Hyperglycinuria: diagnosis in middle age
- 1 Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA
- 2 Internal Medicine, Detroit Medical Center, Detroit, Michigan, USA
- 3 Wayne State University School of Medicine, Detroit, Michigan, USA
- Correspondence to Dr Noreen F Rossi; nrossi@wayne.edu
Abstract
Isolated hyperglycinuria is a rare disorder that is associated with osteoporosis and renal calculi. We report findings in a middle-aged, black woman who presented for renal function evaluation with a history of transient hypobicarbonataemia associated with topiramate therapy. She displayed the full triad of high urinary glycine, early-onset osteopenia despite normal reproductive hormones, and renal calculus with high urinary oxalate, phosphate and uric acid. Parathyroid hormone and fibroblast growth factor 23 were both normal. Formal genetic testing did not reveal mutations in SLC6A20, SLC6A18, SLC6A19, SLC36A2, the known genes associated with glycinuria; however, black individuals are poorly represented in the genetic databases. It may well be that otherwise unidentified mutations may be present or that topiramate may result in a lingering proximal tubule defect even after cessation of the drug.
Background
Glycinuria or hyperglycinuria is a rare disorder with few case reports reported in the literature.1 2 Glycinuria may result either due to a defect in glycine metabolism or to a disturbance of renal reabsorption of glycine.1 2 Typically, glycinuria is encountered as part of other aminoacidurias as in Fanconi syndrome. Glycinuria occurs when glycine is the sole or most significant amino acid excreted into the urine and has been associated with hypophosphataemia, osteoporosis and nephrolithiasis.1 Genetic findings of glycinuria are rare and have not been previously reported in black individuals.
The role of fibroblast growth factor 23 (FGF23) in phosphate metabolism is well established.3 In nephropathic cystinosis, another distinct isolated aminoaciduric syndrome with hypophosphataemia, FGF23 has also been reported to be decreased compared with individuals with similar levels of renal function.4 5 To our knowledge, the level of FGF23 in patients with isolated glycinuria, osteoporosis and nephrolithiasis has not yet been reported.
We report a case of a middle-aged woman with isolated hyperglycinuria, osteopenia and nephrolithiasis in whom we examined the possible role of FGF23.
Case presentation
The patient is a black woman in her 40s with sickle cell trait, congenital neurogenic bladder requiring a stage II bladder nerve stimulator, recurrent urinary tract infections and migraine headaches referred in 2019 for evaluation of renal function. She denied haematuria, proteinuria, deafness or nephrolithiasis. She reported no known history of kidney disease, pyelonephritis or enuresis. She was eating a typical western diet and taking no dietary supplements. Medical history revealed that she was born at less than 7 months gestation and weighed less than 1 kg. Her patent ductus arteriosus was repaired during infancy. She has hypothyroidism and peptic ulcer disease. She was diagnosed with osteoporosis at 28 years of age at which time she had normal gonadal hormone levels. She has had cholecystectomy for cholelithiasis and hysterectomy for adenomyosis. Family history was negative for hereditary or acquired renal tubular disorders, cystic kidney diseases, renal stones or deafness. Medications at the time of evaluation included alendronate 70 mg daily, cetirizine 10 mg daily, pantoprazole 40 mg daily, levothyroxine 112 μg daily, calcium and vitamin D supplement.
On physical examination blood pressure was 106/62 mm Hg, heart rate 71 beats/min, respiratory rate 18 per min, temperature 36.7°C, weight 45.5 kg, height 162.6 cm. Cardiorespiratory and neurological parameters were normal. She had multiple well-healed scars but her abdominal exam was otherwise unremarkable.
Investigations
Her laboratory studies showed serum creatinine 0.91 mg/dL, eGFR 83 mL/min/1.73, BUN 9 mg/dL, sodium 139 mmol/L, potassium 4.2 mmol/L, chloride 105 mmol/L, bicarbonate 26 mmol/L and glucose 83 mg/dL. Calcium was 9.2 mg/dL, albumin 4 g/dL, magnesium 2 mg/dL, phosphate 2.9 mg/dL, 25-hydroxyvitamin D 36 ng/mL (normal 30–100 mg/mL) and intact parathyroid hormone 51 pg/mL (normal 15–69 pg/mL). The patient’s progesterone, follicle stimulating hormone and luteinizing hormone were 1.37 ng/mL, 23.42 mIU/mL and 155.22 mIU/mL, respectively, indicating that the patient is not postmenopausal. The FGF23 level was 143 RU/mL (ref range 44–215 RU/mL).
