. Excess uric acid is known to precipitate in kidneys and joints, resulting in renal calculi and tophi.

The exact pathophysiology of neurological complications in Lesch Nyhan syndrome is unknown. Hyperuricemia is not proposed as a possible mechanism as the less severe variants of HPRT deficiency do not show neurological complications. GTP is necessary for the activation of dopamine receptors. A relative deficiency of GTP in HPRT deficiency, resulting in decreased dopamine receptor activation, is proposed as the likely mechanism. Regions of the brain with high dopamine receptor concentration (caudate nucleus, putamen, and nucleus accumbens ) are the most affected resulting in symptoms. PET scans of dopamine function have shown changes in neurotransmitters and their metabolites in the cerebrospinal fluid.

History and Physical

Individuals with this disease are asymptomatic at birth with normal prenatal growth and development. Although hyperuricemia is typically present at birth, the only clinical presentation in the early days of life could be orange-colored crystals in the diapers. Eventually, hyperuricemia leads to crystalluria, urolithiasis, nephrolithiasis, gout, and juvenile arthritis. Since hyperuricemia is present in all variants of HPRT deficiency independent of severity, the likelihood of neurodevelopmental abnormalities cannot be predicted unless enzyme activity is tested.

Neurological features become noticeable by the age of 4 months. Hypotonia and developmental delay are common early signs. Infants may also have nonspecific symptoms like recurrent vomiting or difficulty managing secretions. Extrapyramidal signs begin to appear at around 8 to 12 months of age. The most common extrapyramidal sign is dystonia. Motor symptoms in Lesch Nyhan syndrome are, in fact, hypotonia superimposed by severe action dystonia. In almost all cases, dystonia progresses to a point where individuals cannot attain milestones like crawling, walking, and in due course, end up dependent on a wheelchair and become completely on others even for activities of daily living. Involuntary movements such as choreoathetosis, ballismus develop within the first few years. Features like dysarthria, dysphagia, and opisthotonus have also been frequently reported. Pyramidal signs (spasticity, hyperreflexia) can develop in the initial years or may not be apparent until later years.

Even though cognitive impairment is present, the degree of impairment cannot be estimated with confidence as the test scores may be affected by the motor disability of the patient. Involuntary movements, dysarthric speech affect verbal intelligence, but non-verbal intelligence in most patients is well preserved.[5]

Self-injurious behavior is the hallmark of Lesch Nyhan syndrome. Self-mutilation is not seen in the variants of Lesch Nyhan syndrome. The most commonly noted behavior is self-mutilation from biting of lips, fingers, cheeks, causing profound disfigurement. This behavior usually begins with the eruption of teeth in infants. Contrary to the thought that patients continue with self-mutilation due to sensory deficits, all sensations, including pain, are intact.[5] Self-injurious behavior is a result of compulsive behavior, and restraints can control these actions. Behaviors like head-banging, limb-banging, eye-poking, which are usual presentations in other disorders, have also been described. Reports have also mentioned compulsive aggressive behavior where patients try to inflict injury to others by pinching, spitting, grabbing, hitting, or verbally abusing.[6][7] Once the compulsion passes away, they usually tend to apologize for their behavior.

Megaloblastic anemia is a common feature of HPRT deficient patients. It is noted in 81 to 92% of patients with Lesch Nyhan syndrome, and the absence of megaloblastic anemia should prompt investigation for coexisting disorders like iron deficiency, thalassemia, chronic diseases, which may falsely normalize the finding.[8]

Evaluation

The relatively late appearance of the distinguishing self-injurious behavior can result in delayed diagnosis if other features are overlooked. Developmental delay in a patient with hyperuricemia should raise suspicion for the diagnosis and should be accordingly evaluated.

Increased serum uric acid (>8 mg/dl) and increased urine uric acid (urinary uric acid: creatinine ratio of ≥3-4: 1) is suggestive but is neither sensitive nor specific to the diagnosis. Neuroimaging is a low yield, as most studies showed no specific structural brain abnormalities. Some have reported the decreased volume of the basal ganglia. Functional abnormality from defective neurotransmitter metabolism is not completely known.

Although these investigations support the diagnosis, the definitive diagnosis is either enzymatic assay or molecular testing. Enzymatic diagnosis is an estimate of HPRT enzyme activity in erythrocyte lysate. Other cells like lymphocytes, cultured fibroblasts can also be used.[1] Molecular genetic testing is by sequencing the HPRT1 gene. Any duplication, deletion, or replacement of one or more exons of the gene results in enzyme defect to variable levels.

