Hprt1 Disorders
Summary
Clinical characteristics.
HPRT1 disorders, caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), are typically associated with clinical evidence for overproduction of uric acid (hyperuricemia, nephrolithiasis, and/or gouty arthritis) and varying degrees of neurologic and/or behavioral problems. Historically, three phenotypes were identified in the spectrum of HPRT1 disorders: Lesch-Nyhan disease (LND) at the most severe end with motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior; HPRT1-related neurologic dysfunction (HND) in the intermediate range with similar but fewer severe neurologic findings than LND and no self-injurious behavior; and HPRT1-related hyperuricemia (HRH) at the mild end without overt neurologic deficits. It is now recognized that these neurobehavioral phenotypes cluster along a continuum from severe to mild.
Diagnosis/testing.
The diagnosis of an HPRT1 disorder is established in a male proband with suggestive clinical and laboratory findings and a hemizygous pathogenic variant in HPRT1 identified by molecular genetic testing and/or low HGprt enzyme activity identified on biochemical testing.
Management.
Treatment of manifestations: Hyperuricemia is most commonly treated with the xanthine oxidase inhibitor allopurinol to reduce the risk for nephropathy, gouty arthritis, and tophi. Febuxostat may be used in case of allopurinol hypersensitivity. Multidisciplinary specialists may be needed to manage the neurologic manifestations. Depending on needs, specialists in medical genetics, neurology, behavioral management, developmental pediatrics, physical medicine and rehabilitation, physical therapy, occupational therapy, speech and language pathology, dentistry, and nephrology may be required.
Surveillance: HPRT1 disorders are not clinically progressive; however, surveillance is important for all HPRT1 disorders. While overproduction of uric acid does not get worse with time, chronic overproduction of uric acid – especially if not well controlled – may lead to cumulative pathology in the kidneys and/or joints. Similarly, new or worsening neurologic problems are not expected over time; however, some evolution of the neurologic problems occurs in the first few years of life, which reflects development of the nervous system in response to a static insult.
Agents/circumstances to avoid: Probenecid and other drugs that increase the risk for precipitation of uric acid in the urinary system and may cause acute renal failure; certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines; periods of relative dehydration because they increase the risk for renal stones or urate nephropathy.
Evaluation of relatives at risk: It is appropriate to clarify the status of males at risk for HPRT1 disorders immediately after birth in order to identify as early as possible those who would benefit from prompt initiation of xanthine oxidase inhibitors and anticipation of future needs.
Genetic counseling.
HPRT1 disorders are X linked. The risk to sibs of a male proband depends on the genetic status of the mother. If the mother of the proband has an HPRT1 variant, the chance of transmitting it in each pregnancy is 50%: males who inherit a pathogenic HPRT1 variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the proband has a known HPRT1 variant that cannot be detected in his mother’s leukocyte DNA, the risk to sibs is low but greater than that of the general population because of the possibility of maternal mosaicism. Once an HPRT1 pathogenic variant has been identified in an affected family member, heterozygote testing for females and prenatal/preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
HPRT1 disorders, which are associated with deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), should be suspected in males with the following clinical and supportive laboratory findings.
Clinical findings
Table 1.
HPRT1 Disorders: Clinical Findings by Phenotype
| HPRT1 Phenotype | Clinical Findings | |||
|---|---|---|---|---|
| Hyperuricemia, nephrolithiasis, or gouty arthritis | NDD w/motor impairment resembling severe cerebral palsy | ID | Self-injurious behavior | |
| Lesch-Nyhan disease | +++ | +++ | ++ | +++ |
| HPRT1-related neurologic dysfunction | +++ | + to +++ | + to ++ | |
| HPRT1-related hyperuricemia | +++ | NA | NA | |
ID = intellectual disability; NA = not applicable; NDD = neurodevelopmental delay
Supportive (but not diagnostic) laboratory findings
- Hyperuricemia is often evident. Serum uric acid concentration greater than 8 mg/dL defines hyperuricemia in adults; however, the upper limit of normal, which varies by age, is lower in children.
- The urate:creatinine ratio, calculated from the concentration of uric acid and creatinine in a spot urine, provides a reliable measure of uric acid overproduction. A urate:creatinine ratio greater than two is characteristic for all HPRT1 disorders.
- Uric acid kidney stones or uric acid crystals present in the urine.
Note: Absence of a known family history does not preclude the diagnosis of an HPRT1 disorder.
