Primary Hyperoxaluria Type 3

1. Disease Information

Overview. Primary hyperoxaluria type 3 (PH3) is an autosomal recessive inborn error of glyoxylate/4-hydroxyproline metabolism caused by biallelic loss-of-function variants in HOGA1, encoding the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase. Loss of this enzyme results in excessive endogenous oxalate synthesis and recurrent calcium oxalate nephrolithiasis, typically beginning in early childhood. It is the most recently described and generally the least severe of the three classic primary hyperoxalurias, with kidney function preserved in most patients and (to date) no reported systemic oxalosis.

Key identifiers:

Synonyms / alternative names: PH3; PH III; HP3; hyperoxaluria, primary, type III; HOGA1-related hyperoxaluria; historically associated with the gene name DHDPSL (dihydrodipicolinate synthase-like), the original name of HOGA1 at discovery.

Sources: OMIM 613616; GeneReviews: PH3, NBK316514 (PMID:26401545); MedlinePlus: HOGA1.

2. Etiology

Primary causal factor (genetic). PH3 is caused by homozygous or compound heterozygous pathogenic variants in HOGA1 (10q24.2). The disease was first defined by Belostotsky et al., who mapped it to DHDPSL/HOGA1 — "Mutations in DHDPSL Are Responsible for Primary Hyperoxaluria Type III" (Belostotsky R et al., Am J Hum Genet 2010; PMID:20797690 — verify). The gene product is a mitochondrial aldolase; its loss increases endogenous oxalate production (OMIM 613616; GeneReviews PMID:26401545).

Genetic risk factors. - Biallelic HOGA1 pathogenic variants are necessary and sufficient to cause the Mendelian disease. - Carrier / heterozygous state as a stone risk modifier: Monico et al. proposed that HOGA1 may be a risk factor for idiopathic calcium oxalate urolithiasis even in heterozygotes — "Primary Hyperoxaluria Type III Gene HOGA1 (Formerly DHDPSL) as a Possible Risk Factor for Idiopathic Calcium Oxalate Urolithiasis" (PMID:21896830). - Consanguinity / founder effects increase homozygote frequency in specific populations (see §9).

Environmental / lifestyle contributors (disease-modifying, not causal). - Dietary oxalate and hydroxyproline load (collagen-rich foods, gelatin) can raise the substrate pool feeding oxalate synthesis. - Dehydration / low fluid intake and low urinary citrate promote calcium oxalate supersaturation and stone formation. - High-dose vitamin C (ascorbate) is a precursor to oxalate and is discouraged.

Gene–environment interaction. The genotype sets excess endogenous oxalate production, but clinical stone burden is modulated by urine volume, citrate, calcium, and dietary oxalate/hydroxyproline — hence the mainstays of management are hydration and citrate rather than gene-directed therapy (GeneReviews PMID:26401545).

3. Phenotypes

PH3 is dominated by stone-related urologic phenotypes and biochemical (laboratory) abnormalities, with kidney-function decline in a minority.

Phenotype characteristics. - Age of onset: Earliest of the three PH types. Median symptomatic onset ~2.7 years; some patients present only in adulthood (PMID:33543760). - Severity: Generally mild-to-moderate; recurrent stones dominate. "Compared to hyperoxaluria type I and type II, HP3 appears to be the least severe, with good preservation of kidney function in most patients" (OMIM 613616). - Progression: Recurrent/episodic stone events that can persist into the sixth decade; kidney function usually stable, but CKD (including rare kidney failure) does occur. - Quality-of-life impact: Driven by recurrent painful stone episodes, procedures, and infections; formal QoL instrument data specific to PH3 are limited/not available.

Sources: Clinical characterization of PH3 vs PH1/PH2 (PMID:33543760); GeneReviews (PMID:26401545).

4. Genetic / Molecular Information

Causal gene: HOGA1 (4-hydroxy-2-oxoglutarate aldolase 1; formerly DHDPSL), HGNC:25155, OMIM 613597, chromosome 10q24.2, NCBI Gene 112817. It has 7 coding exons encoding the mitochondrial aldolase (UniProt Q86XE5; suggested GO:0008700-related aldolase activity; see §6).

