In the present study, we report the case of a patient with bilateral nephrolithiasis, who was subsequently diagnosed with hyperglycinuria, left varicocele, nutcracker syndrome, and right parathyroid adenoma. Based on the important role of genes in disease development, we also analyzed and identified a mutation in the SLC6A19 gene. Our study showed that gene mutations may be a crucial factor in the development of hyperglycinuria and further emphasizes the importance of the timely detection, management, and prevention of hyperglycinuria.
The description of nutcracker syndrome was presented in our report because it was a relatively rare disease and was deemed an important aspect of the past medical history of this patient. After searching for the relevant literature and conducting bioinformatics analysis, we could not identify a common genetic pathway between nutcracker syndrome and hyperglycinuria. Hence, we consider that the coexistence of these two diseases in this patient might be a coincidence. Nutcracker syndrome can be classified as either anterior or posterior. Diagnosis of nutcracker syndrome is challenging due to the absence of definite and uniform criteria [5]. The gold standard way for diagnosing nutcracker syndrome is to measure the renal venous pressure by venography; however, this is an invasive method for patients. Doppler ultrasonography is regarded as a helpful and convenient imaging examination for nutcracker syndrome. Both CT and magnetic resonance imaging can reveal collateral circulation in the renal hilum, premature opacification of the left gonadal vein (suggestive of reflux), and reduction of the aortomesenteric angle (< 10º) [6]. The management of nutcracker syndrome is mainly based on patient age, symptom severity, and expectation for symptom reversal. When the patients are young and symptoms are not obvious, observational or symptomatic treatment is the preferred option. Endovascular surgical procedures or open surgery can be an alternative in cases with severe symptoms. The patient in our report had nutcracker syndrome; however, he did not develop recurrent varicocele or other symptoms such as hematuria or proteinuria. Moreover, the patient was relatively young. Therefore, we did not further treat his nutcracker syndrome and asked him to undergo regular follow-up.
Hyperparathyroidism can present as a solitary disease, or as a part of a syndrome. Germline mutations in the RET, CDC73, and CASR genes have been detected in greater than 10% of patients with hyperparathyroidism [7]. Among patients with multiple endocrine neoplasia type 2 A hyperparathyroidism, 97% showed gene mutations. Such individuals have an increased risk for development of parathyroid adenoma or hyperplasia, medullary carcinoma of the thyroid, and pheochromocytoma [8]. Furthermore, patients with somatic genetic mutations may develop sporadic parathyroid carcinoma. Therefore, patients with hyperparathyroidism could be counseled on germline genetic mutation examination.
In patients with kidney stones, conservative treatment can be applied for smaller stones. Fabris et al. reported that the use of potassium citrate showed good efficacy with a 48% decrease in the calcium levels and a 75% increase in the citrate levels [9]. Some lifestyle changes, such as increasing the intake of water, fruits, and vegetables, may also be helpful. However, if the stones are relatively large, minimally invasive procedures such as f-URS and percutaneous nephrolithotripsy can be used as alternatives [10]. Bilateral nephrolithiasis in this patient were relatively large based on imaging examinations. Thus, f-URS was performed to remove his nephrolithiasis.
Hyperglycinuria usually results from a defect in glycine metabolism or a disturbance in renal tubular reabsorption of glycine [4]. In some patients, factors such as high-glycine diet or total parenteral nutrition can increase glycine levels in the blood. When the elevated blood glycine levels exceed the reabsorption capacity of the renal tubules, the urine glycine levels can subsequently increase, thereby leading to hyperglycinuria. In other patients, a genetic defect or other unknown reasons can trigger a disturbance in renal tubular reabsorption of glycine, which can increase the glycine levels in the urine and cause hyperglycinuria [11].
Glycine plays an important role in oxalate metabolism and may result in an increase in oxalate levels [12]. Excess glycine can directly transform into glyoxylate by oxidative deamination or the serine-glycolate pathway [4]. Oxalate is formed as an end product of glyoxylate metabolism [13]. Thus, the excess glycine can be converted into oxalate following liver metabolism. Oxalate is secreted by glomerular filtration in the proximal nephrons. Urinary oxalate density can increase up to 40% due to continuous abundance from the glycine pool [14]. The increased oxalate levels in the urine can further promote calcium oxalate stones formation.
