Primary hyperoxaluria type 1
1999; Elsevier BV; Volume: 55; Issue: 6 Linguagem: Inglês
10.1046/j.1523-1755.1999.00477.x
ISSN1523-1755
Autores Tópico(s)Pediatric Urology and Nephrology Studies
ResumoAn 11-year-old girl presented to her local nephrology service in Pakistan with a five-month history of fever, bilateral loin pain, and progressive weight loss. Over the preceding one to two months, she had also developed dysuria and intermittent vomiting. She was born by normal vaginal delivery at term and there were no perinatal problems. At three years of age, she was said to have passed a calculus, but no investigations were performed at that time. Her only other significant past history was a single febrile illness associated with vomiting at four years of age, when a presumptive diagnosis of urinary tract infection was made. Unfortunately, no urine was sent for culture, although she was treated with antibiotics and made a full recovery. Her parents, who were first cousins, both were in good health, as were her four sisters and one brother. There was some uncertainty as to whether she and her siblings were from the same marriage. Physical examination revealed a small and clinically anemic girl. Laboratory investigation disclosed: BUN, 42.1 mmol/liter (118 mg/dl); creatinine, 734 μmol/liter (8.3 mg/dl); calcium, 1.75 mmol/liter (7.0 mg/dl); and hemoglobin, 61 g/liter. A renal ultrasound study revealed a 4 mm echogenic stone in the right kidney, a 15 mm and a 10 mm stone in the left kidney, no hydronephrosis, and bilateral small kidneys. A diagnosis of end-stage chronic renal failure secondary to chronic pyelonephritis was made. She was treated with antibiotics, blood transfusions, and twice-weekly hemodialysis via a left Brescia fistula. Further medical details are not available from her Pakistani records. She came to the United Kingdom nine years ago, some six months following her initial presentation. When first seen at the Royal Manchester Children's Hospital, physical examination was essentially unchanged. Her height was 143.5 cm (25th centile) and weight 27.6 kg (3rd centile). She was anemic but there were no other significant findings. Laboratory investigations revealed: hemoglobin, 65 g/liter; white blood cell count, 8.5 × 109/liter; platelets, 228 × 109/liter; sodium, 136 mmol/liter; potassium, 5.2 mmol/liter; calcium, 1.72 mmol/liter; phosphate, 1.9 mmol/liter; albumin, 37 g/liter; urea, 34.8 mmol/liter (97.5 mg/dl); and serum creatinine, 1037 μmol/liter (11.7 mg/dl). She was HBsAg and HBeAg positive and HBeAb negative. She was treated for renal osteodystrophy with 1α-hydroxycholecalciferol and was transferred to North Manchester General Hospital for hemodialysis at the infectious diseases center because of her hepatitis B positivity. Shortly after starting hemodialysis, significant problems with vascular access resulted in her renal replacement treatment being changed to chronic ambulatory peritoneal dialysis (CAPD), and she was transferred back to the care of the Royal Manchester Children's Hospital. She remained well dialyzed and responded well to erythropoietin therapy. Following her conversion to CAPD she spontaneously seroconverted to hepatitis B and cleared her viral load. The other medical problem at that time was her renal osteodystrophy. Despite aggressive medical management and an apparent biochemical response to treatment (calcium and phosphate were both within the normal range, and her PTH was at the lower level of normal), she continued to be troubled by bone and joint pain. This eventually culminated in an undisplaced subcapital fracture of the left hip and bilateral stress fractures of both lower femurs. These were managed conservatively by the orthopedic surgeons at the time but unfortunately resulted in valgus deformities and flexion contractures of both knees. Because of these ongoing bone problems, a bone biopsy was performed to clarify the precise abnormality underlying these problems. The