Pathogenic variant spectrum. - >50 disease-associated variants reported to date; the majority are missense variants, with a loss-of-function mechanism (unstable, aggregation-prone, catalytically inactive protein). "All nine examined PH3 variants were found to be unstable, aggregation-prone, and enzymatically inactive" (Riedel et al., PMID:22771891). A dominant-negative contribution has also been proposed for some alleles (Abid et al., Hum Mutat 2022, PMID:36259736). - Common/recurrent alleles: - c.700+5G>T — a splice-site variant; the most common allele in European/non-Ashkenazi populations (reported allelic frequencies ~35–46%; potential founder mutation) (PMID:22781098; PMID:33948853). - c.944_946delAGG (p.Glu315del) — the predominant Ashkenazi Jewish founder allele (~66% of Ashkenazi PH3 alleles per GeneReviews). - c.107C>T (p.Ala36Val) — second common Ashkenazi allele (~22%). - Variant classification: ACMG/AMP classifications (pathogenic/likely pathogenic vs VUS) are curated in ClinVar; OMIM lists ≥24 disease-causing variants. - Origin: Germline; autosomal recessive. No somatic mechanism. - Functional consequence: Loss of function (protein instability + loss of aldolase activity), possibly with dominant-negative effects on the tetramer.

Modifier genes. Not formally established. Because accumulated HOG inhibits GRHPR (the PH2 enzyme), GRHPR activity/variation is a plausible mechanistic modifier of oxalate output (see §6).

Epigenetics / chromosomal abnormalities. No disease-specific DNA-methylation, histone-modification, aneuploidy, or structural-rearrangement associations are described for PH3. Diagnosis relies on sequencing, not cytogenetics.

Sources: Abid et al. 2022, Hum Mutat; Beck et al. — novel findings/molecular testing; Ethnic associations of HOGA1 variants; GeneReviews (PMID:26401545).

5. Environmental Information

• Environmental/toxic factors: No infectious or toxic environmental cause; PH3 is purely genetic. Relevant exogenous modifiers are dietary oxalate, dietary hydroxyproline (collagen/gelatin), and high-dose ascorbic acid (oxalate precursor).
• Lifestyle factors: Fluid intake (low volume worsens supersaturation), and dietary patterns affecting urinary citrate/calcium. Adequate hydration is protective (see §13).
• Infectious agents: Not applicable as a cause; however, urinary tract infections are a frequent secondary complication of stone disease.

6. Mechanism / Pathophysiology

Normal pathway (mitochondrial hydroxyproline degradation). Dietary and endogenous collagen turnover supplies 4-hydroxyproline (~300–450 mg/day from endogenous collagen turnover). In the mitochondrion, hydroxyproline is metabolized through several steps to 4-hydroxy-2-oxoglutarate (HOG). HOGA1 catalyzes the final step — a retro-aldol cleavage of HOG into glyoxylate + pyruvate (suggested biological process GO:0019471 4-hydroxyproline catabolic process; molecular function: aldolase/lyase activity). Glyoxylate is normally detoxified by: - AGT (AGXT, peroxisomal, PLP-dependent alanine–glyoxylate aminotransferase) → glycine (defective in PH1), and - GR/GRHPR (glyoxylate reductase/hydroxypyruvate reductase, cytosolic) → glycolate (defective in PH2). Any glyoxylate escaping detoxification is oxidized by LDH (lactate dehydrogenase) to oxalate.

PH3 mechanism (loss of HOGA1). Loss of HOGA1 aldolase activity causes accumulation of HOG in urine, serum, and liver. Two complementary, still-debated mechanisms convert this into oxalate overproduction:

1. HOG-mediated inhibition of glyoxylate reductase (GRHPR) — the leading biochemical model. Accumulated HOG specifically inhibits GR, phenocopying PH2: "GR was inhibited by HOG but not by 2-hydroxyglutarate or 2-oxoglutarate" (Riedel et al., PMID:22771891). With GR inhibited, glyoxylate is not efficiently reduced to glycolate and is instead shunted to oxalate via LDH.
2. Ectopic/cytosolic cleavage of accumulated HOG, liberating glyoxylate outside the mitochondrion where detoxification capacity is limited, feeding oxalate synthesis.