However, one recent study reported that high urine glycine levels may also play a potential role in preventing urine oxalate formation. In the study, Lan et al. [15] found that urine glycine levels in patients with calcium oxalate kidney stones were significantly lower than those in healthy people. Furthermore, they revealed that glycine could significantly attenuate ethylene glycol-induced calcium oxalate crystal depositions in the rat kidney by decreasing urine oxalate. Their finding might be different from previous view that glycine could increase oxalate. Consequently, we considered that glycine metabolism was relatively complex in human beings [16]. The conversion of glycine to oxalate may be reversible and depend on many factors.
Some previous reports revealed that the patients with hyperglycinuria were usually complicated by calcium oxalate nephrolithiasis [4, 13]. The patient in the present report was also consistent with this clinical manifestation. Therefore, we speculated that the typical symptom and stone composition in patients with hyperglycinuria may be nephrolithiasis and calcium oxalate, respectively. The formation of nephrolithiasis is a complex process associated with multiple causes. The combination of hyperglycinuria and calcium oxalate nephrolithiasis may indicate a potential link between the two, and relevant gene mutations could be significant.
The SLC6A19 gene can code the amino acid transporter B0AT1, which is crucial for transporting amino acids in the liver, kidney, and intestine [17]. It is well-known that the glomeruli in the renal cortex function to produce an ultrafiltrate. B0AT1 contributes to the reabsorption of amino acids from the ultrafiltration to the blood. Therefore, mutations in the SLC6A19 gene may result in a disturbance in renal reabsorption of amino acids and possible defects in the transportation of relevant metabolites. Disturbance in renal reabsorption of glycine can result in hyperglycinuria. Moreover, a defect in oxalate transportation may increase the urine oxalate content and trigger the damage to the renal tubular epithelial cells, which in turn could promote the formation of calcium oxalate stones [17]. The patient in our report did not receive a high-glycine diet or total parenteral nutrition. However, his urine glycine and oxalate levels were elevated. Thus, we considered that hyperglycinuria and calcium oxalate nephrolithiasis in this patient might mainly result from a disturbance in renal reabsorption of glycine and a defect in oxalate metabolism due to the SLC6A19 gene mutation. Nevertheless, the exact association and mechanism need to be explored and demonstrated in more patients in the future.
The treatment of diseases associated with the B0AT1 transporter or SLC6A19 gene is controversial. Some experts assume that pharmacological inhibition of the B0AT1 transporter or the SLC6A19 gene can be regarded as a method to manage amino acid imbalance with few side effects [18, 19]. The main mechanism of action of the inhibitors depends on the concurrent inhibition of amino acids in the kidneys and intestine in the presence of competing substrates [20, 21]. Javed et al. [22] attempted to predict the inhibition of SLC6A19 using biomarkers in biological samples, such as urine, plasma, and feces. They found that these biomarkers could successfully assess transporter inhibition in a mouse model. Their findings indicated that metabolite biomarkers could be used to confirm the inhibition of the corresponding transporters in the intestine and kidneys. Meanwhile, this also provide significant information on the management of diseases associated with SLC6A19 gene mutations.
The patient in our report had hyperglycinuria combined with left varicocele, bilateral nephrolithiasis, nutcracker syndrome, and parathyroid adenoma. The co-occurrence of these diseases in one patient is relatively rare. Furthermore, we found a relevant mutation in the SLC6A19 gene and possible genetic mechanisms of its association with hyperglycinuria. Therefore, this report is unique because the case was rare with many concurrent diseases in one patient, and it is the first report of the SLC6A19 gene mutation in a Chinese young man with hyperglycinuria.
In conclusion, this article describes the first case of a Chinese young man with hyperglycinuria and nephrolithiasis. It appears that the SLC6A19 gene mutation may have played a significant role in the development of hyperglycinuria in this patient. Further evaluation for the possibility of a glycine excretion disorder could be considered when encountering nephrolithiasis.
