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Primary hyperoxaluria, type I(HP1)

MedGen UID:
75658
Concept ID:
C0268164
Disease or Syndrome
Synonyms: Glycolic aciduria; Hepatic AGT deficiency; HP1; Oxalosis 1; OXALOSIS I; Peroxisomal alanine glyoxylate aminotransferase deficiency; Primary hyperoxaluria type 1; Serine pyruvate aminotransferase deficiency
SNOMED CT: Primary hyperoxaluria, type I (65520001); Glycolic aciduria (65520001); Alanine-glyoxylate aminotransferase deficiency (65520001); 2-Oxoglutarate glyoxylate carboligase deficiency (65520001); Oxalosis type I (65520001); Primary hyperoxaluria type I (65520001); Alanine-glycoxylate aminotransferase deficiency (65520001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): AGXT (2q37.3)
 
Monarch Initiative: MONDO:0009823
OMIM®: 259900
Orphanet: ORPHA93598

Disease characteristics

Excerpted from the GeneReview: Primary Hyperoxaluria Type 1
Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD). Age at onset of symptoms ranges from infancy to the sixth decade. Approximately 10% of affected individuals present in infancy or early childhood with nephrocalcinosis, with or without nephrolithiasis, and failure to thrive related to renal failure. The majority of individuals with PH1 present in childhood or early adolescence, usually with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in renal function as a result of calcium oxalate deposits in kidney tissue and complications of nephrolithiasis (e.g., obstruction and infection) with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD and/or complications of oxalosis. [from GeneReviews]
Authors:
Dawn S Milliner  |  Peter C Harris  |  David J Sas, et. al.   view full author information

Additional descriptions

From OMIM
Primary hyperoxaluria type I is an autosomal recessive disorder characterized by an accumulation of calcium oxalate in various bodily tissues, especially the kidney, resulting in renal failure. Affected individuals have decreased or absent AGXT activity and a failure to transaminate glyoxylate, which causes the accumulated glyoxylate to be oxidized to oxalate. This overproduction of oxalate results in the accumulation of nonsoluble calcium oxalate in various body tissues, with pathologic sequelae (Takada et al., 1990; Danpure et al., 1989; Williams et al., 2009) Genetic Heterogeneity of Primary Hyperoxaluria Type II primary hyperoxaluria (HP2; 260000) is caused by mutation in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296) on chromosome 9. Type III primary hyperoxaluria (HP3; 613616) is caused by mutation in the mitochondrial dihydrodipicolinate synthase-like gene (DHDPSL; 613597) on chromosome 10q24.  http://www.omim.org/entry/259900
From MedlinePlus Genetics
Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end stage renal disease (ESRD), which is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.

Primary hyperoxaluria results from the overproduction of a substance called oxalate. Oxalate is filtered through the kidneys and excreted as a waste product in urine, leading to abnormally high levels of this substance in urine (hyperoxaluria). During its excretion, oxalate can combine with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Deposits of calcium oxalate can damage the kidneys and other organs and lead to blood in the urine (hematuria), urinary tract infections, kidney damage, ESRD, and injury to other organs. Over time, kidney function decreases such that the kidneys can no longer excrete as much oxalate as they receive. As a result oxalate levels in the blood rise, and the substance gets deposited in tissues throughout the body (systemic oxalosis), particularly in bones and the walls of blood vessels. Oxalosis in bones can cause fractures.

There are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary hyperoxaluria type 1, kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary hyperoxaluria type 3, affected individuals often develop kidney stones in early childhood, but few cases of this type have been described so additional signs and symptoms of this type are unclear.  https://medlineplus.gov/genetics/condition/primary-hyperoxaluria

