Cobalamin C (cblC) deﬁciency is the most commonly inherited inborn error of vitamin B12 metabolism. It is characterized by multisystem involvement with severe neurological, hematological, renal and cardiopulmonary manifestations. Disease is most commonly diagnosed early in the ﬁrst decade of life. We report a case of a 20-year-old woman who developed severe pulmonary arterial hypertension while under nephrologic follow-up for chronic kidney disease. She had initially presented at 14 years of age with visual disturbance and acute renal failure and been diagnosed with thrombotic thrombocytopenic purpura on the basis of kidney biopsy ﬁndings of thrombotic microangiopathy and compatible ADAMTS13 (a disentegrin and metalloproteinase with a thrombospondin type 1 motif member 13). When cblC deﬁciency was eventually diagnosed, remarkable improvement in cardiopulmonary function was evident upon initiation of treatment. This case highlights the importance of a timely diagnosis and initiation of treatment for cblC deﬁciency. Clinical diagnosis may be challenged by asynchronous organ symptom presentation and by misleading laboratory tests, in this case: an initial low ADAMTS13. A simple test of plasma homocysteine level should be encouraged in cases of thrombotic microangiopathy and/or pulmonary artery hypertension. Key words: ADAMTS13 activity, cobalamin C deﬁciency, end-stage renal disease, pulmonary arterial hypertension, renal thrombotic microangiopathy Received: June 14, 2017. Editorial decision: September 12, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/310/4566160 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Late onset cobalamin C deficiency | 311 Introduction Combined methylmalonic aciduria with homocystinuria, coba- lamin C (cblC) complementation type, is the most commonly inherited inborn error of intracellular cobalamin (vitamin B12) metabolism. It is caused by an autosomal recessive defect in the MMACHC gene located on chromosome 1p34 leading to impaired conversion of vitamin B12 into its two metabolically active forms: methylcobalamin and adenosylcobalamin . Methylcobalamin is a cofactor for methionine synthase, which is responsible for the remethylation of homocysteine to methio- nine . Adenosylcobalamin is a cofactor for methylmalonyl- CoA, which is responsible for the degradation of methylmalonic acid (MMA) . Deficiency in these cofactors leads to elevated plasma levels of homocysteine (vasculopathy and thrombosis), elevated plasma and urine MMA (neurological toxicity) and low plasma levels of methionine (demyelination) . The clinical presentation of patients with cblC deficiency is Fig. 1. Renal biopsy: this specimen consists of one core of renal cortex and closely related to age of onset. Presentation is usually most medulla containing up to 24 glomeruli, 3 of which are globally sclerosed. Several severe and progressive in those with early-onset cblC deficiency. glomeruli are ischemically shrunken with wrinkled capillary walls. There is Prenatal manifestations can include dysmorphic features, intrau- mild-to-moderate (25%) interstitial ﬁbrosis and tubular atrophy. Several arterio- terine growth retardation, microcephaly, hydrocephalus or les and arteries show mural ﬁbrinoid change with focal mucoid intimal thicken- congenital heart disease [4–6]. Infants and toddlers often demon- ing and ﬁbrin/platelet thrombi. strate failure to thrive, global developmental delay and neurological sequelae such as hypotonia and seizures. In glomerulonephritis, but there was no disease-causing mutation addition, some individuals may present with cytopenias or found in the C3, APLN or THBD gene. A renal biopsy showed severe progressive retinopathy. Renal thrombotic microangiopathy thrombotic microangiopathy with 3 out of 24 glomeruli globally (rTMA) and pulmonary artery hypertension (PAH) are rare, but sclerosed with moderate interstitial fibrosis and tubular atrophy severe complications have been reported in a small number of (Figure 1). cases . In contrast to early-onset cblC deficiency, individuals Given these findings, she was treated for suspected throm- with late-onset cblC deficiency presenting in adolescent or adult- botic thrombocytopenic purpura (TTP) with a course of steroids hood stage typically have less severe manifestations limited to and 12 sessions of plasmapheresis. She initiated hemodialysis, progressive cognitive decline, neuropsychiatric symptoms and which was discontinued after 6 months as she recovered some subacute combined degeneration of the spinal cord [8–10]. Renal renal function. Four months later she was thought to have a manifestations also present in an age-specific pattern: hemolytic relapse of TTP and again was treated with steroids and plasma- uremic syndrome (HUS) generally presents in