A healthy boy was born uneventfully to apparently normal parents. Delayed acquisition of motor skills was suspected by 3 months of age. Over the next year, his parents noted yellow sandy material in the diapers, but its significance was not appreciated. At 12 months of age, involuntary twisting and stiffening movements emerged, leading to a diagnosis of cerebral palsy. Benzodiazepines and baclofen were instituted to attenuate the involuntary movements, but he required full assistance for all voluntary activities. Shortly after the eruption of teeth at 3 years of age, he began to chew on the inside of his lip and occasionally on his index finger. The development of this unusual but telltale feature led to a suspicion of LND. At screening, the level of serum uric acid was found to be elevated, adding further to the suspicion of this disease. The orange sand in the diapers was also identified as being composed of uric acid crystals, and allopurinol was started to reduce uric acid production. Genetic testing revealed a point mutation in the HPRT gene, which had not previously been associated with disease. The functional significance of the mutation was verified by demonstrating a lack of HPRT enzyme activity in fibroblast cultures from a skin biopsy. Attempts to control the lip biting with multiple medications failed, leading to extreme family stress. After dental extraction, the boy and his family were much relieved, although he required limb restraints to prevent other forms of self-injury. He lived until 35 years of age when he succumbed to aspiration pneumonia.[2]
Etiology
Lesch - Nyhan Syndrome, a rare X-linked genetic disorder, is characterized clinically by an overproduction of uric acid, spasticity, developmental delay and behavioural and cognitive abnormalities. Of these, the most diagnostic feature of the syndrome is the self-injurious behaviour. The underlying defect is in the HPRT1 gene coding for the enzyme Hypoxanthine-guanine phosphoribosyl transferase (HPRT), found on the X-chromosome (Xq26-27). Normally, this enzyme is important in the recycling of purine bases, catalyses the conversion of hypoxanthine to inosine monophosphate (inosinic acid, IMP) and guanine to guanine monophosphate (guanylic acid, GMP) in the presence of phosphoribosylpyrophosphate[1,5]. Therefore, a defective or absent HPRT results in the inability of these purine bases to be recycled; hence these are therefore degraded and excreted as uric acid. In light of this, the body compensates by increasing the synthesis of purines, further exacerbating the build up of uric acid, eventually leading to hyperuricemia. Hyperuricemia can account for other clinically relevant features of the syndrome such as nephrolithiasis with renal failure, gouty arthiritis, tophi and persistent urinary tract infections. Physiologically, uric acid is near its solubility limit, and therefore increased uric acid in the blood will lead to the formation of uric acid crystals. Tophi is the accumulation of these crystals in tissues, particularly subcutaneously. Gouty arthritis results from crystal accumulation in the joints, followed by an inflammatory response. The kidneys attempt to remedy hyperuricemia by increasing uric acid excretion, however, this only increases the risk of forming urate stones or calculi in the bladder, ureter and kidneys, which may be passed as characteristic 'orange sand'. Pathology associated with neurological and behavioural abnormalities, including compulsive self-mutilation and varying signs of aggression, has yet to be elucidated. Although studies have shown abnormalities in the function of the dopamine neurons of the basal ganglia in Lesch-Nyhan patients, a significant correlation
Figure 1:
Lesch-Nyhan Patient showing self-mutilation of hands and lips; Premature dental extraction apparent as well. [A]between these findings and an HPRT deficiency is non-existent[3,4].
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Lesch-Nyhan is predominantly a male-associated disorder, with very rare reported female cases. It is inherited in an X-linked manner; the father of the proband will neither be affected or a carrier, but the mother (asymptomatic carrier) will have passed on the mutant allele to her sons. A pregnant carrier mother has a 25% chance of a son with Lesch-Nyhan syndrome, a 25% chance of having a carrier daughter, and a 50% chance of having an unaffected son or daughter. Therefore, with each pregnancy, she has a 50% chance of giving the mutant allele to her offspring [5].
