Pediatr Nephrol DOI 10.1007/s00467-015-3110-x

BRIEF REPORT

Nephrotic syndrome and thrombotic microangiopathy caused by cobalamin C deficiency Jens C. Koenig 1 & Frank Rutsch 2 & Clemens Bockmeyer 3 & Matthias Baumgartner 4 & Bodo B. Beck 5 & Brigitta Kranz 2 & Martin Konrad 2

Received: 21 November 2014 / Revised: 12 March 2015 / Accepted: 26 March 2015 # IPNA 2015

Abstract Background Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce. Case report A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis. Renal biopsy showed TMA with ischemic glomerular collapse, foot process effacement, and tubulointerstitial fibrosis. Elevated serum levels of homocysteine suggested a cobalamin C disorder. This was confirmed by the identification of compound heterozygous mutations in the MMACHC gene. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria. After a definite diagnosis of CblC deficiency, hydroxocobalamin was introduced. Thereafter, homocysteine levels decreased, anemia resolved, and a further decline of

* Jens C. Koenig [email protected] 1

University Children’s Hospital Muenster, Muenster, NRW, Germany

2

Department of General Pediatrics, University Children’s Hospital Muenster, Münster, Germany

3

Department of Nephropathology, University Hospital Erlangen, Erlangen, Germany

4

Division of Metabolism and Molecular Pediatrics, University Children’s Hospital, Zürich, Switzerland

5

Institute of Human Genetics, University of Cologne Medical Center, Kerpenerstr 34, 50931 Cologne, Germany

proteinuria with normalization of serum protein levels was noted. Renal function remained stable. Conclusions Although uncommon, the clinical picture of CblC defects may be ruled by nephrotic syndrome mimicking glomerulonephritis, minimal change disease, or primary focal and segmental glomerulosclerosis. Key to a correct diagnosis is elevated serum levels of homocysteine, and a definite diagnosis can be confirmed by genetic testing. Keywords CblC defect . MMACHC . Nephrotic syndrome . Thrombotic microangiopathy . OH-cobalamin treatment

Introduction Renal thrombotic microangiopathy (rTMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Infection-induced acute hemolytic uremic syndrome (HUS) is the most frequent rTMA in childhood. Other causes of rTMA include disorders of complement regulation and deficiency of ADAMTS-13 [1]. Among other causes, rTMA can be associated with disorders in vitamin B12 metabolism [2]. CblC deficiency is an autosomal recessive disorder of vitamin B12 metabolism. In 2006, molecular defects in MMACHC (methylmalonic aciduria and homocystinuria type C protein) were identified [3]. Cobalamin acts as a cofactor for two known enzymes: (i) methionine synthase, catalyzing the conversion from homocysteine to methionine and (ii) methylmalonylCoA mutase, catalyzing the conversion of methylmalonylCoA to succinyl-CoA [4]. To exert its function, dietary cobalamin has to be converted into methylcobalamin and adenosylcobalamin. Mutations in MMACHC cause a deficient activation resulting in hyperhomocysteinemia, methylmalonic aciduria, and a reduced synthesis of methionine [5].

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Clinical onset of CblC deficiency usually occurs during infancy. Symptoms include failure to thrive, macrocytic anemia, macular degeneration, developmental delay, muscular hypotonia, microcephaly, seizures, and other neurological manifestations. The most frequent renal manifestation is TMA. Other renal manifestations include tubulointerstitial nephritis and proximal renal tubular acidosis. Recently, the combination of severe pulmonary hypertension and rTMA has been reported in five patients with CblC deficiency [6]. However, reports about glomerular pathologies are scarce [7, 8]. Here, we describe a patient with CblC deficiency presenting with nephrotic range proteinuria and arterial hypertension.

