Kidney-Limited Microangiopathy Associated with Methionine Synthase (Cobalamin G) Deficiency in a Pediatric Patient: Case Report and Review of the Literature

Inborn errors of cobalamin metabolism have a wide range of clinical presentations including hematologic, neurologic, cardiovascular, ocular, and kidney manifestations [1]. Thrombotic microangiopathy (TMA) is a recognized sequela of methylmalonic aciduria and homocystinuria, cobalamin deficiency type C [2]. TMA has only rarely previously been reported in methionine synthase (cobalamin G) deficiency [3‒5]. Here, we report on a pediatric patient with cobalamin G deficiency who was found to have kidney limited microangiopathy.

Seven-year-old Latino boy with concern for cobalamin G deficiency who presented with hypertension found on routine clinic visits. The concern for cobalamin G deficiency was initially noted at birth when the patient had a positive newborn screen for low methionine (7) that was identified at 6 days of age. There was no increase in blood methylmalonic acid.

The patient’s birth history was otherwise unremarkable. Confirmatory testing showed a markedly increased blood homocysteine level (223.5 μmol/L). He started treatment, which included cobalamin injections, betaine, methionine, carnitine, and pyridoxine. His clinical course had previously only been significant for mild developmental delay and hypothyroidism (on levothyroxine). There was no family history of kidney disease.

Whole exome sequencing was pursued and no established clinically significant single nucleotide variants or small deletions and insertions (<10 bp) were identified. In total, 15 homozygous and 341 heterozygous rare protein-altering variants of uncertain clinical significance were identified across 340 genes including a heterozygous variants of uncertain clinical significance in transcobalamin 1 (TCN1) (c.473A>G; p.Asn158Ser) which was inherited from the patient’s father. This missense mutation was not predicted to result in functional deficiency of the TCN1 protein and was thought to likely not be the underlying cause of the patient’s biochemical abnormalities. A cobalamin complementation assay performed on cultured skin fibroblasts confirmed likely cobalamin G deficiency.

The patient had a long history of elevated blood pressure (90th percentile for age) that had not required medical intervention; however, at a routine clinic visit at 7 years of age, he was found to have severe hypertension (161/123 mm Hg). The patient also endorsed occasional headaches. Additionally, a urinalysis revealed new-onset hematuria (2+ on dipstick; 12 RBC/HPF) and proteinuria (3+ on dipstick; elevated urine protein to creatinine ratio 8.3 mg/mg. Additional laboratory work showed elevated serum creatinine 0.85 mg/dL and mildly elevated lactate dehydrogenase (310 U/L). Normal hematological parameters including platelet count (390,000), haptoglobin (56 mg/dL), and hemoglobin (12.8 g/dL) were observed. No schistocytes were present on a peripheral smear. Complement values were not low C3 (162 mg/dL) and C4 (42 mg/dL). Aldosterone and renin activity levels were also normal 19.6 ng/dL and 6.6 ng/mL/h, respectively. Pheochromocytoma workup was initiated, which showed normal metanephrines (0.19 nmol/L) and normetanephrines (0.44 nmol/L).

The patient was admitted with concern for thrombotic microangiopathy causing hypertensive urgency. Cardiac echocardiogram did not show coarctation nor left ventricular hypertrophy. Kidney ultrasound was significant only for an area of possible renal artery stenosis in the left kidney; however, follow-up CT angiogram was negative for stenosis. A kidney biopsy was obtained to further investigate hypertension, hematuria, and proteinuria.

The biopsy (Fig. 1) contained 67 glomeruli (42 globally sclerotic). Light microscopy demonstrated thickened glomerular capillary walls with frequent remodeling and double contour formation. Mesangial regions were expanded by sclerosis with features of healed mesangiolysis and mild hypercellularity. Eight glomeruli exhibited segmental sclerosis. There was no endocapillary hypercellularity, necrosis, crescent formation, or membranous injury. Acute thrombi were not present. There was moderate (40%) interstitial fibrosis/tubular atrophy. Focal interstitial foam cells were present. Arteries exhibited minimal intimal sclerosis and arterioles exhibited very focal intimal hyalinosis without mucoid intimal edema, onion skin change, luminal thrombosis, or necrosis. There was no significant glomerular or tubulointerstitial immunofluorescence staining. Electron microscopic studies demonstrated marked widening of subendothelial spaces by electron lucent flocculent material, layers of new subendothelial basement membranes, and cellular interposition. Occasional mesangiolysis was present. Glomerular and peritubular capillary endothelial cells showed cytoplasmic swelling. Glomerular basement membranes exhibited variable corrugation and were of appropriate thickness for the age of the patient. There was segmental moderate podocyte foot process effacement. There were no tubuloreticular inclusions or immune complex deposits. A diagnosis of glomerular predominant chronic active microangiopathy with associated secondary focal segmental glomerulosclerosis was rendered. The microangiopathy was favored to be related to the patient’s methionine synthase (cobalamin G) deficiency.

