Iminoglycinuria
Iminoglycinuria is a rare, usually benign, inherited defect of renal tubular amino‑acid transport characterized by excessive urinary excretion of glycine and the imino acids proline and hydroxyproline, due to impaired reabsorption in the proximal tubule. It is classically inherited as an autosomal recessive trait, often asymptomatic, and may also appear transiently as a normal finding in neonates and young infants.[1][2][3][4][5]
Definition and basic physiology
Iminoglycinuria is defined biochemically as markedly increased urinary levels of glycine, proline, and hydroxyproline in the setting of normal or near‑normal plasma concentrations, indicating a primary defect in renal tubular reabsorption rather than systemic overproduction. These three amino acids share a common low‑molecular‑weight transport system in the apical membrane of proximal tubular cells, so disruption of this transporter pathway leads to their concerted loss in urine.[6][2][3][4][1]
NORD (via MONDO) and Orphanet both classify iminoglycinuria as an inborn error of metabolism within the group of amino‑acid transport disorders affecting the kidney (and sometimes intestine). It is distinct from generalized aminoacidurias (as in Fanconi syndrome), because the defect is largely restricted to glycine and imino acids rather than affecting multiple amino‑acid classes.[3][7][4][5]
Epidemiology
NORD’s MONDO‑linked summary estimates the prevalence of iminoglycinuria at around 1 in 15,000 in the general population, although many cases are probably unrecognized because the condition is often asymptomatic. Earlier nephrology and biochemical surveys similarly reported low but non‑negligible frequencies when systematic urine amino‑acid screening was performed.[4][5][3]
Importantly, several authoritative sources note that transient iminoglycinuria is physiologic in neonates and infants: proximal tubular reabsorption mechanisms are immature, so increased urinary excretion of glycine and imino acids in infants younger than about 6 months can be normal. Persistent, pronounced excretion beyond infancy, especially with an autosomal recessive pattern in families, supports the diagnosis of hereditary iminoglycinuria.[2][5][3][4]
Genetic basis
Key transporters and genes
Human genetic and functional studies have clarified that iminoglycinuria is caused by defects in proline/glycine transporters of the SLC (solute carrier) family, often in a genetically complex pattern:[8][9][6][3]
- SLC36A2 (PAT2)
- SLC6A20 (SIT1, IMINO transporter)
- SLC6A19 (B^0AT1)
- Encodes the major neutral amino‑acid transporter implicated primarily in Hartnup disorder, but early work proposed a contributory role in iminoglycinuria in combination with SLC36A2 variants.[2][3]
- More recent curation suggests that the core iminoglycinuria phenotype is best explained by biallelic SLC36A2 defects, with SLC6A19 variation less clearly involved.[11]
The seminal JCI study by Bröer et al. analyzed multiple families and concluded that iminoglycinuria and isolated hyperglycinuria are discrete phenotypes caused by complex combinations of mutations in proline/glycine transporters, with classical semi‑dominant inheritance (two non‑functional alleles conferring iminoglycinuria and one conferring hyperglycinuria).[12][9][6]
Mode of inheritance
NORD, MedGen, and Orphanet describe iminoglycinuria as transmitted in an autosomal recessive manner. PanelApp and ClinGen evaluations classify SLC36A2‑related iminoglycinuria as a biallelic (recessive) disorder, while also noting that some families show a digenic pattern involving SLC36A2 plus SLC6A20 or SLC6A19.[7][5][9][11][4][8]
Heterozygous carriers often exhibit isolated hyperglycinuria (increased glycine excretion without significant imino‑acid loss), supporting a semi‑dominant continuum from hyperglycinuria to full iminoglycinuria depending on allele burden and transporter combinations.[9][3][6]
Pathophysiology
SLC36A2 encodes a proton‑coupled amino‑acid symporter on the apical surface of proximal tubule cells, which reabsorbs filtered glycine and imino acids (proline, hydroxyproline) from the tubular lumen back into the circulation. When SLC36A2 is non‑functional or severely impaired, these amino acids cannot be effectively reclaimed and are excreted in large amounts in the urine.[3][10][6][8]