Enzyme structure/function. HOGA1 is a mitochondrial homotetramer ("dimer of dimers"); each monomer has an (α/β)₈ TIM-barrel catalytic domain plus a C-terminal three-helix bundle. It uses a Type I aldolase mechanism with a Schiff-base–forming catalytic Lys196 (proton relay via Tyr168/Ser77); no metal cofactor is required. Disease variants disrupt either the active site or tetramer assembly, and are unstable/aggregation-prone (Riedel et al., PMID:21998747; PLOS One PMC3188589). HOGA activity is additionally regulated by pyruvate and α-ketoglutarate (product/substrate feedback), relevant to PH3 (PMID:31696211).

Protein dysfunction: Loss of function via misfolding/aggregation and loss of catalytic activity (possible dominant-negative on the tetramer).

Metabolic changes: Elevated HOG and its reduction product 2,4-dihydroxyglutarate (DHG); increased net oxalate synthesis; urinary glycolate/glycerate typically normal (distinguishing from PH1/PH2).

Tissue damage mechanism: Calcium oxalate crystal deposition → crystal nucleation/aggregation → mechanical/inflammatory tubular injury, stone formation, occasional nephrocalcinosis, and — over time in a minority — chronic kidney injury. (Notably, systemic oxalosis has not been reported in PH3, unlike PH1.)

Cell types & anatomy involved: Hepatic mitochondria (site of HOGA1 expression and oxalate overproduction; suggested CL:0000182 hepatocyte, GO:0005739 mitochondrion) and renal tubular epithelium (site of crystal-related injury; suggested CL:1000507/renal tubule epithelial cells, UBERON:0002113 kidney).

Molecular profiling: No large-scale disease-specific transcriptomic/proteomic/single-cell datasets for PH3; the field is characterized by targeted metabolomics (urine/plasma HOG, DHG, oxalate quantitation by LC-MS/MS) and enzyme kinetics.

Chemical entities (CHEBI suggestions): oxalate (CHEBI:30623), glyoxylate (CHEBI:16891), 4-hydroxyproline (CHEBI:18095), 4-hydroxy-2-oxoglutarate/HOG, 2-oxoglutarate (CHEBI:16810), pyruvate (CHEBI:15361), glycolate (CHEBI:17497), citrate (CHEBI:30769).

Sources: Structural/biochemical HOGA (PLOS One) (PMID:21998747); HOGA inactivity & GR inhibition (PMID:22771891); Regulation of HOGA by pyruvate/α-KG (PMID:31696211).

7. Anatomical Structures Affected

• Primary organ affected clinically: Kidney / urinary tract (UBERON:0002113 kidney; UBERON:0000056 ureter; UBERON:0001255 urinary bladder) — recurrent calcium oxalate stones, occasional nephrocalcinosis.
• Primary organ of the metabolic defect: Liver (UBERON:0002107) — hepatic mitochondria are the site of HOGA1 expression and oxalate overproduction.
• Body systems: Renal/urinary system (primary); hepatic/metabolic (biochemical origin).
• Tissue/cell level: Renal tubular epithelium (crystal-associated injury), hepatocytes (CL:0000182).
• Subcellular level: Mitochondrion (GO:0005739) — HOGA1 localization and HOG cleavage; cytosol — glyoxylate/oxalate handling.
• Localization/laterality: Stones/nephrocalcinosis are typically bilateral but can be unilateral; distribution follows the collecting system.

8. Temporal Development

• Onset: Early childhood, earliest of the three PH types — median symptomatic onset ~2.7 years; stones usually begin before age 5. Some patients are diagnosed only in adulthood (PMID:33543760; GeneReviews PMID:26401545).
• Onset pattern: Insidious biochemically (lifelong hyperoxaluria) with episodic clinical stone events.
• Course: Chronic, recurrent, relapsing stone disease that can continue into the sixth decade; kidney function is usually stable.
• Stages/progression: Most patients remain in early CKD stages; a minority progress to CKD 3–5. A 2024 single-cohort report described one patient reaching CKD stage 5 and two others at CKD stage 2 at last follow-up (Pediatric Nephrology 2024, doi:10.1007/s00467-024-06536-w).
• Critical windows: Early diagnosis and initiation of hydration/citrate before repeated obstructive/infectious insults; closer monitoring for children <4 years and those with reduced kidney function.