Establishing the Diagnosis
Male proband. The diagnosis of an HPRT1 disorder is established in a male proband with suggestive clinical and laboratory findings and a hemizygous pathogenic variant in HPRT1 identified by molecular genetic testing (see Table 2) and/or low HGprt enzyme activity identified on biochemical testing.
Note: Identification of a hemizygous HPRT1 variant of uncertain significance does not establish or rule out a diagnosis of this disorder.
Molecular Genetic Testing
Molecular genetic testing can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of an HPRT1 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
- Single-gene testing. Sequence analysis of HPRT1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.Note: In affected males, lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion. Confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- A multigene panel (such as those for developmental delay, dystonia, spasticity, intellectual disability, or seizures) that includes HPRT1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with this condition. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
- Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used for HPRT1 Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| HPRT1 | Sequence analysis 3, 4 | ~80% 5 |
| Gene-targeted deletion/duplication analysis 6 | ~20% 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Fu et al [2014], Madeo et al [2019]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Biochemical Testing
HGprt enzyme activity. Several enzyme tests are clinically available. These tests can be done on any tissue. Although erythrocyte-based assays are most commonly used because they are technically easiest, assays based on cultured fibroblasts correlate better with phenotypic severity [Fu et al 2015].
- Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%.
- Individuals with HPRT1-related neurologic dysfunction tend to have residual enzyme activity from 2% to 8%.
- Individuals with HPRT1-related hyperuricemia tend to have residual enzyme greater than 10%.
Clinical Characteristics
Clinical Description
Affected Males
Pathogenic variants in HPRT1 are almost always associated with clinical evidence for overproduction of uric acid (hyperuricemia, nephrolithiasis, and/or gouty arthritis) as well as a range of neurobehavioral phenotypes. Historically, three phenotypes recognized in the spectrum of HPRT1 disorders were Lesch-Nyhan disease (LND) at the most severe end, the intermediate phenotype HPRT1-related neurologic dysfunction (HND), and HPRT1-related hyperuricemia (HRH) at the mild end (see Table 1). In reality, these neurobehavioral phenotypes cluster along a continuum from severe to mild [Fu et al 2014].
Overproduction of uric acid is present from birth. The serum uric acid concentration is usually elevated. This finding is often missed because hyperuricemia can be mild; rarely, serum uric acid concentration can be normal.
If untreated, overproduction of uric acid leads to precipitation of uric acid crystals in the urinary system. Crystals appear as an orange sandy material in the diapers. Larger stones may appear as "gravel" in diapers. Larger stones may be difficult to pass. Stones may cause hematuria and increase the risk for urinary tract infections. While crystals or gravel in the diaper may be an early feature, their significance is often not appreciated for years.
Another potential consequence of untreated overproduction of uric acid is gouty arthritis caused by precipitation of uric acid in the joints. Complex precipitates mixed with proteins may form visible swellings known as tophi. Gout is uncommon in children and typically develops long after other manifestations are present.
If overproduction of uric acid is not treated, renal failure is common. Some individuals develop renal failure even with treatment.
Lesch-Nyhan Disease (LND)
LND is characterized by uric acid overproduction, motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior.
Motor dysfunction. Boys with LND typically have normal prenatal and perinatal histories. The most common initial findings during the first year of life are hypotonia and delayed motor skills. Children with LND fail to reach normal milestones such as sitting, crawling, and walking [Jinnah et al 2006].
Within the first few years of life, abnormal movements emerge. The characteristic feature in all individuals is severe action dystonia [Jinnah et al 2006]. Children with LND may also develop opisthotonos, choreoathetosis, and sometimes ballismus. Approximately one third develop corticospinal signs such as spasticity, hyperreflexia, and clonus. The neurologic picture resembles dyskinetic or athetoid cerebral palsy.
The motor disability is sufficiently severe that children with LND do not walk and are usually confined to a wheelchair. Most need assistance with feeding and hygiene.
Cognitive disturbances. Most individuals with LND are cognitively impaired. The degree of impairment is difficult to assess because the neurobehavioral problems make interpretation of standardized tests difficult [Schretlen et al 2001].
In general, individuals with LND do not have severe intellectual disability. Formal psychological testing typically yields scores in the mild-to-moderate range of dysfunction.
Behavioral abnormalities. Almost all affected individuals develop the hallmark feature of recurrent self-injurious behaviors [Schretlen et al 2005]. This problem most often develops between ages two and four years. In some instances, it may begin as early as the first year of life, or it may be delayed until the late teenage years.
Self injury most often involves biting of the fingers, hands, lips, and cheeks [Robey et al 2003]. It may also involve banging the head or limbs against hard objects. The severity and patterns of this behavior evolve over time, but they generally occur daily.