Recently six metabolites have been documented to serve as biomarkers for HPRT deficiency when present in abnormal quantities (excessive increase in either of AICAR, ZTP, vitamin B3 in the form of niacin or niacinamide, S-AMP, or severe depletion of ATP) by biochemical analysis of red blood cell extracts.[9]

Other investigations like CBC to check for megaloblastic anemia, EEG to rule out seizures as the cause for inattention may be considered.

Prenatal testing can be done using either chorionic villus sampling or amniocentesis in male infants with a family history of Lesch Nyhan syndrome.

Treatment / Management

Allopurinol, a drug that blocks the conversion of hypoxanthine and xanthine to uric acid by inhibiting the xanthine oxidase enzyme, is the mainstay of treatment for hyperuricemia. Decreasing uric acid overproduction reduces the complications of urolithiasis, nephrolithiasis, tophi, and gouty arthritis. Since hyperuricemia is present from birth, the earlier the medication is started, the better is the prevention of complications. Long-term efficacy and safety of allopurinol have been studied, which revealed no adverse effects, as long as the dose has been maintained to avoid the formation of xanthine calculi. However, allopurinol treatment does not have any effect on neurodevelopmental and cognitive outcomes. Allopurinol treatment can rarely cause drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Febuxostat, another xanthine oxidase inhibitor, can be used in such cases.[2]

As the pathophysiology behind neurological dysfunction is not precisely known, formulation of treatment strategy is hindered. Decreased dopaminergic neuron concentration in basal ganglia is postulated as the cause. But the use of dopaminergic drugs does not alleviate the symptoms as expected. Treatment with L-DOPA increased dystonia and hyperactivity. Treatment with S-adenosyl methionine, along with an antipsychotic like risperidone, helped with dystonia and self-injurious behavior. The effectiveness of the combination is likely age-dependent, and further studies are required to prove efficacy and complications.[10] Pyramidal signs such as spasticity can be managed with the use of benzodiazepines or baclofen. Physical rehabilitation with walking aids, devices to maintain posture help preventing deformities.(B3)

Behavioral symptoms are managed with psychiatric, physical, and medical interventions. Most cases need a combination of these interventions. Stress increases self-mutilation, and so stress management has shown to be effective. Aversion techniques tend to increase self-mutilation, and so such techniques need to be sidestepped. Physical restraints like elbow restraints, dental guards, lip bumpers are helpful temporarily. Most patients feel relieved with restraints, while some patients themselves request to be restrained when compulsive thoughts set in. Interventions such as extraction of teeth are the long-term treatment for those in whom the conservative measures cannot effectively protect the patient.[11](B3)

Therapies like bone marrow transplantation and exchange transfusion have been tried but were not found successful.[12] 

Currently, studies are in progress for the use and efficacy of treatments like deep brain stimulation [13], dopamine replacement therapy, the use of gabapentin, and local use of botulinum injections.[14](B3)

Differential Diagnosis

With dystonia and developmental delay, many patients are initially diagnosed with cerebral palsy.

Hyperuricemia is the initial sign but other enzyme disorders like phosphoribosyl pyrophosphate (PRPP) synthetase hyperactivity and glucose 6-phosphate dehydrogenase (G6PD) deficiency also result in hyperuricemia with purine overproduction.

Self-injurious behavior can also be seen in Rett syndrome, autism spectrum disorder, Tourette syndrome, Cornelia de Lange syndrome, hereditary sensory neuropathy, and familial dysautonomia.

• Autism spectrum disorder
• Cerebral palsy
• Cornelia de Lange syndrome
• Familial dysautonomia
• Glucose 6-phosphate dehydrogenase (G6PD) deficiency
• Hereditary sensory neuropathy
• Phosphoribosyl pyrophosphate (PRPP) synthetase hyperactivity
• Rett syndrome
• Tourette syndrome

Prognosis

Patients with Lesch Nyhan syndrome have a shorter life span, rarely surviving into their 30s. Renal failure is a major complication, but early diagnosis and prompt treatment with allopurinol have made this a rare cause of death. Reasons for death are respiratory failure and infections like pneumonia. Case reports have documented sudden unexpected death in some patients.[15]

Complications

Uric acid calculi result from precipitation of excess uric acid. As these calculi are radiolucent, they are not seen on abdominal x-ray, which can delay the diagnosis and lead to renal failure. Treatment with allopurinol decreases uric acid production but increases hypoxanthine and xanthine concentrations. Xanthine, being less soluble, can result in xanthine lithiasis, especially if the patient is dehydrated.

Dental guards and other oral protective devices can hamper proper dental hygiene. Extraction of teeth in early childhood can lead to facial disfigurement as the child grows. But failure to extract the teeth can result in tissue damage with worse cosmetic damage. Vital pulpotomy with the preservation of alveolar bone can be the solution to prevent deformity of the face from teeth extraction.[16]