bone biopsy demonstrated the presence of osteomalacia with large quantities of crystals and a probable diagnosis of primary hyperoxaluria. Liver biopsy, urine, CAPD fluid, and plasma samples were sent for diagnostic confirmation. Measurement of alanine:glyoxylate aminotransferase (AGT) catalytic activity in the liver biopsy sample disclosed 0.09 μmol substrate transformed/hr/mg protein (reference range, 2.75 to 8.38 μmol/hr/mg protein). An SDS-PAGE immunoblot test in the liver biopsy sample revealed no AGT immunoreactivity. Analysis of the urine revealed: serum creatinine, 3.42 mmol/liter; oxalate, 0.67 mmol/liter; and glycolate, 0.40 mmol/liter. Analysis of the CAPD fluid disclosed: creatinine, 478 μmol/liter, and oxalate, 36 μmol/liter. The plasma contained 699 μmol/liter of creatinine and 77.8 μmol/liter of oxalate. The results of the assay procedures in the liver biopsy sample are compatible with a diagnosis of the more common variant of primary hyperoxaluria, type 1, with reduced catalytic activity of AGT. The oxalate levels in the urine, plasma, and CAPD fluid support this diagnosis. In view of this diagnosis and the fact that she was free of hepatitis, she was accepted onto the transplant waiting list for combined liver and kidney transplantation. She received a combined transplant four years ago at age 16 years. The donor was a 7-year-old male who had died in a traffic accident. Viral serology was positive for cytomegalovirus only. Mismatches were A2, B2, and DR1. Technically the procedure was uncomplicated, but primary nonfunction of her renal graft necessitated ongoing hemodialysis. Renal biopsies at days 8, 18, 22, and 40 showed acute tubular necrosis and a few crystals, but no evidence of rejection. At day 30 she also developed pelvicalyceal dilation secondary to a vesicoureteral junction urinary leak, for which a nephrostomy was inserted. Following re-exploration on day 37, the donor ureter was anastomosed to her left native ureter over a double-J stent, which was removed at day 50. Her maximal urine output was 200 ml/day and she remained dialysis-dependent throughout. Her poor renal function was attributed to crystal deposition. The liver transplant was a complete success, but despite this and aggressive daily ultrafiltration/hemodialysis, her oxalate levels remained 10 to 20 times greater than the upper limit of normal. Since receiving her transplant, she has had a number of problems. Initially the liver allograft functioned well. Twelve months after the transplant, however, her hepatic function worsened. Laboratory results were: sodium, 137 mmol/liter; potassium, 3.4 mmol/liter; urea, 3.4 mmol/liter; creatinine, 113 μmol/liter; bilirubin, 36 mmol/liter; ALT, 45 mmol/liter; ALP (hepatic isoenzyme), 1464 mmol/liter; and albumin, 28 g/liter. Her cyclosporine A level was 32 ng/ml. She was asymptomatic throughout, and all investigations including ultrasound scan and liver biopsy were normal. Endoscopic retrograde cholangiopancreatography failed for technical reasons. Her liver function returned to baseline levels without specific treatment over a number of months and no cause was ever found for this episode. Since that time she has had no further problems, although her alkaline phosphatase is persistently elevated. She is maintained on cyclosporine A (Neoral) and prednisolone. She has a number of continuing problems related to her renal replacement therapy. She is dialysis-dependent and is maintained on hemodialysis four hours three times per week; this dialysis dose appears to be adequate. Unfortunately, since she lost her first fistula, there has never been successful creation of permanent vascular access despite a number of attempts. Over the last three years, she has been dialyzed with permanent catheters, and she has now exhausted possible access sites for replacement should it become necessary. The possibility of retransplantation has been considered, and her father would be a suitable candidate