Lesch–Nyhan syndrome
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Lesch–Nyhan syndrome | |
---|---|
Other names | Juvenile gout, |
Complications | kidney failure, megaloblastic anemia |
Differential diagnosis | cerebral palsy, dystonia, famillial dysautonomia |
Frequency | 1 in 380,000[2] |
Lesch–Nyhan syndrome (LNS) is a rare
The HGPRT deficiency causes a build-up of
LNS is inherited in an
The symptoms caused by the buildup of uric acid (gout and kidney symptoms) respond well to treatment with medications such as allopurinol that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond well to treatment. There is no cure, but many affected people live to adulthood. Several new experimental treatments may alleviate symptoms.
Signs and symptoms
LNS is characterized by three major hallmarks:
Overproduction of uric acid
One of the first symptoms of the disease is the presence of sand-like crystals of
Nervous system impairment
The periods before and surrounding birth are typically normal in individuals with LNS. The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals are late in sitting up, while most never crawl or walk.[11]
Irritability is most often noticed along with the first signs of nervous system impairment. Within the first few years of life,
Self-injuring behavior
Persons affected are cognitively impaired and have behavioral disturbances that emerge between two and three years of age. The uncontrollable
The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms because of the behavioral disturbances and motor deficits associated with the syndrome. In many ways, the behaviors may be seen as a psychological extension of the compulsion to cause self-injury, and include rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed, and provoking anger from caregivers when affection is desired.[15]
Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and coprolalia (involuntary swearing). The development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life.[16]
LNS in females
While carrier females are generally an
Females who carry one copy of the defective gene are carriers with a 50% chance of passing the disease on to their sons. In order for a female to be affected, she would need to have two copies of the mutated gene, one of which would be inherited from her father. Males affected with LNS do not usually have children due to the debilitating effects of the disease. It is possible for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HGPRT gene. Under these circumstances, a girl could be born with LNS, and though there are a few reports of this happening, it is very rare. The overwhelming majority of patients with LNS are male.[citation needed]
Less severe forms
A less severe, related disease, partial HPRT deficiency, is known as Kelley–Seegmiller syndrome (Lesch–Nyhan syndrome involves total HPRT deficiency). Symptoms generally involve less neurological involvement but the disease still causes gout and kidney stones.[18]
Genetics
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.[citation needed]
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.[citation needed]
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.[citation needed]
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.[citation needed]
Pathophysiology
As in other
A large number of mutations of HPRT are known. Mutations that only mildly decrease the enzyme's function do not normally cause the severe form of LNS, but do produce a milder form of the disease which still features purine overproduction accompanied by susceptibility to
Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthesized de novo from amino acids and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".[citation needed]
HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:[citation needed]
- 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).
It was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotides during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.[citation needed]
Importantly, evidence suggests that one or more lesions in
Another animal model for LNS has been proposed to arise from oxidative damage, caused by the
However, some evidence suggests against a role for uric acid in the neuropathology of Lesch–Nyhan syndrome:
- Hyperuricemia associated with classic renal clearancerather than uric acid overproduction, is not associated with neuropathology.
- Hypouricemia occurs in a number of purine disorders, in particular xanthinuria. Despite having complete absence of blood uric acid, xanthinuria patients do not have any neuropathology, nor any other disease states – other than the kidney stones caused by accumulation of insoluble xanthine in lieu of uric acid.[27]
Similarly, uric acid does not penetrate the blood–brain barrier well. However, oxidative stress due to uric acid is now thought to figure in
Diagnosis
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. Diagnosis is less easy in the early stages, when the three features are not yet obvious. Signs of self-injurious behavior (SIB), results of pedigree analysis and novel molecular biology with
Diagnostic approach
The urate to
Testing
The use of
Molecular genetic testing is the most effective method of testing, as HPRT1 is the only gene known to be associated with LNS. Individuals who display the full Lesch–Nyhan
Treatment
Treatment for LNS is symptomatic. Gout can be treated with
It is essential that the overproduction of uric acid be controlled in order to reduce the risk of
No medication is effective in controlling the
There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. Even children treated from birth with allopurinol develop behavioral and neurologic problems, despite never having had high serum concentrations of uric acid. Self-injurious and other behaviors are best managed by a combination of medical, physical, and behavioral interventions. The self-mutilation is often reduced by using restraints. Sixty percent of individuals have their teeth extracted[citation needed] in order to avoid self-injury, which families have found to be an effective management technique.[citation needed] Because stress increases self-injury, behavioral management through aversive techniques (which would normally reduce self-injury) actually increases self-injury in individuals with LNS. Nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time. This is often at their own request, and occasionally involves restraints that would appear to be ineffective, as they do not physically prevent biting. Families report that affected individuals are more at ease when restrained.[citation needed]
The Matheny Medical and Educational Center [2] in Peapack, NJ, has[when?] six Lesch–Nyhan syndrome patients, believed to be the largest concentration of LNS cases in one location, and is recognized as the leading source of information on care issues.
Treatment for LNS patients, according to Gary E. Eddey, MD, medical director[clarification needed], should include: 1) Judicious use of protective devices; 2) Utilization of a behavioral technique commonly referred to as 'selective ignoring' with redirection of activities; and 3) Occasional use of medications.[citation needed]
An article in the August 13, 2007 issue of
An encouraging advance in the treatment of the neurobehavioural aspects of LNS was the publication in the October, 2006 issue of
Prognosis
The prognosis for individuals with severe LNS is poor. Death is usually due to kidney failure or complications from hypotonia, in the first or second decade of life. Less severe forms have better prognosis.[5]
History
References
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