Clinical features

From HPO
Gangrene
MedGen UID:
6546
Concept ID:
C0017086
Disease or Syndrome
A serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies (necrosis).
Bone pain
MedGen UID:
57489
Concept ID:
C0151825
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Disease or Syndrome
The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).
Hyperoxaluria
MedGen UID:
43782
Concept ID:
C0020500
Disease or Syndrome
Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end stage renal disease (ESRD), which is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.\n\nPrimary hyperoxaluria results from the overproduction of a substance called oxalate. Oxalate is filtered through the kidneys and excreted as a waste product in urine, leading to abnormally high levels of this substance in urine (hyperoxaluria). During its excretion, oxalate can combine with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Deposits of calcium oxalate can damage the kidneys and other organs and lead to blood in the urine (hematuria), urinary tract infections, kidney damage, ESRD, and injury to other organs. Over time, kidney function decreases such that the kidneys can no longer excrete as much oxalate as they receive. As a result oxalate levels in the blood rise, and the substance gets deposited in tissues throughout the body (systemic oxalosis), particularly in bones and the walls of blood vessels. Oxalosis in bones can cause fractures.\n\nThere are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary hyperoxaluria type 1, kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary hyperoxaluria type 3, affected individuals often develop kidney stones in early childhood, but few cases of this type have been described so additional signs and symptoms of this type are unclear.
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Nephrolithiasis, calcium oxalate
MedGen UID:
318935
Concept ID:
C1833683
Disease or Syndrome
Kleta (2006) reviewed aspects of renal stone disease. Nephrolithiasis and urolithiasis remain major public health problems of largely unknown cause. While disorders such as cystinuria (220100) and primary hyperoxaluria (see 259900) that have nephrolithiasis as a major feature have advanced understanding of the metabolic and physiologic processes of stone formation in general, they have not addressed the etiology of calcium oxalate stone formation, responsible for approximately 75% of urolithiasis cases in humans. Men are affected twice as often as women, but children show no such gender bias. The recurrence rate is also high. In populations of European ancestry, 5 to 10% of adults experience the painful precipitation of calcium oxalate in their urinary tracts. Thorleifsson et al. (2009) noted that between 35 and 65% of hypercalciuric stone formers and up to 70% of subjects with hypercalciuria have relatives with nephrolithiasis, and twin studies have estimated the heritability of kidney stones to be 56%. Genetic Heterogeneity of Calcium Oxalate Nephrolithiasis See also CAON2 (620374), caused by mutation in the OXGR1 gene (606922) on chromosome 13q32.
Elevated urinary glycolic acid level
MedGen UID:
1053695
Concept ID:
CN377027
Finding
The amount of glycolic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Atrioventricular block
MedGen UID:
13956
Concept ID:
C0004245
Disease or Syndrome
Delayed or lack of conduction of atrial depolarizations through the atrioventricular node to the ventricles.
Intermittent claudication
MedGen UID:
7115
Concept ID:
C0021775
Disease or Syndrome
Intermittent claudication is a symptom of peripheral arterial occlusive disease. After having walked over a distance which is individually characteristic, the patients experience pain or cramps in the calves, feet or thighs which typically subsides on standing still.
Raynaud phenomenon
MedGen UID:
20474
Concept ID:
C0034735
Disease or Syndrome
An episodic vasoconstriction resulting in discoloration of the skin and pain in the affected areas, often involving fingers or toes. Classically associated with triphasic color changes (white, blue, red) but may be biphasic. Often occurs in response to cold temperatures or emotional stress. May be primary or secondary to an underlying autoimmune disease.
Arterial occlusion
MedGen UID:
78117
Concept ID:
C0264995
Pathologic Function
Blockage of blood flow through an artery.
Peripheral arterial stenosis
MedGen UID:
870815
Concept ID:
C4025272
Disease or Syndrome
Narrowing of peripheral arteries with reduction of blood flow to the limbs. This feature may be quantified as an ankle-brachial index of less than 0.9, and may be manifested clinically as claudication.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Calcinosis cutis
MedGen UID:
472879
Concept ID:
C0006664
Disease or Syndrome
Deposition of calcium in the skin.
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
A pathologic fracture occurs when a bone breaks in an area that is weakened secondarily to another disease process such as tumor, infection, and certain inherited bone disorders. A pathologic fracture can occur without a degree of trauma required to cause fracture in healthy bone.
Increased bone mineral density
MedGen UID:
10502
Concept ID:
C0029464
Disease or Syndrome
An abnormal increase of bone mineral density, that is, of the amount of matter per cubic centimeter of bones which is often referred to as osteosclerosis. Osteosclerosis can be detected on radiological examination as an increased whiteness (density) of affected bones.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Reduced hepatic alanine-glyoxylate aminotransferase activity
MedGen UID:
1841836
Concept ID:
C5826829
Finding
Activity of alanine-glyoxylate aminotransferase in the liver below the lower limit of normal.
Acrocyanosis
MedGen UID:
65138
Concept ID:
C0221347
Finding
Bluish discoloration of the skin of the hands or feet.
Cutis marmorata
MedGen UID:
78093
Concept ID:
C0263401
Disease or Syndrome
A reticular discoloration of the skin with cyanotic (reddish-blue appearing) areas surrounding pale central areas due to dilation of capillary blood vessels and stagnation of blood within the vessels. Cutis marmorata generally occurs on the legs, arms and trunk and is often more severe in cold weather.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Retinopathy
MedGen UID:
11209
Concept ID:
C0035309
Disease or Syndrome
Any noninflammatory disease of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Choroidal neovascularization
MedGen UID:
154726
Concept ID:
C0600518
Pathologic Function
Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye.
Optic neuropathy
MedGen UID:
854546
Concept ID:
C3887709
Disease or Syndrome
Disorder of the optic nerve.
Retinal crystals
MedGen UID:
892979
Concept ID:
C4072992
Finding
Crystalline deposits in the retina.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Primary hyperoxaluria, type I in Orphanet.