A review of her past medical records revealed that the patient had been placed on topiramate for her migraines in 2015. Her serum bicarbonate decreased to a nadir of 15 mmol/L, at which time the medication was stopped. Topiramate was restarted briefly in 2018 with the serum bicarbonate again dropping from 25 to 18 mmol/L. Since the medication did not help her headaches, the patient declined to continue topiramate and bicarbonate returned to normal values (figure 1).
Serum bicarbonate levels from 2010 to 2020. Rectangles (▄) indicate the time during which the patient was on topiramate. Arrows (→) indicate times when she had urinary excretion studies for amino acids.
To evaluate the patient for possible partial or complete Fanconi syndrome urine amino acid screen was performed 18 months after she ceased taking topiramate and revealed a urine glycine level of 2.24 µmol/mg creatinine (normal 0.38–1.59 µmol/mg creatinine). All twenty other amino acids were well within the acceptable levels (<0.50 µmol/mg creatinine) or undetectable in the urine. Repeat assessment was performed three times (most recently in 2021) and confirmed the hyperglycinuria at 2.82 µmol/mg creatinine. The urinary proline level was undetectable on all three occasions. Urine glucose was negative. Fractional excretions of phosphate and uric acid were 10% and 11%, respectively. The patient underwent genetic testing with the sequencing of four genes – SLC6A20, SLC6A18, SLC6A19, SLC36A2. No previously reported sequence variants were identified.
Twenty-four hours urine studies showed a urine volume 2.70 L/day, pH 6.375, calcium 100 mg/day (normal <200 mg/day), oxalate 57 mg/day (normal 20–40 mg/day), phosphate 1360 mg/day (normal 600–1200 mg/day) and uric acid 1185 g/day (normal <750 mg/day).
The first DEXA scan was performed 11 years earlier when she was 30 years old and was consistent with osteoporosis despite having functioning ovaries. L1–L4 bone density displayed a Z-Score of −2.6 and femur density displayed a score of −1.5. The patient later underwent a hysterectomy but did not undergo an ovariectomy. Repeat DEXA scan in 2021 confirmed osteopenia at the femoral necks bilaterally. Ultrasound examination of the kidney revealed a non-obstructing kidney stone, the presence of ovaries was confirmed. CT scan confirmed the presence of renal calculus. Urology determined that the size of the renal stone was too small for adequate lithotripsy especially as the patient was asymptomatic.
Treatment
The patient received standard treatment for osteopenia with bisphosphonates and daily water intake of 2 L to prevent renal stone formation. She was advised to avoid topiramate.
Outcome and follow-up
The patient continues to demonstrate hyperglycinuria with 1.8 µmol/g creatinine on the most recent evaluation in 2021. She remains off topiramate and is being treated for her migraine headaches with intermittent analgesics. She follows a regimen of increased fluid intake to maintain 2 liters of urine daily to prevent further renal calculus formation and takes alendronate 70 mg weekly for her osteoporosis which has not demonstrated further deterioration over the last 3 years.
Discussion
To our knowledge, this is the first case of glycinuria accompanied by osteoporosis and kidney stones in a black woman. Like nephropathic cystinosis with hypophosphataemia,5 6 phosphaturia was present with normal FGF23 levels.
Increased urinary glycine excretion may be caused by either of two mechanisms: an elevated plasma glycine concentration or a defect in renal tubular glycine reabsorption. Hyperglycinaemia may occur in association with total parenteral nutrition7 8 or due to a genetic defect. Non-ketotic (glycine encephalopathy) or ketotic (proprionic acidaemia) hyperglycinaemia are inherited as distinct autosomal recessive disorders that result in abnormal catabolism of glycine. These disorders present at birth or early infancy with hypotonia, lethargy, seizures and even coma. Individuals who survive into childhood display a spectrum of developmental delays.7 9–11 Our patient was ingesting a typical western diet and no dietary supplements nor was she receiving hyperalimentation. At no time did she manifest the constellation of clinical findings observed with hereditary hyperglycinaemia. Thus, the increase in urinary glycine excretion is most likely due to a defect in renal tubular transport.
De Vries et al 12 reported a case of hereditary glycinuria and recurrent nephrolithiasis in a 20-year-old Bulgarian woman with a history of osteoporosis. Oberiter et al 2 reported another case of glycinuria and nephrolithiasis in a seven and half-year-old girl. Osteoporosis was not reported in the child, but bone diagnostics may have been limited due to available methodologies and the age of their patient.