for a live donor. However, because of her persistently raised oxalate levels and the probability that her first transplant was lost through oxalate deposition, retransplantation has not been attempted. Orthopedic issues remain a major problem. Her flexure contractures have failed to respond to treatment, and she is left with 40° fixed deformities of both knees. The fracture of her right hip failed to unite, and the screw with which it was fixed encroached upon the hip joint, necessitating its removal. The hip has since then become dislocated. More aggressive treatment has not been attempted because of the likelihood of further poor healing secondary to her metabolic bone disease, which itself continues to cause bone and joint pain. All these factors in combination have resulted in her now being unable to walk and thus wheelchair-bound. In addition, she has developed chronic osteomyelitis of her left ankle, probably secondary to a dialysis-line infection. Prior to her transplant she had borderline malnutrition; since her surgery, her nutritional state has deteriorated further. Since her transplant, she has not maintained an adequate level of nutrition despite adequate dialysis and has been receiving supplementary nocturnal nasogastric feeding almost continuously over this period. She remains at all times at a barely adequate level of nutrition. She also has developed persistent hypotension over the last year. Earlier, her blood pressure had been on the order of 130/80 mm Hg. Now her systolic blood pressure rarely exceeds 80 mm Hg, despite careful attention to fluid balance. Without a doubt her hypotension has contributed to the difficulties around forming and sustaining permanent vascular access. The question has arisen whether this level of blood pressure would be capable of maintaining a renal transplant. She is currently being evaluated by cardiologists for this problem. Echocardiography has demonstrated good left-ventricular function with no valvular abnormalities. A MUGA scan demonstrated an ejection fraction of 34%. This problem is as yet not resolved. Dr. Pierre Cochat (Head, Renal Unit, Hôpital Edouard Herriot; Professor of Pediatrics, Université Claude Bernard; and INSERM U499, Lyon, France): Primary hyperoxaluria type 1 (PH1, McKusick 259900), the most common form of PH Table 1, is a rare autosomal-recessive disorder characterized by increased urinary excretion of calcium oxalate, recurrent urolithiasis, nephrocalcinosis, and accumulation of insoluble oxalate throughout the body (oxalosis)1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar. The disease is due to a functional defect of the liver-specific peroxisomal alanine:glyoxylate aminotransferase (AGT, E.C. 2.6.1.44). The resulting decreased transamination of glyoxylate to glycine leads to a subsequent increase in its oxidation to oxalate, which is a poorly soluble end product Figure 1. Human liver AGT cDNA and genomic DNA have been cloned and sequenced; the normal AGT gene (that is, AGXT) maps to chromosome 2q37.32.Takada Y. Kaneko N. Esumi H. Purdue P.E. Danpure C.J. Human peroxisomal L-alanine: glyoxylate aminotransferase: Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.Biochem J. 1990; 268: 517-520Crossref PubMed Scopus (104) Google Scholar, 3.Purdue P.E. Lumb M.J. Fox M. Griffo G. Hammon-Benais C. Povey S. Danpure C.J. Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.Genomics. 