infants and young pheresis for a few days. Of note, a repeat ADAMTS13 level done children with median age of 6 years as seen in a review by at that time was normal. Huemer et al. . Conversely, more adults present with renal In 2013, she remained stable with Stage 4 chronic kidney dis- damage in the form of chronic thrombotic microangiopathic glo- ease (CKD). Her vision returned to normal with a normal eye merulonephropathies [11, 12]. examination that showed resolution of her retinal hemor- We report a case of late-onset cblC deficiency presenting rhages. An abdominal ultrasound showed increased echogenic- with rTMA and PAH. ity of the renal cortical tissue of the right and left kidneys, which measured 8.7 and 9.9 cm, respectively. A transthoracic echocardiogram (TTE) showed normal left ventricular size and Case description function with a left ventricle ejection fraction (LVEF) >55%, nor- A previously healthy 14-year-old woman of Jewish descent pre- mal right ventricle size and systolic function, mild-to-moderate sented to hospital in April 2010 with sudden bilateral vision mitral regurgitation and no evidence of pulmonary hyperten- loss. She had an uneventful family history, no siblings and no sion based on the right ventricular systolic pressure (RVSP). evidence of consanguinity. She was a lifetime non-smoker and Over the next 2 years, she developed worsening dyspnea on denied use of alcohol and drugs. Her past medical history exertion until November 2015 at which point she was admitted included an unremarkable childhood with no developmental to hospital with New York Heart Association (NYHA) Class 3 problems. She was known to have hypothyroidism and ovarian symptoms, peripheral edema, abdominal distension and weight cysts. gain. A repeat TTE at that time showed significant changes with Upon admission, she was found to be severely hypertensive mildly decreased left ventricular (LV) systolic function (LVEF and fundoscopy showed hypertensive retinopathy with retinal 50%) and findings suggestive of right ventricular pressure and hemorrhages and bilateral retinal detachment. A cranial magnetic volume overload, specifically a RVSP of 65 mmHg, moderate pul- resonance imaging was done, which showed normal findings. monary regurgitation, severe tricuspid regurgitation, severely Laboratory studies showed acute renal failure, thrombocytopenia enlarged and thickened right ventricle and a 14-mm pericardial and microangiopathic hemolytic anemia. Serum complement lev- effusion (Figure 2). els were normal. Although the ADAMTS13 (a disentegrin and met- She underwent extensive work up for idiopathic PAH. A ven- alloproteinase with a thrombospondin type1 motifmember13) tilation–perfusion scan showed a low probability for pulmonary level was <5%, no antibodies were detected and genetic studies embolism. Right heart catheterization showed severe pulmo- confirmed no mutation. Genetic testing for atypical HUS was also nary hypertension (Table 1). On pulmonary function testing she negative. She was screened for membranoproliferative had an FEV1/FVC ratio of 78%, a decreased FVC and FEV1 at 2.5 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/310/4566160 by Ed 'DeepDyve' Gillespie user on 20 June 2018 312 | T. E. Petropoulos et al. Fig. 2. 1. TTE 2015: (1A) parasternal long axis showing moderate pericardial effusion, (1B) parasternal short axis showing D-shaped septum in diastole, (1C)apicalviewshowing massive RV, (1D) Tricuspid regurgitation, (1E) Pulmonary regurgitation 2. TTE 2017: (2A) parasternal long axis normal, (2B) normal in short axis, (2C) apical view normal. and 2, respectively, a decreased total lung capacity at 4.2 and a a considerably elevated homocysteine level (124 nmol/L) and an diffusing capacity for carbon monoxide of only 6.7 (32% of pre- elevated MMA level that was 100-fold over the expected level for dicted). Computed tomography thorax identified an enlarged patients with renal failure (80.15 lmol/L) (Table 1). She was noted pulmonary artery at 42 mm, a moderately sized pericardial effu- to have normal folate and vitamin B12 levels. Molecular genetic sion, extensive centrilobular ground glass nodules throughout analysis of the MMACHC gene revealed that she was positive for both lungs and some interlobular septal thickening in the right two heterozygous pathogenic variants confirming a diagnosis of lower lobe. cblC deficiency. These variants were c.271dupA, p.Arg91Lysfs14, On this presentation, she was commenced on bosentan for heterozygous (autosomal recessive condition) and c.276G>T, idiopathic PAH. Despite this, she experienced further decom- p.Glu92Asp, heterozygous (autosomal recessive condition). pensation and was started on sildenafil. She continued to show Treatment with 1 mg IM hydroxycobalamin, 3 g PO TID no