More recent genetic studies of the solute carrier family (SLC) of membrane transporters have shed some light on glycinuria, implicating SLC36A1 and SLC36A2. These genes encode the proton-amino acid transporters PAT1 and PAT2, respectively, that transport amino acids and hydrogen ion into the cells. These are distinct and should not be confused with the putative anion transporter that is often similarly abbreviated and exchanges chloride and formate in the gut and is part of the SLC26 family.13 While SLC36A1 is primarily located in the small intestine, SCL36A2 is expressed on the luminal membrane of proximal renal tubule cells.14 Mutations in SLC36A2 are associated with higher urinary excretion of proline, hydroxyproline, and glycine; but some mutations only increase glycine excretion15 Modelling supports the concept that the capacity of the human kidney to reabsorb proline is greater than that for glycine. This may also account for the observation that some mutations in SCL36A2 result in glycinuria rather than prolinuria.16 In addition, the orphan transporter SLC6A18 has been associated with proximal tubular transport of glycine in mice17 and stress fractures in humans.18 This does not, in itself, eliminate a possible inherited hyperglycinuria since available data on genetic associations have largely been performed on individuals of European and east Asian ancestry. Less than 3% of individuals in the GWAS catalog through 2019 were of African descent.19 This makes it very difficult to verify if a given individual possesses a known mutation. There is a real potential for additional untested, possibly undiscovered, genes or a missed alteration in the tested genes to exist. Apart from topiramate resulting in a permanent partial proximal tubule defect in amino acid transport that could cause the hyperglycinuria (see below), the possibility of a recessive mutation, which has not yet been discovered remains. Given her presentation with osteoporosis at a young age and with normal reproductive hormones, we speculate that SLC6A18 is the more likely candidate among the existing genes to harbour a mutation and would welcome the potential of having hyperglycinuria.
The hypobicarbonataemia that occurred in the past during topiramate therapy, which has been reported to cause renal tubular acidosis type II (RTA II) and proximal tubule dysfunction due to inhibition of carbonic anhydrase II,20 prompted the evaluation of proximal tubule function. Notably, our patient was not on the drug at the time of our evaluation but had been challenged twice with a similar decline in serum bicarbonate levels. It may well be that the carbonic anhydrase inhibition by topiramate limits the availability of protons for transport via PAT2, resulting in glycinuria. We did not rechallenge our patient to assess whether glycine excretion increased during topiramate treatment. Nonetheless, the patient did exhibit hyperphosphaturia and uricosuria as well as high urinary oxalate levels, as well as the glycinuria fully 18 months after the drug had been stopped. The patient exhibited osteoporosis at a very young age well before menopause and years before being treated with topiramate. Thus, it may well be that an underlying genetic defect may predispose to topiramate associated RTA II and proximal tubule transport dysfunction that may linger after stopping the drug.
The elevated urinary oxalate, phosphate and uric acid excretory levels certainly predispose her to nephrolithiasis. However, the fractional excretion of phosphate was less than 20% which is considered normal and that of uric acid was mildly elevated (normal <10%). The serum phosphate level was normal, yet the tubular reabsorption rate of phosphate (61%) was substantially lower than the 80% to 85% expected for stage 2 chronic kidney disease.6 The hyperphosphaturia may have contributed to her decreased bone mineralisation, but is not likely to be attributable to the phosphaturic peptide FGF23 which was normal. Although bisphosphonate therapy (alendronate) can lead to phosphaturia and normalise the FGF 23 level, the patient exhibited bone demineralisation several years prior to initiation of bisphosphonate therapy. Nonetheless, assessment of phosphaturia and FGF23 levels could be independently influence by bisphosphonate therapy.
In summary, this article describes the first case of an black female with the triad of isolated hyperglycinuria with nephrolithiasis and osteoporosis. These findings suggest further evaluation for the possibility of a glycine excretion disorder when encountering nephrolithiasis with early-onset osteoporosis or osteopenia. It is possible that an underlying genetic defect may also predispose to disorders of proximal tubule handling of protons with drugs such as topiramate.
Patient’s perspective
Even though a basic cause was not found, I was very grateful that doctors took me seriously and tried to get to the bottom of my problems.
Learning points
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Rare clinical syndromes such as the constellation of osteopenia, renal stones and hyperglycinuria occur in black individuals but may be delayed in diagnosis.
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Genetic screening may be unrevealing due to the lack of extensive genetic databases in this population.
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A thorough evaluation of adverse effects of drugs such as the metabolic acidosis with topiramate may unmask underlying susceptibilities.
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Despite hyperphosphaturia, fibroblast growth factor 23 does not appear to have a role in the bone or nephrolithiasis associated with hyperglycinuria.
Ethics statements
Patient consent for publication
Footnotes
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Contributors HF compiled the clinical and laboratory data and wrote the original draft. SM researched the literature for the background and discussion and contributed to the initial draft. He also worked on the response to the reviewers. NFR cared for the patient, supervised the organisation of the clinical and laboratory data, literature search and edited the final draft, responses and revision of the case report.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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