Case report The male patient was born to unrelated Caucasian parents with no family history of metabolic diseases. Until the age of 3 ½ years, psychomotor development was normal. Ever since repeated upper airway infections, progressive malaise and paleness were noted. At 4 years of age, he presented with pneumonia and night sweat. There was no history of gross hematuria, edema, or jaundice. On clinical examination the patient showed arterial hypertension (149/95 mmHg) and a pale skin color but no edema, jaundice, or signs of bleeding. Neurological examination was normal. Urinalysis revealed gross proteinuria (18.9 g/g creatinine) and microhematuria. Serum creatinine was normal (0.3 mg/ dl), but total serum protein was decreased to 4.5 g/dl (albumin 2.5 g/dl). Further laboratory evaluation revealed macrocytic anemia (Hb 8.4 g/dl) and increased LDH levels (479 U/l) with haptoglobin and thrombocytes being within the normal range. No fragmentocytes were seen in the blood smear. Complement levels (C3 151 mg/dl, C4 32 mg/dl) were normal and there was no evidence of autoantibodies (ANA, cANCA, pANCA, antiGBM) or acute bacterial and viral infections. Renal ultrasound showed enlarged size and echogenicity of both kidneys with regular blood flow velocity and resistance indices. Neither ascites nor pleural effusions were detectable. Echocardiography revealed left ventricular hypertrophy secondary to chronic arterial hypertension but no signs of pulmonary hypertension. No abnormalities were detectable on funduscopy. Renal biopsy revealed TMA with ischemic glomerular collapse and focal and segmental splitting of glomerular basement membranes. Minimal mesangioproliferation was found only in very few glomeruli. Two fibrin microthrombi were detectable in the preglomerular vessels without necrosis of the capillary walls. Additionally, acute interstitial nephritis with histiocytes, lymphocytes, and few eosinophils and neutrophils was present. About 50 % of the cortical tissue showed tubular atrophy and interstitial fibrosis. On electron microscopy, about 80 % foot process effacement of the podocytes,

splitting of glomerular basement membranes, and endothelial swelling without any electron-dense deposits were found. Searching for the underlying cause of rTMA, dysregulations of the complement system as well as ADAMTS13 deficiency were ruled out. Instead, hyperhomocysteinemia with serum levels of 140.7 μmol/l (405 pg/ml). Surprisingly, urinary concentrations of methylmalonic acid were within normal limits. Functional analyses in cultured fibroblasts affirmed the diagnosis of a CblC defect by showing deficient propionate incorporation compared to controls (1.6 vs. 16.1 nmol/mg prot./16 h) and partial recovery after preincubation with OHcobalamin (5.4 vs. 17.9 nmol/mg prot./16 h). Analysis of the cobalamin coenzymes revealed decreased levels of methyland adenosylcobalamin with cyanocobalamin being the predominant vitamer being pathognomonic for CblC deficiency. Finally, direct sequencing of MMACHC identified two heterozygous mutations (c.271dupA; c.276G>T). The c.271dupA mutation causes a frameshift leading to a premature stop codon (p.Arg91Lysfs*14). The nucleotide exchange at position c.276 (G>T) causes an amino acid substitution (p.Glu92Asp). Moreover, since c.276 is located at the donor splicesite of exon2/intron2, it likely interferes with correct splicing of the MMACHC-mRNA [6]. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria (5 g/g creatinine), but serum protein levels remained low (Fig. 1b). After a definite diagnosis of CblC deficiency, hydroxocobalamin treatment was introduced with subcutaneous injections of 5.000 μg for five consecutive days and twice a week thereafter. The patient also received 0.4 mg folate orally every second day. Plasma homocysteine decreased rapidly to 17.5 μmol/l (Fig. 1a) while plasma methionine remained low (20 μmol/l). Anemia improved and the mean corpuscular volume fell from 89 fl to 80 fl. Above all, a further reduction of proteinuria was noted and serum protein levels increased from 4.6 g/dl to values above 6 g/dl. Also arterial hypertension improved so that former quadruple antihypertensive medication could be reduced to a monotherapy with ramipril. Renal function remained stable. To date, there are no signs of significant hemolysis, pulmonary hypertension, neurological symptoms, or any other organ manifestations.

Discussion Different renal pathologies have been reported in association with disorders of vitamin B12 metabolism. Renal tubular

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Fig. 1 Effect of subcutaneous hydroxocobalamin treatment. a Achievement of metabolic control with rapid decrease of plasma homocysteine levels close to the normal range (

Nephrotic syndrome and thrombotic microangiopathy caused by cobalamin C deficiency.

Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestat...
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