1991; 10: 34-42Crossref PubMed Scopus (141) Google Scholar, 4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar.Table 1Classification of primary hyperoxaluriasType 1Increased urinary excretion of glycolateDeficiency of alanine:glyoxylate aminotransferase in liver peroxisomesType 2Increased urinary excretion of L-glycerateDeficiencies of both D-glycerate dehydrogenase and glycosylate reductase in hepatocytes and leukocytesType 3Non-type-1, non-type-2 primary hyperoxaluriaUnidentified enzyme defect Open table in a new tab Because PH1 is a rare, orphan disease, its diagnosis is often delayed and its initial management inappropriate. The medical history of this young woman raises the crucial paradox of successful enzyme replacement and subsequent uncertain quality of life following combined kidney-liver transplantation. This case illustrates the epidemiology and natural history of this disease, as I will discuss in this Nephrology Forum. The average prevalence rate of PH1 has been estimated to be 1.05/106/year and its average incidence rate 0.12/106/year in France (that is, 1:120,000 live births); it is much more frequent when parental consanguinity is present, as in many pedigrees of Muslim families1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar,5.Cochat P. Deloraine A. Rotily M. Olive F. Liponski I. Deries N. on behalf of the Socíeté de Néphrologie and the Société de Néphrologie Pédiatrique Epidemiology of primary hyperoxaluria type 1.Nephrol Dial Transplant. 1995; 10: 3-7Crossref PubMed Scopus (140) Google Scholar. Above all, the approach to diagnosis and management of PH1 is determined by the socioeconomic condition of the country of origin Table 2. As illustrated by the case report, the median age at onset of initial symptoms is five years, ranging from birth to the sixth decade; end-stage renal disease (ESRD) is reached by the age of 15 years in one-half of PH1 patients5.Cochat P. Deloraine A. Rotily M. Olive F. Liponski I. Deries N. on behalf of the Socíeté de Néphrologie and the Société de Néphrologie Pédiatrique Epidemiology of primary hyperoxaluria type 1.Nephrol Dial Transplant. 1995; 10: 3-7Crossref PubMed Scopus (140) Google Scholar. Primary hyperoxaluria type 1 presents with symptoms referable to the urinary tract in more than 80% of cases: loin pain, hematuria, urinary tract infections, or passage of a stone5.Cochat P. Deloraine A. Rotily M. Olive F. Liponski I. Deries N. on behalf of the Socíeté de Néphrologie and the Société de Néphrologie Pédiatrique Epidemiology of primary hyperoxaluria type 1.Nephrol Dial Transplant. 1995; 10: 3-7Crossref PubMed Scopus (140) Google Scholar. Calculi—multiple, bilateral, and radioopaque—are composed of calcium oxalate and accompanied by monohydrate calcium oxalate crystalluria (whewhellite). Nephrocalcinosis, best demonstrated by ultrasound, is present on plain abdominal radiograph at an advanced stage. Most patients develop ESRD over a short period, and infants usually have the most rapid course6.Cochat P. Deloraine A. Olive F. Rolland M.O. Gillet Y. Divry P. Schärer K. Primary hyperoxaluria type 1: The therapeutic dilemma.Adv Nephrol. 1995; 24: 227-242Google Scholar. When the GFR falls to below 20 to 40 ml/min/1.73 m2, continued overproduction of oxalate by the liver along with reduced oxalate excretion by the kidneys leads to increasing oxalate deposition in many organs6.Cochat P. Deloraine A. Olive F. Rolland M.O. Gillet Y. Divry P. Schärer K. Primary hyperoxaluria type 1: The therapeutic dilemma.Adv Nephrol. 1995; 24: 227-242Google Scholar,7.Morgan S.H. Purkiss P. Watts Rwe Mansell M.A. Oxalate dynamics in chronic renal failure: Comparison with normal subjects and patients with primary hyperoxaluria.Nephron. 1987; 46: 253-257Crossref PubMed Google Scholar. Tissue biopsy analyses, rarely required at present for diagnosis, should be limited to patients whose biochemistry and enzyme analyses are not available; I will discuss patients considering liver transplantation in a moment. Infantile oxalosis often presents as a life-threatening disease because of both oxalate load and immature GFR; death can ensue by the age of one year1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar,4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar. On the other hand, some patients are asymptomatic, and PH1 is discovered by family screening.Table 2Current worldwide approach of PH1: The paradoxDeveloped countriesDeveloping countriesIncidence rateLowHigh (when consanguinity is present)Diagnostic procedure Clinical observation+++ Family history+++ Radiology/sonography+++ Kidney/bone biopsy+++ UoxaAbbreviations are: Uox, urine oxalate; Ugl, urine glycolate; AGT, alanine:glyoxylate aminotransferase; Tx, transplantation.