SNOMEDCT: 734990008; ORPHA: 416, 93600; DO: 0111672;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q24.2 | Hyperoxaluria, primary, type III | 613616 | Autosomal recessive | 3 | HOGA1 | 613597 |
A number sign (#) is used with this entry because of evidence that primary hyperoxaluria type III (HP3) is caused by homozygous or compound heterozygous mutation in the HOGA1 gene (613597) on chromosome 10q24.
Primary hyperoxaluria is an autosomal recessive disorder of glyoxylate metabolism that results in excessive endogenous oxalate synthesis and the formation of calcium oxalate kidney stones. Progressive renal inflammation and interstitial fibrosis from advanced nephrocalcinosis, recurrent urolithiasis, and urinary tract infections can cause reduced renal function, systemic oxalate deposition, and end-stage renal failure. Compared to hyperoxaluria type I (HP1; 259900) and type II (HP2; 260000), HP3 appears to be the least severe, with good preservation of kidney function in most patients. The typical clinical characteristic is early onset of recurrent urolithiasis, but less active stone formation later (summary by Wang et al., 2015).
For a discussion of genetic heterogeneity of primary hyperoxaluria, see 259900.
Monico et al. (2011) compared 25 patients with primary hyperoxaluria type III from 19 unrelated families to patients with primary hyperoxaluria type I and type II. Patients with HP3 had lower urine oxalate and higher urine calcium and uric acid when compared to those with HP1 and HP2. HP3 was also characterized by symptomatic calcium oxalate stone disease early in life, with half of patients presenting with stones by age 5 years. After a median follow-up of 7.2 years, mean estimated glomerular filtration rate was 116 mL/min per 1.73 m-2. None of the patients had progressed to end-stage renal disease. The authors also identified 2 patients with mild hyperoxaluria, both of whom developed symptoms in adulthood, and 3 of 100 idiopathic calcium oxalate stone formers who were heterozygous for mutations in the HOGA1 gene.
Wang et al. (2015) reported a 27-month-old Chinese boy with primary hyperoxaluria type III. Age of onset was 10 months when he presented with bilateral renal calculi, multiple bladder stones, and upper ureteral calculi. Clinical features included early onset of nephrolithiasis, abnormal increase in urinary excretion levels of oxalate and calcium, and decreased level of citrate. At age 27 months, his renal function was normal.
Among 7 patients from 6 different families with primary hyperoxaluria type III identified by Allard et al. (2015), 5 patients presented with urolithiasis and 2 presented with urinary tract infection that subsequently led to a diagnosis of urolithiasis. Median age of onset of symptoms was 1.8 years (range, 0.4-9.8), with onset before age 3 years in 5 patients. Urine crystal analysis, performed in 4 patients, showed monohydrated calcium oxalate. All patients had persistent hyperoxaluria. Urine calcium excretion was normal in all but 1 patient. Urine excretion of glycolate was normal in all patients tested. At last follow-up, 2 patients had significantly impaired renal function, evidenced by abnormal glomerular filtration rates of 77 and 83 mL/min per 1.73 m2 at 12.4 and 3.5 years of age, respectively. Three heterozygous parents in these families had a history of urolithiasis, raising the possibility that heterozygous mutations could lead to mild forms of HP3; however, because no investigations of the kidney stones were performed, other causes of the urolithiasis could not be ruled out.
M'dimegh et al. (2017) identified 3 unrelated Tunisian patients, who ranged in age from 2 to 8 years, with primary hyperoxaluria type III. All 3 patients were born to consanguineous parents. The median age of onset of clinical symptoms was 3.93 years, with a range of 1.5 to 5.5 years. All patients had normal renal function at diagnosis. Two of the families had a positive family history for urolithiasis. All patients presented with urolithiasis, but only one had nephrocalcinosis. Urine crystal analysis, performed in 2 cases, revealed monohydrated calcium oxalate. One patient displayed impaired renal function at follow-up.