9. Inheritance and Population

Inheritance: Autosomal recessive (25% recurrence risk per pregnancy for carrier couples). Suggested HPO mode-of-inheritance term: HP:0000007 Autosomal recessive inheritance.

Penetrance / expressivity: Biochemical penetrance (hyperoxaluria) is essentially complete in biallelic carriers; clinical expressivity is variable (stone burden and kidney outcomes differ widely, even within genotype). No genetic anticipation (not a repeat-expansion disorder).

Epidemiology: - Overall primary hyperoxaluria prevalence: ~1–3 per 1,000,000. - PH3 constitutes ~7–12% of all primary hyperoxaluria cases (~10% commonly cited). - Estimated PH3 prevalence: ~1 per 136,000 (GeneReviews). - Carrier frequency: ~1 in 185 general population; ~1 in 55 in Ashkenazi Jews (GeneReviews; PMID:33948853).

Founder effects / population genetics: - Ashkenazi Jewish founder alleles: c.944_946delAGG (p.Glu315del) and c.107C>T (p.Ala36Val). - European/non-Ashkenazi: c.700+5G>T splice variant predominates (potential founder; ~35–46% of alleles). - Consanguinity increases homozygous disease in some populations; genetically homogeneous founder cohorts have been described.

Demographics: No strong sex predilection reported; onset in early childhood; enrichment in populations carrying founder alleles (Ashkenazi Jewish; specific European and Middle Eastern groups).

Sources: GeneReviews (PMID:26401545); Ethnic associations of HOGA1 variants; Beck et al..

10. Diagnostics

Biochemical (urine/blood): - 24-hour urinary oxalate: Elevated (>0.7 mmol/1.73 m²/day); PH3 shows the lowest oxalate of the three types (median ~1.1 mmol/1.73 m²/day). LOINC-type analyte: urine oxalate. - Urinary HOG (4-hydroxy-2-oxoglutarate): The key discriminating biomarker — markedly elevated in PH3 (median ~110 mg/g creatinine, normal <10) and essentially absent in PH1/PH2; described as "an excellent biomarker for PH3 diagnosis" and decreases with age (PMID:33543760). - Urinary 2,4-dihydroxyglutarate (DHG): Elevated; complementary PH3 marker (LC-MS/MS). - Urinary glycolate (PH1) and glycerate (PH2): typically normal in PH3 — helps differentiate. - Urine citrate: normal (contrasts with PH1); urine calcium: normal-to-mildly high (hypercalciuria ~10%). - Plasma oxalate: mildly elevated only with reduced GFR.

Imaging: Renal ultrasound / CT for stones and nephrocalcinosis; stone analysis shows calcium oxalate (often mixed mono-/dihydrate — ~36% mixed in PH3).

Genetic testing (confirmatory / gold standard): - Single-gene HOGA1 sequencing and deletion/duplication analysis, or a primary hyperoxaluria multigene panel (AGXT, GRHPR, HOGA1), or WES/WGS. Testing is available (e.g., GTR-listed labs; PreventionGenetics). - Chromosomal microarray/karyotype/FISH/mtDNA testing are not indicated.

Clinical criteria / differential diagnosis: Diagnosis rests on hyperoxaluria + elevated HOG/DHG + biallelic HOGA1 variants. Differentiate from: - PH1 (AGXT): higher oxalate, high glycolate, ~64% ESKD by 40, systemic oxalosis. - PH2 (GRHPR): elevated urinary glycerate, ~34% ESKD by 40. - Idiopathic calcium oxalate stones / secondary (enteric, dietary, medication) hyperoxaluria.

Screening: Carrier / cascade testing for relatives once familial variants are known; targeted screening in founder populations (Ashkenazi Jewish).

Sources: Clinical characterization PH1/2/3 (PMID:33543760); GeneReviews (PMID:26401545).