+++ Ugl+- AGT activity++- DNA analysis++-Prenatal diagnosis Requirement+++ Availability++-Treatment Conservative+++ Dialysis±++ Kidney Tx±++ Liver-kidney Tx++- Withdrawal-++a Abbreviations are: Uox, urine oxalate; Ugl, urine glycolate; AGT, alanine:glyoxylate aminotransferase; Tx, transplantation. Open table in a new tab Bone is the major compartment of the insoluble oxalate pool, and therefore bone disease is the most disabling complication of oxalosis that cannot be prevented by regular dialysis treatment. Bone oxalate concentration is negligible in normal subjects, whereas it reaches 5.1 ± 3.6 μmol/g of bony tissue in dialyzed patients without PH and 15 to 907 μmol/g in dialyzed patients with PH8.Marangella M. Vitale C. Petrarulo M. Tricerri A. Cerelli E. Cadario A. Portigliatti Barbos M. Linari F. Bony content of oxalate in patients with primary hyperoxaluria or oxalosis-unrelated renal failure.Kidney Int. 1995; 48: 182-187Abstract Full Text PDF PubMed Scopus (41) Google Scholar. Calcium oxalate crystal deposition is progressive and related to time on dialysis. It also affects the histomorphometric patterns. That is, oxalate deposition increases resorptive areas and decreases bone formation rate8.Marangella M. Vitale C. Petrarulo M. Tricerri A. Cerelli E. Cadario A. Portigliatti Barbos M. Linari F. Bony content of oxalate in patients with primary hyperoxaluria or oxalosis-unrelated renal failure.Kidney Int. 1995; 48: 182-187Abstract Full Text PDF PubMed Scopus (41) Google Scholar. Along with the skeleton, systemic involvement includes many organs: heart (cardiomyopathy, conduction defects), nerves (peripheral neuropathy, mononeuritis multiplex), joints (synovitis), arteries (disseminated occlusive vascular lesions, limb gangrene, arteriovenous fistula thrombosis), skin (ulcerating subcutaneous calcium oxalate calcinosis, livedo reticularis), soft tissues, and retina1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar,9.Watts Rwe Mansell M.A. Oxalate livers and kidneys: Combined renal and hepatic transplants transform the outlook in primary hyperoxaluria type 1.BMJ. 1990; 301: 772-773Crossref Scopus (8) Google Scholar. The oxalate burden varies considerably from one individual to another, and transplantation ideally should precede advanced systemic oxalate storage. Criteria for estimating the prediction of further changes in GFR and allowing timely assessment of the oxalate burden are needed. It does appear that close monitoring of GFR, plasma oxalate-to-plasma creatinine (Pox:Pcr) ratio, plasma calcium oxalate saturation, and possibly systemic involvement (as assessed by bone histology, dual-energy x-ray absorptiometry, oxalate metabolic pool size, tissue oxalate accretion rate), should assist in timing transplantation6.Cochat P. Deloraine A. Olive F. Rolland M.O. Gillet Y. Divry P. Schärer K. Primary hyperoxaluria type 1: The therapeutic dilemma.Adv Nephrol. 1995; 24: 227-242Google Scholar, 8.Marangella M. Vitale C. Petrarulo M. Tricerri A. Cerelli E. Cadario A. Portigliatti Barbos M. Linari F. Bony content of oxalate in patients with primary hyperoxaluria or oxalosis-unrelated renal failure.Kidney Int. 1995; 48: 182-187Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 10.Marangella M. Cossedu D. Petrarulo M. Vitale C. Linari F. Thresholds of serum calcium oxalate supersaturation in relation to renal function in patients with or without primary hyperoxaluria.Nephrol Dial Transplant. 