Lesch-Nyhan Syndrome Symptoms, Causes, Treatment

The Lesch-Nyhan syndrome It is a pathology of congenital origin that is characterized by an abnormal accumulation of uric acid in the body (Hyperuricemia) (Hospital Sant Joan de Déu, 2009). It is considered a rare disease in the general population and occurs almost exclusively in men (Cervantes Castro and Villagrán Uribe, 2008).

At the clinical level, this disorder can cause alterations in different areas: neurological manifestations, symptoms associated with hyperuricemia and other widely heterogeneous alterations (Hospital Sant Joan de Déu, 2009).

Some of the most common signs and symptoms include: gouty arthritis, kidney stone formation, delayed psychomotor development, chorea, presence of spasticity, nausea, vomiting, etc. (Hospital Sant Joan de Déu, 2009).

Lesch-Nyhan syndrome is a disease with a hereditary genetic origin, associated with specific mutations in the HPRT gene (Gonzáles Senac, 2016).

The diagnosis is made based on the symptoms present. It is essential to analyze the levels of uric acid in the blood and the activity of various proteins (Hospital Sant Joan de Déu, 2009).

There are no curative treatments for Lesch-Nyhan syndrome. A symptomatological approach is used focused on the control of the etiological cause and secondary medical complications (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Article index

• 1 Characteristics of Lesch-Nyhan syndrome
• 2 Statistics
• 3 Signs and symptoms
  • 3.1 Renal disorders
  • 3.2 Neurological disorders
  • 3.3 Behavioral disturbances
  • 3.4 Gastrointestinal disorders
  • 3.5 Other alterations
• 4 Causes
• 5 Diagnosis
• 6 Is there treatment?
• 7 References

Characteristics of Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is a disease that appears almost exclusively in males (Genetics Home Reference, 2016).

Its clinical characteristics usually present in the early stages of life and are defined by an overproduction of uric acid accompanied by neurological and behavioral alterations (Genetics Home Reference, 2016).

Some institutions, such as the National Organization for Rare Disordes (2016), define Lesch-Nyhan syndrome as an innate anomaly due to the absence or deficient activity of an enzyme known by the name of Hypoxanthine phosphoriboltransferanse-guanine (HPRT) (National Organization for Rare Disordes, 2016).

This enzyme is usually located in all tissues of the body. However, it is usually identified with a higher proportion in the nuclei of the base of the brain (Schalager, Colombo & Lacassie, 1986).

This type of alteration implies both a decrease in the recycling and reuse of purine bases and an increase in their synthesis (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Purines are a type of nitrogen-based biochemical compound that tends to form in the body's cells or access it through food (Chemocare, 2016).

This substance is degraded through various mechanisms to become uric acid (Chemocare, 2016).

The alterations related to the Lesch-Nyhan syndrome result in an inability on the part of the body to convert hypoxanthine into inosine and therefore, the level of uric acid reaches a pathological level (Cervantes Castro and Villagrán Uribe, 2008).

Uric acid is a type of organic metabolic waste compound. It results from the metabolism of nitrogen in the body, the essential substance being urea. High amounts of this can cause serious injuries in the affected areas.

The first descriptions of this type of alterations correspond to the researchers Michael Lesch and William Nyhan (1964) (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Their studies were based on the analysis of the symptoms of two sibling patients. The clinical picture of both was characterized by hyperuricosuria, hyperuricemia and neurological alterations (intellectual disability, choreoathetosis, intoxicating behavior, etc.) (Gozález Senac, 2016).

Therefore, the main characteristics of his clinical report referred to a severe neurological dysfunction associated with the overproduction of uric acid (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Subsequently, Seegmiller specifically described the association of clinical characteristics and deficiency of the enzyme hypoxanthine-guanine-phosphoribosyltransferase (HPRT) (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Statistics

Lesch-Nyhan syndrome is another of the genetic pathologies classified within rare or infrequent diseases (Cervantes Castro and Villagrán Uribe, 2016).

Statistical analyzes indicate a prevalence figure close to 1 case per 100,000 men. It is a rare syndrome in the general population (Cervantes Castro and Villagrán Uribe, 2016).