11. Outcome / Prognosis

• Kidney survival is favorable — the defining prognostic feature. ESKD by age 40 is only ~2.9% in PH3, versus ~63.8% in PH1 and ~34.2% in PH2 (PMID:33543760).
• eGFR at diagnosis is highest among PH types (~96 mL/min/1.73 m²).
• Systemic oxalosis has not been reported in PH3.
• Kidney failure is possible but rare: individual cases are documented — "Primary Hyperoxaluria Type 3 Can Also Result in Kidney Failure: A Case Report" (PMID:34245816) — and a 2024 cohort reported one CKD-5 patient (doi:10.1007/s00467-024-06536-w). Reported ESKD cases often have contributing factors.
• Morbidity is driven by recurrent stones, colic, obstructive events, urologic procedures, and UTIs rather than progressive kidney failure.
• Prognostic factors: degree of hyperoxaluria, stone/nephrocalcinosis burden, hydration/citrate adherence, and baseline kidney function. Life expectancy is essentially normal in most patients.

Sources: (PMID:33543760); (PMID:34245816); GeneReviews (PMID:26401545).

12. Treatment

There is no PH3-specific approved disease-modifying drug; management is conservative/supportive and stone-directed.

Conservative (mainstay) — suggested MAXO terms noted: - High fluid intake (>2.5 L/m²/day) to lower supersaturation — MAXO: increased fluid intake / supportive care (MAXO:0000950). - Alkali citrate supplementation (potassium/sodium citrate, ~1–3 mEq/kg/day) to inhibit CaOx crystallization — pharmacotherapy (NCIT:C15986; therapeutic agent citrate, CHEBI:30769). - Dietary modification — limit oxalate/high-hydroxyproline foods, avoid high-dose ascorbate — MAXO dietary intervention (MAXO:0000088). - Thiazide diuretics for hypercalciuria (selected patients).

Stone/urologic management (interventional): - Extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy as needed; prompt relief of obstruction; treat UTIs — surgical/therapeutic procedure (MAXO:0000004 / NCIT:C15329).

RNAi / advanced therapeutics — important caveat for PH3: - Lumasiran (anti-HAO1/glycolate oxidase siRNA) and nedosiran (anti-LDHA siRNA) are approved/developed primarily for PH1. Lumasiran ILLUMINATE-A: "84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group" (Garrelfs et al., NEJM 2021, PMID:33356090 — verify). - Mechanistic limitation in PH3: glycolate-oxidase inhibition (lumasiran) is not expected to reduce hepatic oxalate to the same extent in HOGA1 deficiency; more PH2/PH3 patients need testing. Nedosiran (LDH-directed) is being studied across PH types but PH3 efficacy data remain limited. - Transplantation: Rarely needed in PH3 (kidney failure is uncommon); combined liver–kidney transplantation (standard in severe PH1) is generally not required.

Pharmacogenomics: Not established for PH3.

Sources: RNAi for PH systematic review; Nedosiran design/development; ERKNet/OxalEurope expert consensus, Nat Rev Nephrol 2023 (s41581-022-00661-1).

13. Prevention

• Primary prevention: Not preventable (genetic); genetic counseling and reproductive options (carrier testing, prenatal/preimplantation genetic testing once familial variants known) — MAXO genetic counseling (MAXO:0000079).
• Secondary prevention (early detection): Cascade/carrier screening of relatives; targeted screening in founder populations (Ashkenazi Jewish); early biochemical/genetic diagnosis in children with early stones.
• Tertiary prevention (complication avoidance): Lifelong hydration + citrate, dietary control, avoidance of volume contraction, high-dose vitamin C, and nephrotoxins; prompt treatment of obstruction/UTI; regular surveillance (annual clinical assessment, kidney imaging, serum creatinine/eGFR, 24-h urine oxalate/supersaturation; more frequent for young children and impaired kidney function).
• Immunization / public-health / environmental interventions: Not applicable.

Sources: GeneReviews (PMID:26401545); ERKNet/OxalEurope consensus (Nat Rev Nephrol 2023).

14. Other Species / Natural Disease

• Taxonomy: Human disease (Homo sapiens, NCBITaxon:9606). No naturally occurring HOGA1-deficiency disease is well described in companion animals or wildlife (OMIA has no established PH3 entry analogous to human PH3). Calcium oxalate urolithiasis occurs naturally in dogs/cats but is not attributed to HOGA1 loss.
• Orthology: HOGA1 is evolutionarily conserved across vertebrates (mouse Hoga1, NCBI Gene present; conserved in the hydroxyproline-degradation pathway), enabling model-organism study.
• Comparative biology: The hydroxyproline→HOG→glyoxylate pathway is conserved; however (see §15) the mouse phenotype does not fully recapitulate human hyperoxaluria, an important interspecies difference.
• Zoonotic potential / transmission: None (non-communicable genetic disease).