Figure 2:
Typical Pedigree for Lesch-Nyhan Sydrome. [B]
In the female reported cases of Lesch-Nyhan syndrome, non-random X-chromosome inactivation with normal HPRT1 genes was the underlying cause[5]. Mutations of the HPRT1 gene include point mutations, insertions, deletions, all of which lead to a defective or completely absent HPRT enzyme[3]. For this reason, variants of Lesch-Nyhan exist, whereby there is partial activity of the enzyme is maintained (above that of classical Lesch-Nyhan patients, but still well below normal), resulting in less severe manifestations of the syndrome. These variants most times exhibit only hyperuricemia or signs of motor delay, with no neurological or behavioural impairment. That is, they do not exhibit the hallmark feature of self-mutilation, which makes misdiagnosis possible[3,4]. Commonly variants are misdiagnosed with cerebral palsy due to the presence of spasticity, a common feature of both disorders[4].
Following an uneventful pregnancy and birth, most Lesch-Nyhan Syndrome patients do not reach normal motor milestones within their first year of life, presenting with hypotonia or low muscle tone. In the following years, dystonia, choreoathetosis, spasticity and hyperreflexia are apparent, indicating the involvement of extrapyramidal and corticospinal (pyramidal) involvement. After age 6, motor disability does not progress, however, most patients are confined to a wheelchair, having been delayed in sitting and never walked[5]. Other presenting features include renal failure, gout, and "orange sand" in diapers due to uric acid crystals. Although present in all classical Lesch-Nyhan cases, self-mutilation is not a presenting feature. Growth retardation, testicular atrophy, delayed or absent puberty, is also grossly associated with the syndrome. Patients do, however, show an average intellectual quotient (IQ), and intact sensory function[3].
Diagnosis
Although elevated uric acid levels in the blood and urine (twenty-four-hour urate excretion & urate:creatinine ratio) may be helpful in the diagnosis of Lesch-Nyhan Syndrome, it is certainly not definitive. This is because normal serum uric acid levels have been reported in some cases of the syndrome and a urine test is not sensitive or specific enough[3,5]. The measurement of the HPRT enzyme activity provides a more definitive diagnostic tool; an HPRT enzyme activity of less than 1.5% is strongly indicative of Lesch-Nyhan Syndrome, while variants show above 10% activity. Confirmatory tests involve the identification of the HPRT1 gene mutation via genetic testing. Imaging of the kidney and urogenital tract are suggested for detection of obstructive renal calculi[4].
Sequence analysis or mutation scanning can detect mutations in the HPRT1 gene in majority of Lesch-Nyhan cases. These methods can also be employed to detect most female carriers. Some cases, however, are due to large deletions that cannot be detected in female carriers by aforementioned methods. To remedy this, deletion/duplication testing methods can be utilized to detect these exonic of whole-gene deletions. Prenatal diagnosis can also be done in cases of pregnant carrier mothers or evidence of disease-causing mutation the family[5].
Treatment/Management
The overproduction of uric acid is controlled with Allopurinol, which inhibits the activity of xanthine oxidase; hypoxanthine and guanine metabolism to uric acid is curtailed. Titrated doses are administered to maintain the serum uric acid at normal levels. Constant hydration is also required to encourage constant excretion of purine metabolites as Allopurinol intake results in increased hypoxanthine and oxypurine metabolites. Benefits of allopurinol and hydration include reduced risk of tophi, nephrolithiasis and gout[2]. Prenatal testing or after-birth testing can provide early insight into the status of the infant of a carrier mother; allopurinol can thus be administered soon after delivery[5].
Motor impairment and behavioural problems, however, are not mitigated by controlling uric acid level as their pathogenesis is unrelated to uric acid levels. Muscle relaxant Benzodiazepines (diazepam, alprazolam), and anti-spastic drug, such as baclofen help reduce motor dysfunction, but no definitive agent has been proven helpful in all cases. Behavioural therapy and supplemental medications (gabapentin, benzidiazeoines) are used to manage behavioural abnormalities. Restraints are used to present self-injurious behaviour such has self-hitting and biting. In severe cases where pharmacological and behavioural interventions are ineffective, complete dental extraction is necessary to prevent tissue injury. However, lip and tongue biting is not easily prevented[2,3].
Prognosis
Lesch-Nyhan Syndrome patients who are optimally managed survive until their thirties or forties. Death is often due to aspiration pneumonia or complications from nephrolithiasis. Many individuals die suddenly from unknown causes[3,5].
