Introduction

Lesch–Nyhan syndrome (LNS), also referred to as HPRT (hypoxanthine-guanine phosphoribosyltransferase) deficiency, is a rare X-linked recessive condition, meaning it is caused by a genetic mutation on the X chromosome. As a result, it primarily affects males, who only need one copy of the altered gene to develop the disorder, while females are typically asymptomatic carriers.¹

This condition is caused by a mutation in the HPRT1 gene, which supplies the body with instructions for producing a specific protein. That protein is an enzyme engaged in what is known as the purine salvage pathway, a process that helps the body recycle purines.¹

Purines are vital building blocks used in the formation of DNA and as a source of energy for our cells. When this recycling pathway does not function properly, purines can ​​accumulate in the body. This can lead to a diversity of LNS-associated symptoms, such as dystonia (a movement disorder in which muscles contract involuntarily), gout (a type of arthritis in which extra uric acid in your body creates sharp crystals that collect in your joints), impaired kidney function, intellectual disability, and self-mutilation (self-harm, intentional actions of causing damage to oneself). The mechanism by which defects in purine recycling, linked to HPRT1 mutations, result in these neurological effects remains unknown.²

Genetic counselling is the process of investigating individuals and families affected by or at risk of inheriting a genetic disorder such as LNS. It helps them understand the medical, psychological and familial implications of the disease.³ Genetic counselling is essential for families affected by LNS due to the condition’s severe neurological symptoms and the need for long-term care and support. This article provides an in-depth explanation of X-linked inheritance and genetic counselling for LNS. 

Basics of X-linked inheritance

Humans have 23 pairs of chromosomes (46 in total), which are long strands of DNA that contain a variety of genes, carrying instructions for the development and function of the body. One pair of chromosomes determines sex; females have two X chromosomes (XX) while males only have one X, paired with a Y chromosome (XY). 

X-linked inheritance describes a way a trait or condition can be passed from a parent to their children. An X-linked condition refers to a disorder caused by mutations in genes located on the X chromosome. Males are more likely to be affected by X-linked conditions because they have only one X chromosome and lack a second copy to compensate for the genetic defect. Females, on the other hand, have two X chromosomes, and if they have a disease-causing gene copy, they can also possess a healthy copy on their other X chromosome, which can help prevent the disease from being expressed, especially if two mutated copies are required for the condition (X-linked recessive disease). These individuals are known as carriers and are generally unaffected, with no symptoms.³ 

In some rare cases, a carrier female exhibits symptoms if, following random X inactivation (the process by which one of the X chromosomes is inactivated in each cell), the majority of the active X chromosomes carry a mutant allele, known as skewed X inactivation.⁴ This has been documented in a female patient affected by LNS.⁵ On the other hand, for ‘dominant’ conditions (where only one mutant copy is needed to cause disease), a female with one disease copy would express the disease regardless of them possessing a functional gene copy on the other X chromosome.⁴

The genetic cause of LNS

LNS arises due to mutations in the HPRT1 gene on the X chromosome. Mutations in the HPRT1 gene lead to a deficiency of the protein HPRT, which functions as an enzyme (enzymes are proteins that speed up chemical reactions in the body, allowing the reaction to occur). LNS patients have an HPRT activity approaching zero, and this affects purine metabolism.² 

Purines are nitrogen-containing compounds which are present in many foods. In LNS, the absence of HPRT means purines are not built into nucleotides, which are essential organic molecules used to make DNA, RNA, and for cellular energy. HPRT deficiency leads to hyperuricemia and other gout-related problems because the enzyme HPRT is absent or deficient, preventing the recycling of purines. These unrecycled purines are then metabolised into uric acid, causing its overproduction and accumulation in the blood.⁵

Understanding inheritance patterns in LNS Families

As the HPRT1 gene is located on the X chromosome, LNS displays an X-linked inheritance pattern. To understand how LNS is inherited in this pattern, we will look at some possible scenarios. 

Scenario 1: Carrier mother and unaffected father

The mother has a mutated HPRT1 gene on one X chromosome but a normal one on the other, making her a healthy carrier. Because sons only inherit one X chromosome, there is a 50% chance they get the mutated X from their mother and will be affected by LNS. Daughters will receive one X from the mother and one from the father; there is a 50% chance they inherit the mutated X, making them carriers, and a 50% chance they inherit the normal X, remaining unaffected. 

Scenario 2: Non-carrier mother and affected father

The affected father will not pass the mutated gene to his sons (because sons inherit the Y chromosome), but he will pass his mutated X chromosome to all his daughters, making them carriers.

Role of genetic counselling

Genetic counselling is centred around providing information to families and individuals affected by genetic conditions. Counselling also helps people understand the information they are provided to aid health-related decision-making. Genetic counselling aims to communicate complex genetic science with an empathetic understanding of families' and patients' concerns and needs.³

Families undergoing genetic counselling can expect to endure practices such as the creation of a pedigree analysis (family tree/history) to determine the inheritance pattern of a condition, and genetic testing. Emotional and psychological support is also provided for families through counselling. Information delivered may include how the condition is inherited and the health challenges a child with LNS may face, such as symptoms and potential complications. It may also cover how the condition is typically managed and what options are available for families at risk. Furthermore, identifying the presence of a genetic mutation in a family can aid in early diagnosis of affected children, which in turn can facilitate care planning and symptom management.³

Options for at-risk families

Genetic testing for women with a family history will help identify possible carriers and make them aware that they might want to consider different reproductive options if they are at risk of having children affected by LNS. Reproductive options for individuals at risk of passing on a genetic condition include: Natural conception with prenatal testing, which can determine whether a baby is more or less likely to have a particular genetic condition; in an LNS case, the fetus’s HPRT1 will be tested for mutation. IVF (in vitro fertilisation) with preimplantation genetic diagnosis (PGD); in an LNS case, embryos are screened for genetic disorders before implantation in IVF. This process helps select only genetically healthy embryos, therefore reducing the risk of passing on inherited diseases to the next generation. Use of donor eggs eliminates the risk of a carrier mother passing a mutated X copy to their sons. 

Summary 

LNS is an X-linked recessive genetic disorder caused by mutations in the HPRT1 gene, which leads to a deficiency of the enzyme HPRT. This enzyme is vital for purine recycling, and its lack causes an overproduction of uric acid, resulting in symptoms like gout, intellectual disability, and kidney stones. The X-linked inheritance explains why LNS primarily affects males, as they only need one copy of the affected gene to develop the condition, while females are typically carriers but remain asymptomatic. Genetic counselling is vital for families affected by LNS. Genetic counselling helps explain LNS and how it is inherited, assisting them to make informed decisions.