HPRT1 partial deficiency

HPRT1 Partial Deficiency (Kelley-Seegmiller Syndrome): A Comprehensive Review

Introduction

HPRT1 partial deficiency, commonly known as Kelley-Seegmiller syndrome, is a rare, X-linked recessive disorder of purine metabolism caused by decreased activity of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. Unlike complete HPRT deficiency (Lesch-Nyhan syndrome), this disorder presents primarily with hyperuricemia and gout, with little or no neurological or behavioral abnormalities. The clinical and biochemical spectrum is broad, ranging from isolated renal and joint manifestations to cases with mild neurological symptoms.^[1][2][3]

Biochemical and Genetic Basis

The HPRT enzyme plays a crucial role in the purine salvage pathway, recycling hypoxanthine and guanine into their respective nucleotides. HPRT1 partial deficiency leads to the underutilization of these bases and an increase in uric acid production. The degree of residual HPRT activity defines the clinical phenotype:

• Partial deficiency (Kelley-Seegmiller): 1.5–30% of normal enzymatic activity
• Complete deficiency (Lesch-Nyhan): <1.5% activity.^[2][1]

The disease is caused by pathogenic variants in the HPRT1 gene on the X chromosome (Xq26); over 300 mutations have been identified.^[1][2]

Epidemiology

HPRT1 deficiency is rare, with an estimated prevalence in Canada of 1 in 380,000 live births and 1 in 235,000 in Spain. The prevalence of partial deficiency is unknown but believed to be underdiagnosed since many cases present solely with gout or urolithiasis—features common in the general population.^[4][2][1]

Clinical Manifestations

Manifestation	Partial Deficiency (Kelley-Seegmiller)	Lesch-Nyhan Syndrome
Hyperuricemia	Universal	Universal
Juvenile gout	Very common	Common
Urolithiasis	Frequent (kidney stones)	Frequent
Neurologic symptoms	Mild, non-progressive, no self-injury	Severe, progressive, self-injury
Self-mutilation	Absent	Characteristic
Cognitive impairment	Absent or mild	Moderate to severe
Megaloblastic anemia	Possible	Possible

• Symptoms typically begin in late childhood or adolescence with attacks of gout, joint pain, and sometimes tophi.^[5][6][4]
• Renal complications (nephrolithiasis) are common and can result in kidney failure if untreated.^[6][5]
• Neurologic symptoms, if present, are subtle and do not include the self-injury or severe dystonia seen in Lesch-Nyhan syndrome (reports suggest about 25% may have some mild neurological signs).^[7][8][9]

Diagnosis

1. Biochemical findings:
   1. Persistent hyperuricemia
   1. Hyperuricosuria
   1. Elevated uric acid:creatinine ratio in urine
2. Enzyme assay:
   1. Demonstrates reduced HPRT activity in erythrocytes, fibroblasts, or other cells—values between 1.5% and 30% of normal support diagnosis.^[2][1]
3. Molecular genetics:
   1. Identification of a pathogenic mutation in HPRT1.^[3][1]

Differential Diagnosis: Juvenile idiopathic gout, primary hyperuricemia (PRPP synthetase superactivity), and other causes of nephrolithiasis or hyperuricemia should be considered.^[10][4][1]

Management

• Urate-lowering agents: Allopurinol is the mainstay, titrated to maintain serum uric acid <6 mg/dL; febuxostat may be considered in select cases.^[11][1]
• Dietary modifications: Low-purine diet, increased fluid intake, avoidance of alcohol.^[11]
• Treatment of acute gout: NSAIDs, colchicine (avoid in renal impairment), or corticosteroids if needed.
• Kidney stone prevention: Hydration, potassium citrate to alkalinize urine, and avoidance of uricosuric drugs if stones present.^[6]
• Monitoring: Renal function, urate levels, and screening for complications.

When mild neurologic symptoms are evident, routine developmental and cognitive screening is advised, and interventions are tailored as needed.

Prognosis

With appropriate urate-lowering therapy, patients with HPRT1 partial deficiency typically enjoy a normal lifespan. Renal failure, deforming tophi, and destructive arthritis can be prevented or minimized if treatment is started early and maintained. Neurological symptoms, if present, are static—not progressive.^[5][1][2]

Genetic Counseling

The disorder is X-linked recessive:

• Affected males pass the gene to all daughters (carriers), not sons.
• Female carriers have a 50% risk of transmitting the variant; sons of carriers have a 50% chance of developing the condition, and daughters a 50% chance of carrier status.^[1][2]
• Carrier and prenatal diagnoses are possible via DNA analysis; enzyme-based screening is less reliable in female carriers due to X-inactivation.^{[12][13][3][1]}

Summary Table: Classic Phenotypes of HPRT1 Deficiency

Phenotype	Enzyme Activity	Clinical Features
Lesch-Nyhan syndrome	<1.5%	Hyperuricemia, severe neurobehavioral
HPRT-related neurologic disease	1.5–8%	Mild neurological dysfunction, gout
Kelley-Seegmiller syndrome (HRH)	8–30%	Isolated gout/nephrolithiasis

References

• GeneReviews: HPRT1 Disorders^[1]
• Orphanet: Hypoxanthine-guanine phosphoribosyltransferase deficiency^[3][2]
• Torres RJ, Puig JG. Hypoxanthine-guanine phosphoribosyltransferase deficiency. Orphanet J Rare Dis. 2007^[14]
• Rodionovskaya SR et al. Description Kelley-Seegmiller syndrome (partial HPRT deficiency)^[5]
• Medicover Hospitals: Kelley-Seegmiller Syndrome^[11]

Sources

1. https://www.ncbi.nlm.nih.gov/books/NBK1149/           
2. https://www.orpha.net/en/disease/detail/206428       
3. https://www.orpha.net/en/disease/detail/79233   
4. https://saudijournals.com/media/articles/SIJTCM_38_162-164.pdf  
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC3194690/   
6. https://karger.com/uin/article/102/2/233/305604/Kelley-Seegmiller-Syndrome-Urolithiasis-Renal-Uric  
7. https://www.sciencedirect.com/science/article/abs/pii/S0010482519300617
8. https://pubmed.ncbi.nlm.nih.gov/17687757/
9. https://www.clinexprheumatol.org/article.asp?a=1535
10. https://en.wikipedia.org/wiki/Lesch–Nyhan_syndrome
11. https://www.medicoverhospitals.in/diseases/kelley-seegmiller-syndrome/  
12. https://pubmed.ncbi.nlm.nih.gov/7617574/
13. https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.1970150406
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC2234399/
15. https://en.wikipedia.org/wiki/Hypoxanthine-guanine_phosphoribosyltransferase
16. https://www.sciencedirect.com/science/article/abs/pii/S1096719212002375
17. https://www.sciencedirect.com/topics/neuroscience/hypoxanthine-phosphoribosyltransferase
18. https://www.sciencedirect.com/science/article/pii/S0925443999001039
19. https://www.spandidos-publications.com/10.3892/wasj.2025.331