improvement in her symptoms and she progressed to requir- betaine, 5 mg PO OD folic acid and 660 mg PO TID carnitine was ing home oxygen. During this period, at age 20 years, she pro- initiated. She subsequently reported significant improvement gressed to end-stage renal disease and was commenced on in her dyspnea to NYHA Class 1 and no longer required supple- dialysis. Unfortunately, her RVSP did not improve following ini- mental oxygen. A repeat TTE showed normal LV size and func- tiation of dialysis (Table 1). tion with a markedly improved right ventricular (RV) size and It was considered that her PAH could represent extra-renal function (Figure 2). A repeat right heart catheterization also manifestations of thrombotic microangiopathy (TMA). As a result, showed significant improvement (Table 1). Overall, she demon- she was considered for treatment with an anti-complement C5 strated an excellent response to treatment with a significantly monoclonal antibody, eculizumab. In the process of her work up, improved hemodynamic profile and resolution of her PAH. she was investigated for cblC deficiency, by measuring plasma Renal function also improved. After 15 months on hemodial- homocysteine levels and MMA levels. Laboratory testing revealed ysis the patient regained enough renal function so as to stop Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/310/4566160 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Late onset cobalamin C deficiency | 313 Table 1. Clinical, biochemical and hemodynamic trends a c After diuresis After PAH TX/intermittent After cblC TX Characteristic Initial 2015/11 2015/12 hemodialysis 2016/3–6 2017/1 Echocardiogram Left ventricular ejection fraction (%) 53 — 67 59 Right ventricular systolic pressure (mmHg) 65 — 122 33 Cardiac catheterization Pulmonary arterial pressure (mmHg) 72/34 (49) 69/28 (46) 60/20 (44) 50/18 (32) Pulmonary capillary wedge pressure (mmHg) 20 9 12 13 Mixed venous O (%) 51 70 Transpulmonary pressure gradient (mmHg) 30 32 8 Cardiac output (L/min) 3.58 3.6 — 6.8 Biochemical markers MMA (nmol/L) — — 80.15 2.31 Homocysteine (lmol/L) — — 124 37.7 Clinical features NYHA Class 3 3 3 1 Following aggressive diuresis. Following treatment with sildenaﬁl and bosentan and initiation of hemodialysis. Following treatment with hydroxycobalamin, betaine, folic acid and carnitine. dialysis. At the time of writing she has been off dialysis for Another interesting clinical fact is that the patient initially 6 months with an estimated glomerular filtration rate of 12 mL/ presented with low ADAMTS13 levels. One of the possible min (CKD-EPI). explanations could be the association of low ADAMTS13 with Written informed consent was obtained from the patient severe cblC deficiency . Though no mechanism has been dis- for publication of this case report and accompanying images. covered, a low ADAMTS13 may potentially be falsely low in A copy of the written consent is available for review by the patients with cblC deficiency. Editor-in-Chief of this Journal. Other renal presentations well documented in the pediatric nephrology literature include presentation with renal tubular acidosis, tubulointerstitial nephritis and acute renal failure Discussion from thrombotic microangiopathy . We report a case of a 20-year-old female with cblC deficiency who Endothelial dysfunction has been shown to play a pivotal presented with rTMA and PAH. In the absence of newborn screen- role in the pathogenesis of both rTMA and PAH . In the case ing, cblC deficiency is difficult to recognize due to the wide variety reported by Losito et al., the patient experienced improvement of clinical manifestations. In most cases, those with severe multi- in both his renal function and PAH following treatment with system involvement tend to present in early childhood. bosentan, an oral endothelin receptor antagonist [13, 15]. This, Individuals with a late-onset form typically present with a milder however, was not true for the patient in our case. In contrast, phenotype limited to neurological disturbances. Those with late- our patient experienced dramatic resolution of her PAH follow- onset cblC deficiency may be missed on newborn screening, as ing treatment of her cblC deficiency with initiation of the treat- the biochemical abnormalities at 48–72 h of life will be too mild ment regimen used in this condition (hydroxycobalamin, for identification. As a result, physicians need to consider this betaine, folate and carnitine) [13, 15]. Based on this, the poten- condition despite the presence of negative newborn screening. tial therapeutic value of bosentan and hydroxycobalamin/ The association of rTMA with PAH in cblC deficiency is rare betaine/carnitine/folate in patients with cblC deficiency and has only been described in a few cases . The