15. Model Organisms

• Mouse (Hoga1 knockout): The principal PH3 model. Key finding & human–model mismatch: Hoga1-null mice did not develop hyperoxaluria on a hydroxyproline-free diet, in marked contrast to PH3 patients, although urine/plasma HOG and DHG and hepatic DHG were significantly elevated — Li et al., "Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3" (PMID:26428388, PMC4615548), extended by "4-hydroxy-2-oxoglutarate metabolism in a mouse model of Primary Hyperoxaluria Type 3" (Mol Genet Metab Rep 2024, ScienceDirect S2405580824001298). This mismatch (suggests HUMAN_MODEL_MISMATCH rather than a clean phenotype recapitulation) indicates additional/diet-dependent factors in human oxalate overproduction.
• In vitro / biochemical models: Recombinant human HOGA1 expression for enzyme kinetics, stability, and structural studies (crystal structures; Type I aldolase mechanism) — used to demonstrate variant instability/inactivity and HOG-mediated GRHPR inhibition (PMID:21998747; PMID:22771891; PMID:31696211).
• Model utility: Study of HOG/DHG metabolism, the reduction of HOG→DHG as a possible oxalate-limiting shunt, and metabolic perturbations of glyoxylate handling (PMID:22729392).
• Limitations: Mouse does not reproduce spontaneous hyperoxaluria; heavy reliance on dietary hydroxyproline loading; no robust stone-forming small-animal model of PH3.

Sources: Hydroxyproline metabolism in Hoga1-KO mouse (PMID:26428388); HOG metabolism in PH3 mouse (2024); PH3 as a model for glyoxylate perturbations (PMID:22729392).

Consolidated Ontology-Term Suggestions (for KB population)

• MONDO: MONDO:0013327 (primary hyperoxaluria type 3)
• Gene (HGNC): hgnc:25155 (HOGA1)
• Phenotypes (HP): HP:0000787 Nephrolithiasis; HP:0003159 Hyperoxaluria; HP:0000790 Hematuria; HP:0000121 Nephrocalcinosis; HP:0002150 Hypercalciuria; HP:0000010 Recurrent UTI; HP:0012622 CKD; HP:0000007 Autosomal recessive inheritance
• Biological process (GO): GO:0019471 4-hydroxyproline catabolic process; GO:0006979/oxidative response context; oxalate biosynthetic/metabolic process
• Cellular component (GO): GO:0005739 mitochondrion
• Cell types (CL): CL:0000182 hepatocyte; renal tubular epithelial cell
• Anatomy (UBERON): UBERON:0002113 kidney; UBERON:0002107 liver; UBERON:0000056 ureter; UBERON:0001255 urinary bladder
• Chemicals (CHEBI): CHEBI:30623 oxalate; CHEBI:16891 glyoxylate; CHEBI:18095 4-hydroxyproline; CHEBI:16810 2-oxoglutarate; CHEBI:15361 pyruvate; CHEBI:17497 glycolate; CHEBI:30769 citrate
• Treatments (MAXO): MAXO:0000950 supportive care; MAXO:0000088 dietary intervention; MAXO:0000079 genetic counseling; MAXO:0000004 surgical procedure

Key Citations (verify PMIDs/snippets before KB entry)

Bottom line for the KB entry: PH3 is an autosomal-recessive, HOGA1-driven inborn error of hydroxyproline/glyoxylate metabolism. Loss of mitochondrial 4-hydroxy-2-oxoglutarate aldolase causes HOG accumulation, which (chiefly via HOG-mediated GRHPR inhibition) shunts glyoxylate to oxalate, producing early-childhood-onset recurrent calcium oxalate nephrolithiasis. It is the mildest primary hyperoxaluria (low ESKD, no systemic oxalosis), diagnosed by elevated urinary HOG/DHG plus biallelic HOGA1 variants (founder alleles c.700+5G>T in Europeans; p.Glu315del/p.Ala36Val in Ashkenazi Jews), and managed conservatively with hydration and citrate — RNAi therapies validated in PH1 have uncertain benefit in PH3.