In Spain these figures are around 1 case for every 235,000 live births, while in the United Kingdom this rate is 1 case for every 2 million newborns (González Senac, 2016).

Deficiency in HPRT activity is usually transmitted genetically as a trait associated with the X chromosome, which is why men are the most affected by Lesch-Nyhan syndrome (Torres and Puig, 2007).

Signs and symptoms

The characteristics of the clinical course of Lesch-Nyhan syndrome are usually classified into three areas or groups: renal, neurological, behavioral and gastrointestinal disorders (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002).

Kidney disorders

Signs and symptoms related to the renal system are fundamentally associated with the presence of hyperuricemia, crystalluria, and hematuria..

Hyperuricemia

In the medical field, this term is used to refer to a condition characterized by an excess of uric acid in the bloodstream (Chemocare, 2016).

Under normal conditions, uric acid levels are usually at (Chemocare, 2016):

• Women: 2.4-6.0 mg / dl
• Men: 3.4-7.0 mg / dl.

When the level of uric acid rises above a value of 7 mg / dl, it is considered a pathological situation and harmful to our body (Chemocare, 2016).

Despite the fact that in initial moments, hyperuricemia may remain asymptomatic, it entails important medical complications (Niesvaara, Aranda, Vila, López, 2006):

• Gouty arthritis: This is a medical condition characterized by the accumulation of urate monosodium monohydrate crystals in the synovial fluid of the joints. It is usually characterized by episodes of pain and acute joint inflammation.
• Tophi: the accumulation of monohydrate crystals acquires a solid and considerable volume in various tissues forming nodules.
• Nephrolithiasis: this pathology is associated with the presence of crystallized substances in the renal system. Generally, this condition is known as kidney stones. Often causes significant episodes of acute pain.
• Chronic kidney disease: it is a physical disorder that refers to the progressive and irreversible loss of kidney functions. In severe situations, chronic kidney disease requires kidney transplantation.

Crystalluria

With this term we refer to the presence of solid formations in the urine (crystals)

These can develop by accumulation of various substances: uric acid, brushite, calcium oxalate dihydrate, calcium oxalate monohydrate, etc..

This medical condition, like any of those described above, can cause severe episodes of pain, irritation of the urinary tract, nausea, vomiting, fever, etc..

Hematuria

The presence of blood in the urine is another of the frequent alterations in the syndrome in Lesch-Nyhan syndrome.

It is not usually considered a central sign or symptom since it is derived from other types of pathologies of the renal and genitourinary system.

Neurological disorders

Neurological involvement can be widely heterogeneous in people with Lesh-Nyhan. These may vary depending on the nerve areas that are most affected.

Some of the most common include (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002):

• Dysarthria: it is possible to appreciate a significant difficulty or inability to articulate the sounds of language due to an affectation of the nervous areas responsible for their control.
• Osteotendinous hyperreflexia: reflex responses may appear abnormally increased. Usually affects tendon groups, such as the patellar or Achilles reflex.
• Ballism: presence of episodes of involuntary, sudden and irregular movements of neurological origin. It usually affects a single limb or one of the body halves.
• Muscle hypotonia: muscle tension or tone is usually significantly decreased. A flaccidity can be observed in the extremities that makes it difficult to carry out any type of motor activity.
• Spasticity- some specific muscle groups may show elevated tone causing tension, stiffness and some involuntary spasms.
• Chorea and muscle dystonia: pattern of involuntary rhythmic movements, twisting or contortion. This movement disorder is often repetitive and can sometimes be described as a persistent tremor.. 

Behavioral disturbances

One of the central characteristics of the Lesch-Nyhan syndrome is the identification of various atypical behavioral traits (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002; National Organization for Rare Disorders, 2016):

• Self harm and aggressive impulses: It is common to observe in children affected by this syndrome some self-injurious actions such as repetitive biting of fingers and lips. It can also be hit with or against objects.
• Irritability: They tend to have an irritable mood that is not very resistant to stressful situations, periods of tension or unfamiliar environments.
• Depression: in some affected, a depressive mood can be identified characterized by loss of initiative and interest, low self-esteem, feelings of sadness, etc..