Professional guidelines

PubMed

Weerakkody RM
Saudi J Kidney Dis Transpl 2016 Nov-Dec;27(6):1283-1284. doi: 10.4103/1319-2442.194694. PMID: 27900983
Xu H, Zisman AL, Coe FL, Worcester EM
Expert Opin Pharmacother 2013 Mar;14(4):435-47. doi: 10.1517/14656566.2013.775250. PMID: 23438422Free PMC Article
Broyer M, Jouvet P, Niaudet P, Daudon M, Revillon Y
Kidney Int Suppl 1996 Jan;53:S93-8. PMID: 8770999

Recent clinical studies

Etiology

Merz LM, Born M, Kukuk G, Sprinkart AM, Becker I, Martin-Higueras C, Hoppe B
Pediatr Nephrol 2023 Jul;38(7):2083-2092. Epub 2022 Dec 6 doi: 10.1007/s00467-022-05836-3. PMID: 36472654
Lin JA, Liao X, Wu W, Xiao L, Liu L, Qiu J
Urolithiasis 2021 Oct;49(5):425-431. Epub 2021 Mar 15 doi: 10.1007/s00240-021-01249-3. PMID: 33721035Free PMC Article
Kotb MA, Hamza AF, Abd El Kader H, El Monayeri M, Mosallam DS, Ali N, Basanti CWS, Bazaraa H, Abdelrahman H, Nabhan MM, Abd El Baky H, El Sorogy STM, Kamel IEM, Ismail H, Ramadan Y, Abd El Rahman SM, Soliman NA
Pediatr Transplant 2019 Feb;23(1):e13313. Epub 2018 Nov 26 doi: 10.1111/petr.13313. PMID: 30475440
Bruel A, Bacchetta J, Ginhoux T, Rodier-Bonifas C, Sellier-Leclerc AL, Fromy B, Cochat P, Sigaudo-Roussel D, Dubourg L
Pediatr Nephrol 2019 Feb;34(2):319-327. Epub 2018 Oct 1 doi: 10.1007/s00467-018-4081-5. PMID: 30276532
Oppici E, Dindo M, Conter C, Borri Voltattorni C, Cellini B
Handb Exp Pharmacol 2018;245:313-343. doi: 10.1007/164_2017_59. PMID: 29071511

Diagnosis

Merz LM, Born M, Kukuk G, Sprinkart AM, Becker I, Martin-Higueras C, Hoppe B
Pediatr Nephrol 2023 Jul;38(7):2083-2092. Epub 2022 Dec 6 doi: 10.1007/s00467-022-05836-3. PMID: 36472654
Recker P, Beck BB, Sikora P, Göbel H, Kemper MJ, Nazco A, Martin-Higueras C, Hoppe B
Sci Rep 2022 Oct 6;12(1):16725. doi: 10.1038/s41598-022-19584-9. PMID: 36202824Free PMC Article
Lin JA, Liao X, Wu W, Xiao L, Liu L, Qiu J
Urolithiasis 2021 Oct;49(5):425-431. Epub 2021 Mar 15 doi: 10.1007/s00240-021-01249-3. PMID: 33721035Free PMC Article
Hoppe B
Nat Rev Nephrol 2012 Jun 12;8(8):467-75. doi: 10.1038/nrneph.2012.113. PMID: 22688746
Latta K, Brodehl J
Eur J Pediatr 1990 May;149(8):518-22. doi: 10.1007/BF01957682. PMID: 2189732

