Lesch–Nyhan syndrome

Lesch–Nyhan syndrome (LNS), also referred to as Nyhan's syndrome, Kelley-Seegmiller syndrome, and juvenile gout, is a rare, inherited metabolic disorder resulting from a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), due to mutations in the HPRT gene situated on the X chromosome. The disorder predominantly affects males, with an occurrence rate of approximately one in 380,000 live births. The condition was first delineated in 1964 by Michael Lesch, a medical student, and his mentor, pediatrician William Nyhan.

Pathophysiology

The absence or shortage of HGPRT enzyme activity culminates in an accumulation of uric acid in bodily fluids. This high concentration of uric acid leads to both hyperuricemia and hyperuricosuria, causing severe gout, renal issues, and specific neurological manifestations, including diminished muscle control and mild to moderate intellectual disability. Distinctively, starting from the second year of life, LNS patients may exhibit self-mutilating behaviors like biting of the lips and fingers. These patients also present with symptoms mirroring those observed in Huntington's disease, such as involuntary writhing and facial grimaces. The genesis of these neurological symptoms remains a subject of research. Additionally, the body's inability to effectively use vitamin B12 due to the HGPRT deficiency may precipitate megaloblastic anemia in some affected males.

Genetics

LNS is classified as an X-linked recessive disorder. Typically, the defective gene mutation is transmitted from the mother to her son. However, around one-third of all LNS cases stem from spontaneous mutations and don't showcase any familial lineage. Though LNS chiefly affects males, a few documented cases have reported females with the condition.

Clinical Presentation

Signs and Symptoms

• Neurologic Dysfunction: Affected individuals display impaired muscle control, involuntary writhing movements, and symptoms akin to athetoid cerebral palsy. The majority of LNS patients remain non-ambulatory and depend on wheelchairs for mobility.
• Behavioral Disturbances: By the age of three, most LNS patients begin exhibiting self-mutilating behaviors, including biting of fingers, lips, and occasionally head banging. Stress can exacerbate the self-harming tendencies. Moreover, cognitive impairments coupled with aggressive tendencies, vomiting, compulsive behaviors, and even involuntary swearing (coprolalia) characterize the behavioral aspect of LNS.
• Uric Acid Overproduction (Hyperuricemia): A defining symptom of LNS, excessive uric acid production can cause orange sand-like crystals to appear in the diapers of affected infants. As the condition progresses, these uric acid crystals can form kidney stones, leading to hematuria (blood in urine) and increasing susceptibility to urinary tract infections. Uric acid accumulation in joints can also lead to gout-like arthritis symptoms.

Associated Conditions

• Kelley-Seegmiller Syndrome: A milder manifestation related to LNS, it arises due to partial HPRT deficiency. While it still triggers gout and kidney stones, it generally exhibits less profound neurological symptoms.

Diagnosis

A clear diagnosis of LNS is feasible when a patient displays the triad of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances. Early-stage diagnosis can be more elusive until all three symptoms are prominently exhibited. Typically, suspicion arises from observed developmental delays combined with hyperuricemia, or when these delays coincide with renal manifestations like kidney stones or hematuria. Often, the self-harming behaviors linked to LNS act as the initial red flags for a possible diagnosis. However, it's vital to distinguish these behaviors from those observed in other disorders, such as autism, Rett syndrome, and Tourette syndrome.

Treatment

While no definitive cure exists for LNS, symptom management remains the primary therapeutic approach. Drugs like allopurinol can mitigate the symptoms resulting from uric acid accumulation, namely gout and renal issues. However, the behavioral and cognitive impairments associated with LNS remain resistant to current treatments. Research and clinical trials continue in hopes of finding more effective interventions and potential cures.

Prognosis

Despite the challenges posed by LNS, many patients manage to reach adulthood. Experimental treatments hold promise in alleviating the debilitating symptoms associated with this rare condition.

Lesch–Nyhan syndrome Resources
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