In digenic cases, concurrent reductions in SLC6A20‑mediated imino‑acid transport or SLC6A19‑mediated neutral‑amino‑acid transport further compromise reabsorption, pushing the phenotype from hyperglycinuria toward full iminoglycinuria. Despite substantial urinary losses, systemic pools of glycine and proline are usually maintained by dietary intake and endogenous synthesis, which helps explain the absence of a consistent clinical syndrome in most patients.[5][4][6][8][9][3]
Clinical features
Typical presentation
Authoritative summaries (NORD, Orphanet, MedGen) agree that iminoglycinuria is usually asymptomatic and often discovered incidentally when urine amino‑acid chromatography is performed for unrelated reasons. The cardinal biochemical feature is:[7][4][5]
- Markedly elevated urinary excretion of glycine, proline, and hydroxyproline, often several‑fold above the upper limit of normal, with otherwise unremarkable urinalysis and normal renal function tests.[1][4][3]
No consistent systemic phenotype is described by NORD or Orphanet; they explicitly state that the disorder is “usually asymptomatic” and not associated with a specific clinical picture.[4][3][7]
Possible associated findings
Older case reports and biochemical reviews (summarized in secondary sources) have occasionally linked iminoglycinuria to features such as nephrolithiasis, mild developmental anomalies, or ocular changes; however, these associations are inconsistent and not firmly established, and major rare‑disease databases do not list them as core diagnostic features.[5][1][3]
Importantly, iminoglycinuria can also appear as part of generalized aminoaciduria in Fanconi renotubular syndrome, in which many amino acids are lost along with glucose, phosphate, and bicarbonate. In that context, the clinical picture is dominated by rickets, growth failure, and metabolic acidosis, not by isolated iminoglycinuria per se.[3][5]
Diagnosis
Biochemical testing
Diagnosis is primarily biochemical, based on urine amino‑acid analysis:[1][4][3]
- High‑performance liquid chromatography (HPLC) or ion‑exchange chromatography shows a characteristic pattern of excess glycine, proline, and hydroxyproline.
- Plasma amino‑acid profile is usually normal, differentiating iminoglycinuria from amino‑acid overproduction disorders.[5][3]
Because iminoglycinuria can be physiologic in infants, elevated urinary excretion of these amino acids in neonates and infants under ~6 months should be interpreted with caution and re‑evaluated later. Persistent marked excretion beyond infancy supports a genetic transport defect.[2][3][5]
Genetic confirmation
Genetic testing can confirm the diagnosis and define the underlying mechanism:[10][8][9]
- Targeted sequencing of SLC36A2 is the most direct approach for suspected monogenic iminoglycinuria.
- If SLC36A2 variants are mild or absent, sequencing of SLC6A20 and SLC6A19 can identify potential digenic combinations.[8][9]
- Broader gene panels for “amino‑acid transport disorders” or “renal tubulopathies” may also include these genes.[11][2]
MedGen and OMIM entries (linked via NORD’s iminoglycinuria page) summarize published variants, and ClinGen has formally evaluated the SLC36A2–iminoglycinuria gene–disease relationship as having limited‑to‑moderate but increasing evidence.[4][8][5]
Differential diagnosis
The differential for elevated urinary glycine and imino acids includes:[2][3][5]
- Physiologic neonatal iminoglycinuria: transient in early months of life, due to immature proximal tubular transport.
- Hyperglycinuria: typically heterozygous state with isolated glycine over‑excretion and minimal or no imino‑acid involvement; can share genetic background with iminoglycinuria (SLC36A2 variants).[6][8][3]
- Fanconi renotubular syndrome: generalized aminoaciduria plus glucosuria, phosphaturia, bicarbonaturia, and clinical signs of proximal tubular dysfunction.[3][5]
- Other specific amino‑acid transport disorders (e.g., Hartnup disorder, cystinuria), which show distinct patterns on amino‑acid chromatography and associated systemic findings such as pellagra‑like rash or nephrolithiasis.[2][3]
Careful interpretation of urine amino‑acid patterns and clinical context usually enables straightforward distinction.