majority of requires further investigation. these cases occur with early-onset cblC deficiency presenting in The patient in our case was found to be positive for two heter- childhood . As a result, a unique feature of our case was the ozygous pathogenic variants in the MMACHC gene: c.271dupA, patient’s age at the onset of her clinical manifestations. To our p.Arg91Lysfs14, heterozygous and c.276G>T, p.Glu92Asp, hetero- knowledge, only two other cases of late-onset cblC deficiency zygous. The first variant is the duplication of an adenine at presenting with rTMA and PAH have been reported. Grange ´ nucleotide position 271, which is predicted to result in a change et al. reported a case of an 18-year-old male who presented with from an arginine to a lysine at amino acid position 91 and a shift renal failure, PAH, hemolytic anemia and thrombocytopenia in the reading frame thereafter. A termination codon is predicted . Losito et al. reported a case of a 14-year-old male who pre- 13 codons beyond this change. This variant is a common patho- sented with hypertension and was found to have rTMA and genic variant in patients with methylmalonic acuduria and nephromegaly [13, 15]. He subsequently developed PAH 5 years homocystinuria and has been associated with early-onset cblC later and was diagnosed with cblC deficiency 18 years after ini- disease. In a case series by Ko ¨mhoff et al., five cases of combined tial presentation [13, 15]. As in our case, both of these cases pre- PAH and rTMA in cblC deficiency are reported. In addition to sented a considerable diagnostic challenge leading to a delayed our patient, four of these cases were positive for heterozygous diagnosis and initiation of treatment. To allow for a timely diag- mutations at nucleotide 276 in the MMACHC gene (c.276G>T nosis, it is evident that screening for cblC deficiency through or c.276G>A) . Based on this, it can be speculated that muta- evaluation of homocysteine and MMA levels needs to be tions at nucleotide 276 may be associated with the presence included in the investigation of rTMA regardless of the age at of combined PAH and rTMA in cblC deficiency. Furthermore, presentation . two of these cases had the same two heterozygous mutations Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/310/4566160 by Ed 'DeepDyve' Gillespie user on 20 June 2018 314 | T. E. Petropoulos et al. 7. Kind T, Levy J, Lee M et al. Cobalamin C disease presenting as as our patient, but in contrast, presented with early-onset disease. hemolytic-uremic syndrome in the neonatal period. J Pediatr Overall, the combined presence of rTMA and PAH in cblC Hematol Oncol 2002; 24: 327–329 deficiency is rare, but is heterogeneous with regards to age of 8. Bodamer O, Rosenblatt D, Appel SH et al. Adult-onset com- onset, presentation and response to treatment. The prognosis bined methylmalonic aciduria and homocystinuria (cblC). for these patients is variable, but mortality rates approach Neurology 2001; 56: 1113 100% in untreated patients [20, 21]. As aresult, atimely 9. Ben-Omran TI, Wong H, Blaser S et al. Late-onset cobalamin- diagnosis is important to allow for early initiation of treat- C disorder: a challenging diagnosis. Am J Med Genet A 2007; ment with hydroxocobalamin, betaine, folinic acid and 143: 979–984 carnitine . 10. Thauvin-Robinet C, Roze E, Couvreur G et al. The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 2008; 79: 725–728 Conclusions 11. Huemer M, Scholl-Burgi S, Hadaya K et al. Three new cases of We have described a unique case of late-onset cblC deficiency late-onset cblC defect and review of literature illustrating presenting with rTMA and PAH. Determining the etiology of when to consider inborn errors of metabolism beyond these conditions is necessary to evaluate the severity of disease, infancy. Orphanet J Rare Dis 2014; 9: 161 devise a management plan and assess prognosis. When consid- 12. Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect: ering a differential diagnosis for these patients, a careful meta- natural history, pathophysiology and treatment. J Inherit bolic screen should be included to ensure timely diagnosis and Metab Dis 2011; 34: 127–135 treatment of cblC deficiency . 13. Ko ¨ mhoff M, Roofthooft MT, Westra D et al. Combined pulmo- nary hypertension and renal thrombotic microangiopathy in cobalamin C deﬁciency. Pediatrics 2013; 132: e540–e544 Conflict of interest statement 14. Grange ´ S, Bekri S, Artaud-Macari E et al. Adult-onset renal None declared. thrombotic microangiopathy and pulmonary arterial hyper- tension in cobalamin C deﬁciency. Lancet 2015; 386: 1011 15. 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Clinical Kidney Journal – Oxford University Press
Published: Oct 26, 2017
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