In addition to self-injurious behavior, affected individuals often have other difficult behaviors including impulsiveness, aggressiveness, oppositional defiance, recurrent vomiting, spitting at others, and coprolalia.
Other manifestations can include the following:
- Testicular atrophy with delayed growth and puberty is very common.
- Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [Cakmakli et al 2019].
- Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [Schretlen et al 2013].
- Approximately one third have seizures [Leeman-Markowski & Jinnah 2018]. EEG shows nonspecific slowing or disorganization in most others.
- Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [Jinnah et al 2006].
- Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [Neychev & Jinnah 2006], recurrent unexplained emesis, or dystonic crisis with severe autonomic changes.
Life expectancy. LND is not a progressive neurodegenerative disorder [Göttle et al 2014]. If management of manifestations is effective, individuals with LND may survive into the second to fourth decades of life.
The most common causes of death include pulmonary failure (from pneumonia or recurrent aspiration from dysphagia), renal failure, or sepsis from different causes. Sudden unexplained death in an otherwise well-tended individual may also occur [Neychev & Jinnah 2006].
HPRT1-Related Neurologic Dysfunction (HND)
HND is similar to LND, except the neurologic features are often less severe and self-injurious behavior does not occur. The spectrum of the severity of neurologic features in HND is broad. The most severely affected individuals are neurologically indistinguishable from those with LND; the least severely affected individuals may have only minor clumsiness with fine motor activity or relatively minor cognitive deficits [Jinnah et al 2010]. Intermediate grades of severity may also occur.
The severity and spectrum of problems related to uric acid are indistinguishable from LND.
Macrocytic anemia is common, but many of the other problems such as growth delay, dysphagia, seizures, and sudden death are less common.
Life span is longer than in LND and may be normal for the least severely affected.
HPRT1-Related Hyperuricemia (HRH)
HRH is similar to HND, except that clinically obvious neurologic deficits do not occur. While mild clumsiness may occur, clinically overt problems are not usually apparent and are only evident on detailed neurologic examination [Jinnah et al 2010].
Mild cognitive deficits, especially problems with attention, are common but are not usually identified without formal neuropsychological testing [Schretlen et al 2001].
The severity and spectrum of problems related to uric acid are indistinguishable from LND and HND.
Life span is normal.
Heterozygous Females
Heterozygous females are virtually always clinically normal without evidence for motor or cognitive deficits. Production of uric acid may be slightly elevated, and some heterozygous females may develop gout when they are older [Puig et al 1998].
Rarely the LND phenotype has been observed in heterozygous females as the result of skewed (nonrandom) X-chromosome inactivation of the chromosome bearing the normal HPRT1 allele. (Of note, discordant phenotypes were observed in monozygotic twin girls [1 normal; 1 with LND] due to skewed X-chromosome inactivation [De Gregorio et al 2005].)
Presence of biallelic HPRT1 pathogenic variants has also been reported in females [Fu et al 2014].
Genotype-Phenotype Correlations
Because the amount of residual HGprt enzyme activity correlates with the severity of the phenotype [Fu et al 2014, Fu et al 2015], some general genotype-phenotype correlations are seen.
LND is associated with complete or near-complete loss of enzyme activity from the following types of HPRT1 variants:
- Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions
- Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability.
- Most (but not all) splice site variants that result in major changes in the protein coding region
HND is associated with HPRT1 variants that result in small amounts of residual enzyme activity (usually 2%-8% of normal):
- Most HND-causing variants are missense variants.
- Occasionally variants affect splice sites, leaving a small proportion of correctly spliced transcripts.
- Rare variants are duplications, which may rarely revert to normal to varying degrees in different tissues, producing somatic mosaicism with varying residual HGprt enzyme activity [Fu et al 2014].
HRH is associated with missense HPRT1 variants that retain the highest level of abnormal enzyme activity (usually >8% of normal):
- Most individuals with the same HPRT1 variant have the same phenotype, although exceptions exist [Fu et al 2014].
- Splice site variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in splicing fidelity.
- Some missense variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in protein stability [Ceballos-Picot et al 2013].
Nomenclature
Although LND may also be referred to as Lesch-Nyhan syndrome, Lesch-Nyhan disease is the more accurate term because the cause of phenotypic elements that constitute the disorder is known.
HRH may also be referred to as Kelley-Seegmiller syndrome.
Prevalence
The prevalence of LND is approximately 1:380,000. The prevalence of the milder phenotypes (HND and HRH) is not well studied, but they appear to be less common than LND.
