Lesch-Nyhan Syndrome
Introduction[edit | edit source]
Lesch-Nyhan syndrome (LNS) is a rare, inherited X-linked genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT),an enzyme of purine salvage pathway. The enzyme is responsible for recycling purines by converting guanine and hypoxanthine into guanosine monophosphate and inosine monophosphate, respectively. Lack of the enzyme causes an increase in guanine and hypoxanthine, which eventually gets converted into uric acid,[1] Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys.
LNS is inherited as an X-linked recessive genetic disorder that mostly affects males, with rare female exceptions.[2] Lesch-Nyhan syndrome was first described in 1964 by Lesch and Nyhan, when two brothers originally diagnosed with cerebral palsy were later recognized as living with a previously undescribed inherited metabolic disease because of the familial occurrence and unusual clinical features.[3]
Causes[edit | edit source]
Lesch-Nyhan syndrome is an X-linked recessive disorder resulting from mutation of the HPRT1 gene, located at a q26-27 position on the long arm of the X chromosome. Though only a single gene is associated with this syndrome, over 600 mutations have been identified, each leading to varying levels of severity of clinical presentations making HPRT enzyme deficiency a spectrum rather than a single disease.[5] Males who receive the defective X chromosome from the carrier mothers manifest the disease. Females are mostly carriers but may develop the disease if the healthy X chromosome undergoes lionization, and the defective X chromosome is expressed phenotypically.
Signs and Symptoms[edit | edit source]
The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to symptoms such as:
- Severe gout
- Poor muscle control
- Moderate developmental disabilities, 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.
That increase in uric acids causes them to appear normal when they are born, but by about the third month they are unable to lift their heads or sit up. They display hypotonia, a lack of muscle tone, and many also suffer from dystonia, a lack of motor control. Clinically, LNS is characterized by mental retardation, choreo-athetosis(Involuntary writhing), spastic cerebral palsy, and aggressive self-mutilating behavior.[6]
Other neurological sign and symptoms in people with LNS includes the following:
- Facial grimacing
- Repetitive movements of the arms and legs similar to Huntington's disease
Because a lack of HPRT causes the body to poorly utilize vitamin B12, some males may develop a rare disorder called megaloblastic anemia.
A consistent presentation in all cases of LNS is the abnormal compulsion toward self-mutilation usually reported after 1 year of age. This behavior begins as soon as the child’s teeth come in and typically results in parents frantically calling pediatricians asking why their children are trying to eat themselves.
Perioral self-mutilating behavior is thought to begin with the eruption of teeth. The behavior continues and results in partial or total destruction of perioral tissue, especially the lower lip. Partial or complete amputation of fingers, toes, and tongue is also common. Lesch-Nyhan syndrome sufferers have been known to stab themselves in their eyes with sharp objects and some have bitten off their tongues.
Epidemiology[edit | edit source]
The prevalence of Lesch-Nyhan syndrome that has been estimated is between 1:235,000 and 1:380,000.[7]Although it is an X-linked genetic disorder manifesting mostly in males, a few females with Lesch Nyhan syndrome have been reported and studies show that it occurs in relatively equal frequencies in all populations.
Diagnosis[edit | edit source]
- The definitive diagnosis of LNS is either enzymatic assay or molecular testing. Enzymatic diagnosis is an estimate of HPRT enzyme activity in erythrocyte lysate. Other cells like lymphocytes, cultured fibroblasts can also be used.[1]
- Complete blood count(CBC) can also be used to check for megaloblastic anemia and An electroencephalogram (EEG) to rule out seizures as the cause for inattention may be considered.
- Increased serum uric acid (>8 mg/dl) and increased urine uric acid (urinary uric acid: creatinine ratio of ≥3-4: 1) is suggestive but is neither sensitive nor specific to the diagnosis.
- Prenatal testing can be done using either chorionic villus sampling or amniocentesis in male infants with a family history of Lesch Nyhan syndrome.
References[edit | edit source]
- ↑ 1.0 1.1 Fu R, Sutcliffe D, Zhao H, Huang X, Schretlen DJ, Benkovic S, Jinnah HA. Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways. Mol Genet Metab. 2015,114(1):55-61.
- ↑ https://www.ninds.nih.gov/health-information/disorders/lesch-nyhan-syndrome#:~:text=What%20is%20Lesch%2DNyhan%20syndrome,present%20at%20birth%20in%20males.
- ↑ Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. 1964;36:561-570.
- ↑ Animated biology With arpan. Lesch-Nyhan syndrome | What are the symptoms of Lesch-Nyhan syndrome? | Treatment options | USMLE. Available from: https://www.youtube.com/watch?v=7FbM5VtKWz0 [last accessed 24/6/2023]
- ↑ Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, Yamada Y, Nguyen KV, Hegde M, Visser JE, Schretlen DJ, Nyhan WL, Puig JG, O'Neill PJ, Jinnah HA., Lesch-Nyhan Disease International Study Group. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014:1282-303.
- ↑ Jathar P, Panse AM, Jathar M, Gawali PN. Lesch-Nyhan Syndrome: Disorder of Self-mutilating Behavior. Int J Clin Pediatr Dent 2016;9(2):139-142.
- ↑ Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated varaints of Lesch-Nyhan disease. Brain 2010;133:671–89