Gastrointestinal disorders

Although less frequent, it is also possible to identify some symptoms associated with the gastrointestinal system (De Antonio, Torres-Jiménez, Verdú-Pérez, Prior de Castro and García-Puig, 2002):

• Vomiting and nausea
• Esophagitis: inflammatory process associated with the esophagus. Normally it is due to an affectation of the mucosal layer that covers this structure. Causes abdominal pain and bloating, difficulty swallowing, loss of body weight, vomiting, nausea, reflux, etc..
• Intestinal motility: Various alterations may also appear in the movement and movement of food content through the digestive system..

Other alterations

We must also refer to the fact that most of those affected present a variable degree of intellectual disability accompanied by significant delays in psychomotor development.

Causes

The origin of Lesch-Nyhan syndrome is genetic and is associated with the presence of specific mutations in the HPRT1 gene (Genetics Home Reference, 2016).

This type of alterations will produce the deficiency in the enzyme hypoxanthine-guanine-phosphoribosyltransferanse that gives rise to the clinical picture of this syndrome (Genetics Home Reference, 2016).

The most recent research associates these alterations to an inheritance linked to the X chromosome that mainly affects the male sex (National Organization for Rare Disorders, 2016).

As we know, the chromosome composition of men is XY, while that of women is XX (National Organization for Rare Disorders, 2016).

In the case of this syndrome, the alteration affects a specific gene located on the X chromosome. Thus, women do not usually show associated clinical symptoms since they are able to compensate for the abnormalities with a functional activity of the other X pair (National Organization for Rare Disorders, 2016).

However, men contain a single X chromosome, so if the defective gene associated with this pathology is located in this chromosome, it will develop its clinical characteristics (National Organization for Rare Disorders, 2016).

Diagnosis

In the diagnosis of Lesh-Nyhan syndrome, both the clinical findings and the results of various laboratory tests are important (Cervantes Castro and Villagrán Uribe, 2016).

One of the first signs of suspicion is the presence of orange or reddish crystals in the urine of affected children (Cervantes Castro and Villagrán Uribe, 2016).

As they usually appear in early stages, the most common is that they are perceived in diapers as sandy deposits (Cervantes Castro and Villagrán Uribe, 2016).

This, together with the rest of the renal, gastrointestinal, neurological and renal characteristics results in the performance of various laboratory tests to confirm the presence of Lesch-Nyhan syndrome (Gonzáles Senac, 2016):

• Purine metabolism analysis.
• Analysis of HPRT enzyme activity.

In addition, the use of various complementary tests such as imaging techniques is essential to rule out other types of diseases..

Is there treatment?

There is no cure for Lesch-Nyhan syndrome. Treatment is based on symptomatic management and avoidance of secondary medical complications..

The classic approaches focus on (Torres and Puig, 2007):

• Control of uric acid overproduction with pharmacological administration of inhibitors.
• Treatment of motor and muscle disorders and abnormalities. Rehabilitation drug administration and therapy.
• Control of behavioral disturbances through physical restraints and psychological therapy.

References

1. Cervantes Castro, K., & Villagrán Uribe, J. (2008). Patient with Lesch-Nyhan syndrome treated at the Pediatric Stomatology Department of the Tamaulipas Children's Hospital. Mexican Dental Journal.
2. De Antonio, I., Torres-Jiménez, R., Verdú-Pérez, A., Prior de Castro, C., & García-Puig, J. (2002). Lesch-Nyhan syndrome treatment. Rev Neurol.
3. González Senac, N. (2016). LESCH-NYHAN DISEASE: Clinic of HPRT deficiency in a series of 42 patients. Autonomous University of Madrid.
4. Sant Joan de Déu Hospital. (2016). Lesch-Nyhan disease. Monitoring Unit for PKU and other Metabolic Disorders Hospital Sant Joan de Deu.
5. NIH. (2016). Lesch-Nyhan syndrome. Obtained from Genetics Home Reference.
6. NORD. (2016). Lesch Nyhan Syndrome. Obtained from National Organization for Rare Disorders.
7. Schlager, G., Colombo, M., & Lacassie, Y. (1986). Lesch-Nyhan disease. Rev Chil. Pediatr.
8. Torres, R., & Puig, J. (2007). Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Obtained from BioMed Central.