1993; 8: 1333-1337PubMed Google Scholar. Primary hyperoxaluria type 1 can be diagnosed by measurement of urine oxalate (Uox) and glycolate (Ugl) excretion rates and by plasma oxalate measurement Table 3. Concomitant hyperoxaluria and hyperglycolic aciduria are indicative of PH1, but some patients with PH1 do not have hyperglycolic aciduria4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar.Table 3Plasma and urine concentrations of oxalate and glycolate: Normal values1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar, 11.Gaulier J.M. Cochat P. Lardet G. Vallon J.J. Serum oxalate microassay using chemiluminescence detection.Kidney Int. 1997; 52: 1700-1703Abstract Full Text PDF Scopus (11) Google Scholar, 12.Kasidas G.P. Plasma and urine measurements for monitoring of treatment in the primary hyperoxaluria patient.Nephrol Dial Transplant. 1995; 10: 8-10Crossref Scopus (8) Google Scholar, 13.Barratt T.M. Kasidas G.P. Murdoch I. Rose G.A. Urinary oxalate and glycolate excretion and plasma oxalate concentration.Arch Dis Child. 1991; 66: 501-503Crossref PubMed Scopus (62) Google Scholar, 14.Matos V, Van Melle G, Werners D, Bardy D, Guignard JP: Urinary oxalate and rate to creatinine ratios in a healthy pediatric population. Am J Kidney Dis (in press)Google ScholarUrineUox/24 hrChild<0.46 mmol/1.73 m2Adult<0.40 mmol/1.73 m2Uox/Ucr<1 year<0.25 mmol/mmol1–4 years<0.13 mmol/mmol5–12 years<0.07 mmol/mmolAdult<0.08 mmol/mmolUgl/24 hrsChild<0.55 mmol/1.73 m2Adult<0.26 mmol/1.73 m2Ugl/Ucr<1 year<0.07 mmol/mmol1–4 years<0.09 mmol/mmol5–12 years<0.05 mmol/mmolAdult<0.04 mmol/mmolPlasmaPoxChild<7.4 μmol/literAdult<5.4 μmol/literPox/PcrChild<0.189 μmol/μmolAdult<0.055 μmol/μmolAbbreviations are: Uox, urine oxalate; Ucr, urine creatinine; Ugl, urine glycolate; Pox, plasma oxalate; Pcr, plasma creatinine. Open table in a new tab Abbreviations are: Uox, urine oxalate; Ucr, urine creatinine; Ugl, urine glycolate; Pox, plasma oxalate; Pcr, plasma creatinine. Sample collection and storage conditions are critical to securing meaningful results for diagnosis and treatment. Indeed, Pox measurement can be influenced by in-vitro generation of oxalate from ascorbate, blood pH, and certain drugs; preferred collection methods are oxalate oxidase-based coupled with a colorimetric detection using chemiluminescence, ion chromatography, or high-performance liquid chromatography11.Gaulier J.M. Cochat P. Lardet G. Vallon J.J. Serum oxalate microassay using chemiluminescence detection.Kidney Int. 1997; 52: 1700-1703Abstract Full Text PDF Scopus (11) Google Scholar,12.Kasidas G.P. Plasma and urine measurements for monitoring of treatment in the primary hyperoxaluria patient.Nephrol Dial Transplant. 1995; 10: 8-10Crossref Scopus (8) Google Scholar. Both Uox and Ugl can be assessed by an oxalate oxidase-based kit, gas chromatography coupled with mass spectrometry, or isotope dilution1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar,12.Kasidas G.P. Plasma and urine measurements for monitoring of treatment in the primary hyperoxaluria patient.Nephrol Dial Transplant. 1995; 10: 8-10Crossref Scopus (8) Google Scholar. Alanine:glyoxylate aminotransferase (AGT) catalytic activity can be assessed in a freshly frozen liver specimen (2 mg of liver tissue) taken by percutaneous needle biopsy. However, glutamate:glyoxylate aminotransferase (GGT) also can catalyze alanine:glyoxylate transamination to the level of around 65%; therefore the GGT assay must be coupled and the appropriate correction made for the crossover15.Danpure C.J. Jennings P.R. Further studies on the activity and subcellular distribution of alanine:glyoxylate aminotransferase in the livers of patients with primary hyperoxaluria type 1.Clin Sci. 1988; 75: 315-322Crossref PubMed Scopus (56) Google Scholar. Immunoreactive AGT protein can be assessed by immunoblotting and is much more stable than AGT catalytic activity16.Wise P.J. Danpure C.J. Jennings P.R. Immunological heterogeneity of hepatic alanine:glyoxylate aminotransferase in primary hyperoxaluria type 1.FEBS Lett. 1987; 222: 17-20Abstract Full Text PDF PubMed Scopus (37) Google Scholar. However, patients with AGT activity between 15% and 50% cannot be distinguished from carriers on the basis of catalytic activity alone, and the intracellular