Lesch-Nyhan syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

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Lesch-Nyhan’s syndrome, is a rare, inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

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It was first described in 1964 by Dr. Michael Lesch and Dr. William Nyhan.^[1]

• Michael Lesch was a medical student at Johns Hopkins Hospital, where pediatrician/pediatric oncologist Bill Nyhan was a faculty member, when the two identified LNS and its associated hyperuricemia in two affected brothers, ages 4 and 8.^[2]
• Lesch and Nyhan published their findings in 1964.^[3]
• Within three years, the metabolic cause was identified by J. Edwin Seegmiller and his colleagues at NIH.^[4]
• The gene encoding the human enzyme was cloned and sequenced by Friedmann and colleagues in 1985.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [5]

It is an inborn error in purine metabolism resulting in deficiency of HGPRT enzyme, resulting in increased conversion of glycine to uric acid with excessive purine synthesis and hyperurecemia.

• HGPRT is the “salvage enzyme” for the purines: it channels adenosine (in its hypoxanthine form) and guanine back into DNA synthesis. Failure of this enzyme has two results:
  • Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
  • The de novo pathway is stimulated due to an excess of PRPP (5-phospho-D-ribosyl-1-pyrophosphate or simply phosphoribosyl-pyrophosphate).
• Patients have severe mental and physical problems throughout life. The lack of HGPRT causes a build-up of uric acid in all body fluids, and leads to problems such as severe gout, poor muscle control, and moderate mental retardation, which appear in the first year of life.
• A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life.
• Abnormally high uric acid levels can cause sodium urate crystals to form in the joints, kidneys, central nervous system and other tissues of the body, leading to gout-like swelling in the joints and severe kidney problems.
• Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. The direct cause of the neurological abnormalities remains unknown. Polymorphisms for enzymes in the de novo pathway may contribute to the disease, but this would not be the case if uric acid neurotoxicity were the main cause of the symptoms.
• Moreover, evidence suggests that one or more lesions in striatal dopaminergic pathways is at least partially responsible for the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation.^[1][2][3]. Thus, 6-hydroxydopamine toxicity in rodents is a useful animal model for the syndrome.^[4] Another putative animal model, Hyperuricemic syndrome in Dalmatian dogs, presents with the characteristic arthritis and kidney failure, but not the neurological findings.
• Because a lack of HGPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.
• The symptoms caused by the buildup of uric acid (arthritis and renal symptoms) respond well to treatment with drugs such as allopurinol that reduce the levels of uric acid in the blood.
• The mental deficits and self-mutilating behavior do not respond to treatment. There is no cure, but many patients live to adulthood.

LNS is an X-linked recessive disease. The gene is carried by the mother and passed on to her son. LNS is present at birth in baby boys.

LNS is due to mutations in the HPRT1 gene,^[5][6] so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT, EC 2.4.2.8). This enzyme is involved in the biochemical pathways the body uses to produce purines, one of the components of DNA and RNA. Defects of this enzyme lead to increased production of uric acid. Since the HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease.

The father of an affected male will not be the carrier of the mutant allele, and will not have the disease. An obligate carrier would be a woman who has an affected son and one other affected relative in the maternal line.

If a woman is the first in her family with an affected son, Haldane’s rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation. However, in this case Haldane’s prediction is incorrect due to an increased risk of mutation arising from the father when compared to the mother.

The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female.

Males with LNS do not reproduce due to the characteristics of the disease. However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected.

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Differentiating Lesch-Nyhan syndrome from other similarly presenting diseases is crucial as the treatment protocol varies with the diagnosis. The diagnosis should be alleged when developmental delay is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), caused by uric acid stones. For the most part, Lesch-Nyhan syndrome is first suspected when self-inflicted injury behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific mental retardation, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch-Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence. Biting the fingers and lips is a definitive feature of Lesch-Nyhan syndrome; in other syndromes associated with self-injury, the behaviors usually consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers. Lesch-Nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction.

