Purine Salvage Deficiencies

Overview

Definition

Purines are used for cellular energy and may be recycled through a salvage pathway that is susceptible to enzyme deficiencies that cause Lesch-Nyhan syndrome and adenine phosphoribosyltransferase (APRT) deficiency.

Epidemiology

• Lesch-Nyhan syndrome: 
  • Incidence: 1 in 380,000 live births 
  • Males are affected (X-linked disorder).
  • Females are heterozygous carriers.
• APRT deficiency: 
  • Incidence: 1 in 15,000–100,000 live births
  • Japanese and Icelandic patients are more susceptible to disease.
  • Equal prevalence in males and females

Etiology

• Lesch-Nyhan syndrome: 
  • Due to hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency
  • Caused by mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of HPRT1 gene
  • Rare
  • X-linked recessive inheritance
• APRT deficiency:
  • Caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in APRT, leading to excessive production and renal excretion of 2,8-dihydroxyadenine (DHA)
  • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance

Pathophysiology

Lesch-Nyhan syndrome

• HPRT deficiency
• Results in failure of salvage pathway for hypoxanthine and guanine; purines degraded to uric acid
• Decreased inositol monophosphate and guanosyl monophosphate results in an increase in conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) to 5-phosphoribosylamine:
  • Exacerbates uric acid overproduction
  • Hyperuricemia predisposes to gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout and further complications.

Adenine phosphoribosyltransferase deficiency

• Deficiency in the APRT enzyme that hinders salvaging of adenine
• Accumulation of adenine results in its oxidation into DHA → precipitates in the urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract 
• Can cause nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis and renal failure

Clinical Presentation

Lesch-Nyhan syndrome

• Presents within the 1st year of life: xanthine in the urine (orange sandy precipitate) often 1st sign
• Neurologic dysfunction: 
  • Cognitive dysfunctions
  • Intellectual disability
  • Spastic cerebral palsy Cerebral palsy Cerebral palsy (CP) refers to a group of conditions resulting in motor impairment affecting tone and posture and limiting physical activity. Cerebral palsy is the most common cause of childhood disability. It is caused by a nonprogressive CNS injury to the fetal or infant brain. Cerebral Palsy
  • Hypotonia
  • Involuntary movements
• Psychiatric problems:
  • Behavioral dysfunctions
  • Self-mutilating behavior
• Hyperuricemia:
  • Urolithiasis
  • Nephropathy
  • Gouty arthritis
  • Tophi
• Hematologic: macrocytic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview

Adenine phosphoribosyltransferase deficiency

• There is no typical age for clinical onset.
• Renal dysfunction:
  • Uric acid nephropathy
  • Renal colic
  • Frequent infections
  • Renal failure

Diagnosis

Lesch-Nyhan syndrome

• Laboratory tests show hyperuricemia.
• Urine studies show an elevation in the urate:creatinine concentration.
• Genetic testing is diagnostic.

Adenine phosphoribosyltransferase deficiency

• Diagnosis is made by identification of DHA in urine.
• Other components of workup:
  • Physical examination of the eyes for patients with ophthalmologic symptoms
  • Laboratory studies of serum creatinine, urine studies
  • Imaging of the kidney with CT or ultrasonography to evaluate for kidney stones

Management

Lesch-Nyhan syndrome

• There is no cure for this disorder.
• Treatments are aimed at reducing symptoms:
  • Allopurinol for hyperuricemia
  • Baclofen or benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines for spasticity
  • Behavioral and physical intervention for self-injurious behavior
• Prognosis is poor, and patients most often die within the 1st 2 decades of life.

Adenine phosphoribosyltransferase deficiency

• Treatment involves:
  • Purine restriction
  • High fluid intake
  • Avoidance of urine alkalinization
  • Allopurinol
  • Renal transplantation for end-stage renal disease
• Prognosis is better than for Lesch-Nyhan syndrome if treatment controls renal disease. However, there is a risk of end-stage renal disease in patients who do not receive appropriate treatment.

Clinical Relevance

• Urolithiasis: formation of stones in kidney, bladder, and/or urethra. The most common type of stone is a calcium oxalate stone. Patients often present with colicky flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain radiating to the groin and hematuria. Patients are diagnosed using non–contrast-enhanced CT of the abdomen and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis. Management depends on the size of the stone. Small stones will pass spontaneously with conservative management (hydration, analgesics); large stones require intervention with extracorporeal shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock wave lithotripsy or percutaneous nephrolithotomy. Complications include hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis and pyelonephritis Pyelonephritis Pyelonephritis is infection affecting the renal pelvis and the renal parenchyma. This condition arises mostly as a complication of bladder infection that ascends to the upper urinary tract. Pyelonephritis can be acute or chronic (which results from persistent or chronic infections). Typical acute symptoms are flank pain, fever, and nausea with vomiting. T Pyelonephritis and Perinephric Abscess.
• Gout: medical condition caused by elevated uric acid levels and monosodium urate deposition in the tissue. The most common presentation is monoarticular acute arthritis. Most often, the first metatarsophalangeal joint is affected. Other organs, such as the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys can be affected. Diagnosis is confirmed with identification of urate crystals from a joint aspiration. Treatment for acute flares may include NSAIDs, colchicine, or glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
• Tophi: deposit of monosodium urate crystals in hyperuricemic conditions. Tophi are most commonly seen in patients with gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout and develop over time, usually appearing many years after a patient is noted to have hyperuricemia. Tophi can form throughout the body in locations such as joints, cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage, and bones. These formations may lead to poor mobility and can cause bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones destruction.