Lesch-Nyhan Syndrome or Lesch-Nyhan Disease is a rare genetic disorder occurring with both physiological as well as behavioral symptoms. Let us broaden our understanding of this uncommon illness by examining its symptoms and exploring available treatment options.
Also known as Nyhan’s syndrome or Kelley-Seegmiller syndrome, Lesch-Nyhan Syndrome (LNS) is a rare, genetically inherited disorder. It is caused by the deficiency or near absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Owing to the deficiency of this enzyme, the affected person’s body is unable to metabolize purines from DNA and RNA, resulting in the excessive build up of uric acid, manifesting in a condition called hyperuricemia. Michael Lesch and William Nyhan were the first to clinically describe the disease in 1964. Edwin Seegmiller and his colleagues identified the enzyme defect and the metabolic effects of the enzyme deficiency in 1967.
*Please note that the adjacent picture is for representational purposes only.
Hereditary Risk Factors
LNS is an X-linked genetic disorder. This means, the gene mutation is present on the X-chromosome (that comes from the mother). Therefore, as is the case with all X-linked genetic disorders, Lesch-Nyhan syndrome is more prevalent in men and is rarely found in women. However, females can be carriers of LNS, thus passing on the rogue gene to future generations. The rarity of the disease is compounded by the fact that males affected with LNS are often unable to reproduce due to the physical manifestations of the disease. Unfortunately, the genetic malfunction is irreversible and hence, treatment for LNS is administered purely to give relief from the painful symptoms of the disease.
Lesch-Nyhan Syndrome Symptomatology
LNS symptoms can be broadly classified into physical, neurological and behavioral indications.
Physical Symptoms
LNS manifests the following physiological symptoms:
- Kidney stones, bladder stones due to overproduction of uric acid
- In infants as young as 3 months, orange-colored crystal like deposits seen in their diaper indicating uric acid deposits (the earliest sign of LNS)
- Blood in the urine
- Testicular atrophy seen as the affected male goes through delayed physical growth and delayed puberty
- Gout like arthritis with swelling of joints
- Difficulty in swallowing
Neurological Symptoms
LNS affects muscle coordination manifesting mainly as dystonia in different parts of the body. Until an affected infant is three to six months old, these symptoms will not be obvious. Motor functions are gradually diminished resulting in developmental delay. The infant will be late in sitting up, turning on his/her back, crawling and walking. Late speech or inability to speak clearly is also common. In fact, most are not able to walk at all and will be bound to a wheelchair for their entire lives. In addition, there may be arching of the spine and overactive reflexes. These neurological dysfunction symptoms often resemble symptoms of cerebral palsy leading to misdiagnosis.
Cognitive and Behavioral Symptoms
LNS causes cognitive impairment and presents involuntary behavioral disruptions that are seen from 2-3 years of age. A distinctive characteristic of LNS is physical and emotional self-injury. Self-mutilation starts from infancy where the child begins to bite his/her fingers, lips and inside the mouth. As the child becomes older, aggression is more pronounced with leg banging, partial amputation of fingers, hurting his/her own eyes and gouging his/her nose, extending arms in doorways and hurting those around him/her.
Emotional aggression is displayed by swearing, spitting, inappropriate remarks, frequent lying, etc. It is extremely vital to understand that this is involuntary behavior. The patient is not doing it on purpose and should not be mistaken as an attempt to draw attention. In fact, despite serious injuries being caused, due to lack of cognitive responses, the patient repeats the episodes. This is different from attention-seeking behavior where a person knows what he/she is doing. In fact, LNS patients are often said to behave in a way contrary to what they want.
Diagnosis, Treatment and Prevention Options
A physical exam and analysis of behavioral traits is the beginning of diagnosis. HGPRT enzyme activity is measured to confirm the deficiency. Enzyme deficiency usually confirms diagnosis. Alternatively, molecular genetic testing may be carried out to confirm diagnosis or to confirm “carrier status” in high-risk females. The following treatment options are explored for LNS patients.
Treatment for Physical Symptoms
- Overproduction of uric acid is treated with allopurinol, however excess of this drug is not recommended.
- Kidney stones and gallstones are often treated using a minimally-invasive procedure called lithotripsy that employs laser beams or shock waves to break down the stones into smaller pieces.
- Treatment for injuries depends on the age of the patient and nature of injury.
- Adoption of a low-purine diet is sometimes helpful, though not clinically proven to be helpful in controlling gout in all patients.
Treatment for Neurological Symptoms
Muscle dysfunction, spasms and anxiety is mitigated using drugs such as baclofen, diazepam and clonazepam, but strictly under medical supervision only. There’s no standard treatment to improve motor functions. Devices such as wheelchairs improve mobility but care should be taken to make sure that the scope for self-injury using these devices is minimized.
Treatment for Behavioral Symptoms
Medication cannot reverse the behavioral manifestations. However, many patients and their families have benefited from the use of protective devices (to limit chances of self-injury), behavioral therapy techniques such as selective ignoring and redirection to curb self-destructive behavior. Experimental techniques such as deep brain simulation have been tried on few patients and there is hope for extending such techniques if trials are found to be successful.
Prevention
Genetic testing is the only way to predict the chances of passing LNS to the next generation. There’s no other way to prevent this rare hereditary gene mutation.
Life Expectancy of Lesch-Nyhan Syndrome Patients
The average life expectancy is estimated at 25-30 years. Early death due to incorrect diagnosis, self-injury fatalities and renal complications were common until recently, however, present day awareness levels and advancements aiding early diagnosis have helped bring down the number of early deaths. Respiratory failure often causes sudden death in LNS patients. Few men live up to their late 40s. Proper diagnosis, some lifestyle changes, and family and community support can help LNS patients live with dignity and lead relatively normal and longer lives.
It is indeed a sad twist of fate that a child should be inflicted with such a terrible disease. Having to live an entire life struggling within the shackles of physical restraining devices, wheelchairs and self-inflicted pain is reason enough for medical science to push its limits and come up with a cure. Well, there’s a ray of hope in techniques like gene therapy where medical scientists are expecting to find some positive signs. Hopefully, LNS patients will soon get lucky and be rid of this life sentence of a disease.
Disclaimer: Please be aware that this article is for informative purposes only. It is neither intended nor implied to be a substitute for professional medical advice.