The transmission pattern of HP3 in the family reported by Belostotsky et al. (2010) was consistent with autosomal recessive inheritance.
Belostotsky et al. (2010) performed high-density SNP array analysis in 15 patients with non-HP1/non-HP2 calcium oxalate nephrolithiasis and 24 unaffected relatives from 8 unrelated families. Using a strategy of 'heterozygosity mapping' followed by reconstruction of haplotypes, they identified a 6.1-Mb critical region on chromosome 10 containing 19 genes.
In affected members of 9 unrelated families with non-HP1/non-HP2 calcium oxalate nephrolithiasis mapping to chromosome 10, Belostotsky et al. (2010) analyzed the candidate gene DHDPSL and identified homozygosity or compound heterozygosity for 6 different mutations (613597.0001-613597.0006, respectively). The unaffected parents were all heterozygous for 1 of the mutations, respectively.
In a 27-month-old Chinese boy with primary hyperoxaluria in whom mutations in the AGXT (604285) and GRHPR (604296) genes had been excluded, Wang et al. (2015) identified compound heterozygous mutations in the HOGA1 gene (613597.0007 and 613597.0008). The parents were each heterozygous for one of the mutations.
Among 7 patients from 6 different families with HP3, Allard et al. (2015) identified 7 different homozygous or compound heterozygous mutations in the HOGA1 gene.
In 3 unrelated boys, born to consanguineous Tunisian parents, with primary hyperoxaluria, who did not have mutations in the AGXT or GRHPR genes, M'dimegh et al. (2017) identified mutations in the HOGA1 gene: 2 boys were homozygous for a P190L and a G287V (613597.0002) mutation, respectively, and the other boy was heterozygous for the G287V mutation. Two of the families had a positive family history for recurrent urolithiasis.
Allard, L., Cochat, P., Leclerc, A.-L., Cachat, F., Fichtner, C., De Souza, V. C., Garcia, C. D., Camoin-Schweitzer, M.-C., Macher, M.-A., Acquaviva-Bourdain, C., Bacchetta, J. Renal function can be impaired in children with primary hyperoxaluria type 3. Pediat. Nephrol. 30: 1807-1813, 2015. [PubMed: 25972204] [Full Text: https://doi.org/10.1007/s00467-015-3090-x]
Belostotsky, R., Seboun, E., Idelson, G. H., Milliner, D. S., Becker-Cohen, R., Rinat, C., Monico, C. G., Feinstein, S., Ben-Shalom, E., Magen, D., Weissman, I., Charon, C., Frishberg, Y. Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am. J. Hum. Genet. 87: 392-399, 2010. [PubMed: 20797690] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.023]
M'dimegh, S., Aquaviva-Bourdain, C., Omezzine, A., Souche, G., M'barek, I., Abidi, K., Gargah, T., Abroug, S., Bouslama, A. HOGA1 gene mutations of primary hyperoxaluria type 3 in Tunisian patients. J. Clin. Lab. Anal. 31: e22053, 2017. Note: Electronic Article. [PubMed: 27561601] [Full Text: https://doi.org/10.1002/jcla.22053]
Monico, C. G., Rossetti, S., Belostotsky, R., Cogal, A. G., Herges, R. M., Seide, B. M., Olson J. B., Bergstrahl, E. J., Williams, H. J., Haley, W. E., Frishberg, Y., Milliner, D. S. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin. J. Am. Soc. Nephrol. 6: 2289-2295, 2011. [PubMed: 21896830] [Full Text: https://doi.org/10.2215/CJN.02760311]
Wang, X., Zhao, X., Wang, X., Yao, J., Zhang, F., Lang, Y., Tuffery-Giraud, S., Bottillo, I., Shao, L. Two novel HOGA1 splicing mutations identified in a Chinese patient with primary hyperoxaluria type 3. Am. J. Nephrol. 42: 78-84, 2015. [PubMed: 26340091] [Full Text: https://doi.org/10.1159/000439232]