HPRT1 disorders occur in all populations that have been studied, and with relatively equal frequency.
Differential Diagnosis
Lesch-Nyhan disease (LND). When fully developed with the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, the diagnosis of LND is straightforward. There are no other genetic causes of the full phenotype. The main diagnostic difficulties arise during early stages when all the features are not yet apparent, and in individuals who have milder phenotypes.
The index of suspicion is raised when developmental delay is associated with evidence of overproduction of uric acid, such as hyperuricemia, uric acid nephrolithiasis or crystals in the urine, or gouty arthritis.
LND is first suspected when self-injurious behavior emerges. However, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism spectrum disorder, Tourette syndrome, McLeod neuroacanthocytosis syndrome, Rett syndrome, Cornelia de Lange syndrome, glutaric acidemia type 1, familial dysautonomia, chorea-acanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1 (see SPTLC1 Hereditary Sensory Neuropathy), and several psychiatric conditions. Finger and lip biting is so severe and so characteristic of LND that it is referred to as a behavioral phenotype. In other self-injury syndromes, the behavior tends to be less severe, and the topography of behaviors is different, with head banging and/or nonspecific self biting but not biting of the fingers and lips that results in tissue damage.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and the needs in an individual diagnosed with an HPRT1-related phenotype, the evaluations summarized in Tables 3, 4, and 5 are recommended. These tables begin with HPRT1-related hyperuricemia (HRH) because these needs are shared by all phenotypes (Table 3). Table 4 adds the needs for neurologic assessment in HPRT1-related neurologic dysfunction (HND). Since neurologic involvement varies considerably, the assessment must be tailored to individual needs. Table 5 adds the needs for behavioral assessment in Lesch-Nyhan disease (LND).
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with HPRT1 Disorders: HRH
| System/Concern | Evaluation | Comment | |
|---|---|---|---|
| Hyperuricemia | Serum uric acid | Establish baseline uric acid & need for allopurinol. | |
| Nephropathy | Renal function | Serum chemistry incl BUN & creatinine | Establish any renal dysfunction. |
| Urolithiasis | Abdominal US for renal calculi | Establish existence of:
| |
| Gout | Assessment of joints | Establish existence of:
| |
| Macrocytic anemia | Complete blood count | Typically unresponsive to vitamins & only rarely needs treatment. | |
| Genetic counseling | Provide patients & families w/:
| ||
BUN = blood urea nitrogen; MOI = mode of inheritance; US = ultrasound
Table 4.
Additional Recommended Evaluations Following Initial Diagnosis in Individuals with HPRT1 Disorders: HND
| System/Concern | Evaluation | Comment |
|---|---|---|
| Motor abnormalities |
| Assess:
|
| Intellectual/ behavioral problems | Neurocognitive & behavioral assessments | Assess:
|
| Communication | Speech/language pathology eval | Assess dysarthria & need for intervention. |
| Feeding/Nutrition | Gastroenterology / nutrition / feeding team eval | Assess nutritional status & aspiration risk. |
| Family support/ resources | Assess need for:
|
ADLs = activities of daily living
Table 5.
Additional Recommended Evaluations Following Initial Diagnosis in Individuals with HPRT1 Disorders: LND
| System/Concern | Evaluation | Comment |
|---|---|---|
| Self-injurious behavior | History & exam for evidence of self injury |
|
| Behavioral assessment | History & exam for other difficult behaviors |
|
| Teeth | Dental eval |
|
Treatment of Manifestations
Following initial evaluations (Tables 3, 4, and 5), treatments for specific problems may be needed. Treatment recommendations are summarized in Tables 6, 7, and 8. They begin with HRH because these needs are shared by all phenotypes (Table 6). Table 7 adds the needs for neurologic interventions in HND. Since neurologic involvement varies considerably, needs vary. Table 8 adds the needs for behavioral interventions in LND [Olson & Houlihan 2000].
A multidisciplinary team may be needed. Depending on needs, this team may require specialists in medical genetics, neurology, behavioral management, developmental pediatrics, physical medicine and rehabilitation, physical therapy, occupational therapy, speech and language pathology, dentistry, and nephrology.
Table 6.
Treatment of Manifestations in Individuals with HPRT1 Disorders: HRH
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Hyperuricemia | Xanthine oxidase inhibitor |
|
| Renal complications | Xanthine oxidase inhibitor |
|
| Lithotripsy or surgery | Renal stones that form despite treatment may require lithotripsy or surgery. | |
| Gouty arthritis | Xanthine oxidase inhibitor |
|
| Macrocytic anemia | None |
|