Approach

Lesch-Nyhan disease (LND) should be considered when delayed development is accompanied by a hyperkinetic disorder, particularly when brain MRI is normal.

It should be suspected if delayed development is accompanied by self-injurious behavior or evidence of excessive production of uric acid. A clinical suspicion should always be confirmed by hypoxanthine-guanine phosphoribosyltransferase (HPRT) molecular gene analysis, and preferably also HPRT enzyme activity.

Virtually all patients are male, owing to the X-linked recessive mode of inheritance. However, a few female patients have been described.[3] A history of LND in other family members might point toward the diagnosis. LND has been reported in most ethnic groups, with approximately equal rates.

Clinical features

Classic LND patients usually come to clinical attention before the age of 1 year.[22] Most patients come to medical attention early in life, usually before 4 years of age. People with an LN variant (LNV) might present at a later age, depending on the age of onset of renal or neurologic problems.[3]

Typically, self-injurious behavior starts at age 2 to 5 years, although cases of around 18 years of age at onset have been described.[22] Finger and lip biting is a frequently seen form of self-injurious behavior. Subsequent partial amputations of the fingers, lips, tongue, and oral mucosa are common. Such topographic preference is rarely seen in other diseases with self-injury.

Among the most frequent presenting symptoms in classic LND is a failure to reach motor milestones.[22] Sometimes previously achieved motor milestones are lost. Cognitive function is usually impaired, with average intelligence quotient values of approximately 70, although normal intelligence has been described in some patients. Patients do not have global intellectual disability, but rather have impairments in specific cognitive domains involving attention and mental flexibility. Involuntary movements are common among the presenting symptoms, although they may develop later in the course of the disease.[3] A generalized action dystonia is present, characterized by frequent extraneous movements in the face, neck, and limbs, with sustained muscle contractions. This results in twisted postures that interfere with voluntary movement.[3][22]

On examination, somatic growth is affected more than head circumference or bone age.[23][24][25] A generalized hypotonia is frequently seen at presentation.[22] Spasticity and hyperreflexia, implying the involvement of corticospinal pathways, may be present;[3] these features usually appear later in the course of the disease, and are often asymmetrical. The cause is unknown, but they may be a result of myelopathy resulting from forceful involuntary movements of the neck.[3] The presence of orange "sand" crystals in the diaper should be checked or asked about if it is not reported spontaneously. The "sand" and orange color is caused by uric acid crystals and microhematuria.[24][25] Testicular atrophy is commonly seen, and puberty is often delayed or absent.[23] Undescended testes also occur.[23][24][26][Figure caption and citation for the preceding image starts]: Examples of self-injurious behavior seen in patients with classic Lesch-Nyhan diseaseFrom the collection of H.A. Jinnah, MD, PhD; used with permission [Citation ends].com.bmj.content.model.Caption@21903c66

Hyperuricemia

The majority of LND patients have elevated uric acid levels in serum and urine as a result of HPRT deficiency.[22]Uric acid levels are frequently evaluated as part of the metabolic workup of developmental delay or hypotonia. Urine is best evaluated by 24-hour urinary uric acid-creatinine ratio, or a total 24-hour uric acid excretion.[13] Although high uric acid levels may provide important clues to the diagnosis, they lack sufficient sensitivity and specificity for definitive diagnosis.

The hyperuricemia is also associated with nephrolithiasis, gouty arthritis, and subcutaneous tophi.[Figure caption and citation for the preceding image starts]: Uric acid levels in patients with classic Lesch-Nyhan disease (LND), patients with Lesch-Nyhan variants (LNV), and healthy controls. SD, standard deviation; HRH: hypoxanthine-guanine phosphoribosyltransferase (HPRT)-related hyperuricemia; HRD: HPRT-related neurologic diseaseFrom the collection of J.E. Visser, MD, PhD and H.A. Jinnah, MD, PhD; used with permission [Citation ends].com.bmj.content.model.Caption@fb91fa9

HPRT enzyme activity

Measurements of HPRT activity in cultured intact cells, such as fibroblasts, are considered more accurate than those in cell lysates.[3] The percentage of residual HPRT activity can provide some predictive value concerning disease severity. The clinical phenotype is a continuum:[27][28][29]

  • Near complete absence of HPRT activity results in the full phenotype of classic LND

  • A residual activity of ≥1.5% usually prevents self-injury and other behavioral disturbances

  • Residual activity >8% rarely causes obvious neurologic impairment.

Laboratories where HPRT activity can be measured are listed on the website of the Lesch-Nyhan Disease International Study Group. Lesch-Nyhan disease international study group Opens in new window

HPRT gene analysis

Rapid and reliable tests have been developed to identify HPRT gene mutations using molecular genetic methods. The mutations are heterogeneous, including point mutations and other substitutions, deletions, and insertions.[11][12] Mutations that predict large aberrations in the resulting protein, such as large deletions or early nonsense mutations, or a mutation identified in a prior patient, appear to be good predictors of disease severity.[11][12] Point mutations may cause either classic LND or an LNV, depending on the ultimate effect on enzyme activity.

In the US, molecular samples can be sent to Emory Genetics Laboratory. Emory genetics laboratory Opens in new window Other laboratories are listed on the website of the Lesch-Nyhan Disease International Study Group. Lesch-Nyhan disease international study group Opens in new window

Brain imaging

Brain imaging is not normally necessary for diagnosis and management of Lesch-Nyhan disease, but may be helpful if there is clinical suspicion of other diagnoses. Generally, neither CT scanning nor MRI reveal any obvious structural malformations or signal changes.[22][30] Routine imaging is usually normal, but may reveal mild loss of brain volume.[31]

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