• Cerebral palsy^[1]
• Diseases with developmental delay
• Diseases with dystonia
• Mental retardation
• Autism
• Rett syndrome
• Tourette syndrome
• Prader-Willi syndrome
• Fragile X syndrome
• Cornelia de Lange syndrome

The above conditions present similar to Lesch-Nyhan syndrome with developmental delay, hypotonia and dystonia as prominent features in early phases of the disease process^[2], until later in the course, self mutilation, spasticity and seizures develop. However, they can be differentiated on the basis of laboratory tests:

• Blood urea levels:
  • Hyperuricemia is typical for Lesch-Nyhan syndrome.
• HGPRT gene analysis
• HGPRT enzyme activity provide confirmatory diagnosis

Lesch-Nyhan syndrome must be differentiated from other diseases that cause neurological manifestations in infants.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

As Lesch-Nyhan syndrome follows a X-linked inheritance pattern, nearly all cases are seen in males.

• The worldwide prevalence of Lesch-Nyhan syndrome varies from 1 in 235,000 to 1 per 380,000 population, with no major variations amongst individual ethnic groups.^[1]

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Lesch–Nyhan syndrome is first suspected when self-inflicted injury behavior develops. When an affected individual has fully developed the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. It is, however, difficult to confirm diagnosis in early stages of disease progression, when treatment can potentially delay the development of above mentioned complications.

• Genetic consultation
• Antenatal diagnosis
• The use of biochemical testing for the detection of carriers is technically demanding and not often used.
• Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both false positive and false negative outcomes.
• If only a suspected carrier female is available for HGPRT mutation testing, it is appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only HGPRT-deficient cells to survive. A mutant frequency of 0.5-5.0 x 10-2 is found in carrier females, while a non-carrier female has a frequency of 1-20 x 10-6. This frequency is usually diagnostic by itself.
• Molecular genetic testing is the most effective method of testing, as HGPRT1 is the only gene known to be associated with LNS. Individuals who display the full Lesch-Nyhan phenotype all have mutations in the HGPRT1 gene.
• Sequence analysis of mRNA is available clinically and can be utilized in order to detect HGPRT1 mutations in males affected with Lesch-Nyhan syndrome.
• Techniques such as RT-PCR, multiplex genomic PCR, and sequence analysis (cDNA and genomic DNA), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests result in cDNA showing the absence of an entire exon or exons, then multiplex genomic PCR testing is performed. Multiplex genomic PCR testing amplifies the nine exons of the HGPRT1 gene as eight PCR products.
• If the exon in question is deleted, the corresponding band will be missing from the multiplex PCR. However if the exon is present, the exon is sequenced to identify the mutation, therefore causing exclusion of the exon from cDNA.
• If no cDNA is created by RT-PCR, then multiplex PCR is performed on the notion that most or all of the gene is obliterated.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

• Patients with HGPRT deficiency are normal at birth.
• One of the first signs of the disease may be the observation of orange crystals in the diapers, or crystalluria with obstruction of the urinary tract.
• Other uncommon forms of presentation include renal failure or acidosis with repeated vomiting. Psychomotor delay, when present, becomes evident within 3 to 6 months.
• A delay in the acquisition of sitting and head support with hypotonia and athetoid movements may lead to neurological consultation. Self-mutilation, in the form of lip biting or finger chewing, can appear as soon as teeth are present.
• Eventually, as uric acid builds up in tissues, symptoms of spasticity, seizures, nephrolithiasis and self mutilation develop.

• Severe, progressive disability if likely.
• Spasticity
• Dystonia
• Choreoathetosis
• Ophisthotonus
• Nephrolithiasis
• Urinary tract infection
• Gouty arthritis
• Skin and soft tissue infections
• Hip dysplasia and subluxation
• Pneumonia
• Scoliosis
• Fractures
• Atlanto-axial joint subluxation^[1]

The prognosis for individuals with LNS is poor. Death is usually due to renal failure in the first or second decade of life.

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