distribution of immunoreactive AGT must be documented by immunoelectron microscopy4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar. In our experience of patients with a presumptive diagnosis of PH Table 4, 14% were identified as non-PH1 because AGT activity and immunoreactivity were normal. Although 82% of PH1 patients have undetectable levels of AGT catalytic activity (enz-), the remainder have activities in a range of 5% to 50% of the mean normal activity (enz+); most of enz- (10 of 12) patients also have no immunoreactive AGT protein (crm-); in enz+ patients the level of immunoreactive protein parallels the level of enzyme activity. These data are comparable to those obtained by Danpure and Rumsby4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar. There is no clear relationship between residual AGT catalytic activity and clinical severity in PH1.Table 4AGT catalytic activity (N = 51) and DNA analysis (N = 25) in patients presenting with a presumptive diagnosis of primary hyperoxaluriaAGT catalytic activity<5%N = 36 (70%)enz-5%–50%N = 8 (16%)enz+NormalN = 7 (14%)PH1 excludedDNA analysisPolymorphismsIVS1 duplication16 (64%)Pro11Leu16 (64%)MutationsGly41Arg0Gly82Glu1 (4%)Phe152Ile3 (12%)Gly170Arg5 (20%)Complete deletion of the gene1 (4%)Abbreviations are: AGT, alanine:glyoxylate aminotransferase; enz-, undetectable AGT catalytic activity; enz+, significant or normal AGT catalytic activity. Open table in a new tab Abbreviations are: AGT, alanine:glyoxylate aminotransferase; enz-, undetectable AGT catalytic activity; enz+, significant or normal AGT catalytic activity. In normal human hepatocytes, AGT, exclusively localized within the peroxisome, is unable to achieve its metabolic function (that is, glyoxylate detoxification) when located within the mitochondria1.Barratt TM,Danpure CJ:Hyperoxaluria, inPediatricNephrology (3rd ed), edited by HollidayMA, Barratt TM, Avner ED, Baltimore, Williams & Wilkins, 1994, p 557Google Scholar,17.Cooper P.J. Danpure C.J. Wise P.J. Gutridge K.M. Immunocytochemical localization of human hepatic alanine:glyoxylate aminotransferase in control subjects and patients with primary hyperoxaluria type 1.J Histochem Cytochem. 1988; 36: 1285-1294Crossref PubMed Scopus (55) Google Scholar. In most enz-/crm+ PH1 patients, the immunoreactive but catalytically defunct AGT is also localized totally within the peroxisomes; in enz+/crm+ PH1 patients, 90% of the immunoreactive AGT is localized in the mitochondria and only 10% in the peroxisome4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar,18.Danpure C.J. Cooper P.J. Wise P.J. Jennings P.R. An enzyme trafficking defect in two patients with primary hyperoxaluria type 1: Peroxisomal alanine:glyoxylate aminotransferase rerouted to mitochondria.J Cell Biol. 1989; 108: 1345-1352Crossref PubMed Scopus (136) Google Scholar. Polymorphic variations have been identified in AGXT (74 bp duplication within intron 1, Pro11Leu substitution); such a minor allele is present in 20% of normal Caucasoids4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar. So far, 15 to 20 mutations in genomic DNA have been identified and might play a role in enzyme trafficking4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar: for example, Gly170Arg substitution is found in 30% of PH1 patients and appears to act with Pro11Leu polymorphism, leading to peroxisome-to-mitochondrion AGT mistargeting; and Gly82Glu mutation is associated with normal localization but loss of catalytic activity. The study of DNA among different ethnic groups has revealed clinically relevant information. The minor allele has a frequency of only 2% in Japanese populations4.Danpure C.J. Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type 1: Consequences for clinical management.Calcium Oxalate in Biological Systems. CRC Press, Boca Raton1995Google Scholar. In our experience, the complete deletion of the AGXT gene has been
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