Therapy

Dindo M, Conter C, Oppici E, Ceccarelli V, Marinucci L, Cellini B
Urolithiasis 2019 Feb;47(1):67-78. Epub 2018 Nov 14 doi: 10.1007/s00240-018-1089-z. PMID: 30430197
Bruel A, Bacchetta J, Ginhoux T, Rodier-Bonifas C, Sellier-Leclerc AL, Fromy B, Cochat P, Sigaudo-Roussel D, Dubourg L
Pediatr Nephrol 2019 Feb;34(2):319-327. Epub 2018 Oct 1 doi: 10.1007/s00467-018-4081-5. PMID: 30276532
Oppici E, Dindo M, Conter C, Borri Voltattorni C, Cellini B
Handb Exp Pharmacol 2018;245:313-343. doi: 10.1007/164_2017_59. PMID: 29071511
Xu H, Zisman AL, Coe FL, Worcester EM
Expert Opin Pharmacother 2013 Mar;14(4):435-47. doi: 10.1517/14656566.2013.775250. PMID: 23438422Free PMC Article
Latta K, Brodehl J
Eur J Pediatr 1990 May;149(8):518-22. doi: 10.1007/BF01957682. PMID: 2189732

Prognosis

Lin JA, Liao X, Wu W, Xiao L, Liu L, Qiu J
Urolithiasis 2021 Oct;49(5):425-431. Epub 2021 Mar 15 doi: 10.1007/s00240-021-01249-3. PMID: 33721035Free PMC Article
Kotb MA, Hamza AF, Abd El Kader H, El Monayeri M, Mosallam DS, Ali N, Basanti CWS, Bazaraa H, Abdelrahman H, Nabhan MM, Abd El Baky H, El Sorogy STM, Kamel IEM, Ismail H, Ramadan Y, Abd El Rahman SM, Soliman NA
Pediatr Transplant 2019 Feb;23(1):e13313. Epub 2018 Nov 26 doi: 10.1111/petr.13313. PMID: 30475440
Oppici E, Montioli R, Cellini B
Biochim Biophys Acta 2015 Sep;1854(9):1212-9. Epub 2015 Jan 22 doi: 10.1016/j.bbapap.2014.12.029. PMID: 25620715
Latta K, Brodehl J
Eur J Pediatr 1990 May;149(8):518-22. doi: 10.1007/BF01957682. PMID: 2189732
Watts RW, Calne RY, Williams R, Mansell MA, Veall N, Purkiss P, Rolles K
Q J Med 1985 Oct;57(222):697-703. PMID: 3909198

Clinical prediction guides

Recker P, Beck BB, Sikora P, Göbel H, Kemper MJ, Nazco A, Martin-Higueras C, Hoppe B
Sci Rep 2022 Oct 6;12(1):16725. doi: 10.1038/s41598-022-19584-9. PMID: 36202824Free PMC Article
Bruel A, Bacchetta J, Ginhoux T, Rodier-Bonifas C, Sellier-Leclerc AL, Fromy B, Cochat P, Sigaudo-Roussel D, Dubourg L
Pediatr Nephrol 2019 Feb;34(2):319-327. Epub 2018 Oct 1 doi: 10.1007/s00467-018-4081-5. PMID: 30276532
Dindo M, Oppici E, Dell'Orco D, Montone R, Cellini B
J Inherit Metab Dis 2018 Mar;41(2):263-275. Epub 2017 Nov 6 doi: 10.1007/s10545-017-0105-8. PMID: 29110180
Oppici E, Montioli R, Cellini B
Biochim Biophys Acta 2015 Sep;1854(9):1212-9. Epub 2015 Jan 22 doi: 10.1016/j.bbapap.2014.12.029. PMID: 25620715
Watts RW, Calne RY, Williams R, Mansell MA, Veall N, Purkiss P, Rolles K
Q J Med 1985 Oct;57(222):697-703. PMID: 3909198

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