Management
General approach
Because iminoglycinuria is regarded as a benign biochemical phenotype in the vast majority of cases, no specific treatment is required. NORD and Orphanet do not recommend dietary restriction of glycine or imino acids, and there is no evidence that supplementation is needed given adequate dietary intake and normal systemic levels.[7][4][5][3]
Management therefore focuses on:[7][4][5]
- Reassurance of patients and families regarding the benign nature of the finding.
- Avoiding unnecessary invasive renal investigations in asymptomatic individuals.
- Periodic monitoring of renal function and urinalysis, especially if other tubular abnormalities are suspected.
When to investigate further
Further evaluation is warranted when:[5][3][2]
- Aminoaciduria is generalized, raising concern for Fanconi syndrome or other tubular disorders.
- There are clinical symptoms (growth failure, rickets, metabolic acidosis, nephrolithiasis) incompatible with benign isolated iminoglycinuria.
- Iminoglycinuria appears in the context of a broader congenital anomaly or metabolic syndrome, where it may be one feature among many.
In such cases, a full renal and metabolic work‑up, and possibly genetics consultation, is appropriate.
Prognosis
NORD, MedGen, and Orphanet explicitly state that iminoglycinuria is usually asymptomatic and considered benign. Longitudinal observational data show no consistent progression to renal insufficiency, no requirement for amino‑acid supplementation, and no specific systemic complications attributable solely to the transport defect.[6][4][3][7][5]
As a result, life expectancy and quality of life for individuals with isolated inherited iminoglycinuria are expected to be normal, and long‑term follow‑up can be minimal once the benign nature of the condition is established.[4][3][5]
Genetic counseling
Given the underlying autosomal recessive inheritance in classic cases:[9][4][5]
- Parents of an affected child are typically heterozygous carriers.
- Each pregnancy carries a 25% risk of iminoglycinuria, a 50% chance of carrier status (often manifesting as hyperglycinuria), and a 25% chance of an unaffected non‑carrier.
However, because the phenotype is usually benign, the clinical implications of carrier and affected status are modest, and many families opt only for informational counseling rather than active reproductive interventions.[3][4]
When SLC36A2 (with or without SLC6A20/SLC6A19 variants) is confirmed molecularly, carrier testing for other family members is technically feasible and may be relevant in research settings or in families with additional metabolic concerns.[10][8][9]
Key points for practice and writing
- Iminoglycinuria is a benign inborn error of renal amino‑acid transport characterized by defective reabsorption of glycine, proline, and hydroxyproline, causing marked urinary excretion but no consistent clinical syndrome.[4][5][3]
- It is primarily caused by biallelic SLC36A2 variants, with occasional digenic contributions from SLC6A20 or SLC6A19, and exhibits a semi‑dominant spectrum from hyperglycinuria (carriers) to full iminoglycinuria (homozygotes/compound heterozygotes).[8][9][10][6]
- The condition is often incidentally detected on urine amino‑acid chromatography and must be distinguished from normal neonatal excretion and from generalized aminoacidurias (Fanconi syndrome).[5][2][3]
- According to NORD, Orphanet, and NIH GARD/MedGen, no specific therapy is needed, prognosis is excellent, and management consists mainly of reassurance and minimal long‑term monitoring.[7][4][5]
References
- https://en.wikipedia.org/wiki/Iminoglycinuria
- https://panelapp-aus.org/panels/3468/gene/SLC6A19/
- https://www.malacards.org/card/iminoglycinuria
- https://rarediseases.org/mondo-disease/iminoglycinuria/
- https://www.ncbi.nlm.nih.gov/medgen/124342
- https://www.jci.org/articles/view/36625
- https://www.orpha.net/ORDO/Orphanet_42062
- https://thegencc.org/submissions/SGC-104708.2
- https://panelapp-aus.org/panels/3468/gene/SLC36A2/
- https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC36A2
- https://panelapp.genomicsengland.co.uk/panels/activity/?panel=302&entity=SLC36A2
- https://www.jci.org/articles/view/36625/figure/8
- https://rarediseases.info.nih.gov/diseases/8424/iminoglycinuria/
- https://www.jci.org/articles/view/36625/citations/year/2021
- https://jbcgenetics.com/files/articles/pdf/2173/show