The patient’s blood pressure was acutely controlled with nicardipine drip. He was subsequently started on amlodipine and lisinopril. He was continued on betaine, hydroxocobalamin, folic acid, and methionine. The patient’s blood pressures have been stable as has his serum creatine (0.53–0.65 mg/dL) since the biopsy. The hematuria and proteinuria have been persistent and stable 1-year post-symptomatic onset.

Methionine synthase (cobalamin G) deficiency is a rare inborn error of cobalamin metabolism typically characterized by megaloblastic anemia and neurological symptoms as well as elevated levels of plasma homocysteine, low levels of serum methionine and normal urine and plasmatic methylmalonic acid levels. The TMA is thought to result from endothelial damage induced by hyperhomocysteinemia, impairment of the nitric oxide-dependent inhibition of platelet aggregation, or the procoagulant state of the endothelium, leading to the formation of microthrombi [6].

The current case is somewhat atypical due to the absence of megaloblastic anemia and presentation driven by sequelae of the kidney limited TMA. No definite genetic etiology was identified on whole exome sequencing. Complementation assays performed on the patient’s cultured fibroblasts were confirmatory of cobalamin G deficiency. It is thus likely that the patient carries a mutation in the gene that causes cobalamin G deficiency outside of coding regions.

Eight cases (including current case) of microangiopathy associated with methionine synthase (cobalamin G) deficiency have been reported and only a single prior report provided a detailed description of a kidney biopsy with accompanying images (Table 1) [3‒5, 7, 8]. TMA onset is typically present before age 2; however, the current case and one other occurred later in childhood and adolescence. Common clinical findings included hypertension (5/8), systemic TMA features (5/8), proteinuria (4/8), and hematuria (3/8). At least two TMA cases (including the current case) were kidney limited [5]. Acute kidney injury (2/8) was relatively uncommon, and only 1 patient required dialysis at presentation [7]. When available, the genetic studies demonstrated compound heterozygous 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene mutations with a high number of splice site variant mutations, and the remainder composed of missense point mutations.

Three prior patients had kidney biopsies reported. In an adolescent patient, a glomerular predominant chronic TMA with conspicuous capillary wall double contours as well as lesions of focal segmental glomerulosclerosis was observed [5]. In at least 1 younger patient, acute TMA involving both glomeruli, and arterioles was observed [3]; however, more detailed information regarding kidney biopsy findings besides the current case was extremely limited. In the current case presentation, the TMA was also predominantly kidney and glomerular limited with active and chronic features and presented later in life than other reported cases; although subclinical TMA was most likely ongoing for some time prior to the biopsy, given the high degree of chronic glomerular changes observed.

The differential diagnosis for microangiopathy on kidney biopsy is broad. In children, the main causes of microangiopathy include Shiga toxin-induced hemolytic uremic syndrome, complement-mediated TMA, and Streptococcus-induced TMA. Other rare genetic disorders such as other vitamin B12 metabolism defects (cobalamin C defects) and coagulation disorders (e.g diacylglycerol kinase epsilon mutation) can also manifest as a microangiopathy and should be considered in the differential diagnosis, especially patients <2 years of age [9]. In the above case, the patient’s congenital metabolic deficiency was determined to be the most likely etiology for the microangiopathy. No evidence for any infectious etiology as a trigger was identified. Diacylglycerol kinase epsilon deficiency or other genetic TMAs were not revealed by whole exome sequencing. Further complement functional assays were not pursued. ADAMTS13 studies were not pursued; however, no other features of thrombocytopenic purpura were present in this case. The patient was not on any medication or supplements associated with TMA. While some consider chronic hypertension as an etiology for microangiopathies; in this case, in the absence of other etiologies for hypertension, we believe the microangiopathy and subsequent kidney injury were the underlying etiology for the hypertension.

Continued treatment with hydroxocobalamin, folic acid, methionine, and new lisinopril and amlodipine treatment were pursued in the above case resulting in improved chronic hypertension and stable hematuria and proteinuria. Prior reported cases have predominantly pursued hydroxocobalamin and to varying degrees ACE inhibitor, folic acid supplementation, as well as other supplements. Most patients showed persistent stable or improved chronic hypertension and persistent hematuria/proteinuria. One patient showed resolution of proteinuria [5] and one had progressed to end stage kidney disease [3]; long-term follow-up on most patients was limited.

This case report highlights the differential diagnosis of kidney-limited TMA includes cobalamin G disorder which may present with hypertension, proteinuria, and hematuria. Furthermore, review of prior reported cases demonstrates variable clinical presentation and responses to cobalamin supplementation and ACE inhibition.

Informed written consent was obtained from the patient’s parent for publication of the details of their medical case and any accompanying images. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines.

The authors have no conflicts of interest to declare.

The authors do not have any research funding relevant to this study.

J.E.Z. and R.S. both wrote this manuscript.

The data that support the findings of this study are not publicly available due as they contain information that could compromise the privacy of research participants but are available from the corresponding author (J.E.Z.) upon reasonable request.