• Acidémie méthylmalonique et homocystinurie
• Angiographie par tomographie par cohérence optique
• Cobalamin C defect
• Défaut en cobalamine C
• Fossettes rétiniennes
• Methylmalonic acidemia with homocystinuria
• Microangiopathie
• Microangiopathy
• Métabolisme de la vitamine B12
• Optical coherence tomography
• Optical coherence tomography-angiography
• Retinal dimples
• Tomographie par cohérence optique
• Vitamin B12 metabolism

• Humans
• Homocystinuria/complications
• Homocystinuria/diagnosis
• Female
• Adult
• Retinal Diseases/diagnosis
• Retinal Diseases/etiology
• Retinal Diseases/pathology
• Tomography, Optical Coherence
• Fluorescein Angiography
• Amino Acid Metabolism, Inborn Errors/complications
• Amino Acid Metabolism, Inborn Errors/diagnosis
• Electroretinography
• Age of Onset
• Retina/pathology
• Vitamin B 12 Deficiency/congenital

• MMACHC
• Cobalamin C disease
• Homocystinuria
• Renal tubular injury
• Thrombotic microangiopathy

• Adolescent
• Humans
• Male
• Amino Acid Metabolism, Inborn Errors/complications
• Amino Acid Metabolism, Inborn Errors/diagnosis
• Betaine/therapeutic use
• Carnitine/therapeutic use
• Carnitine/deficiency
• Carrier Proteins/genetics
• Homocystinuria/complications
• Homocystinuria/diagnosis
• Hydroxocobalamin/therapeutic use
• Kidney Tubules/pathology
• Oxidoreductases
• Thrombotic Microangiopathies/etiology
• Thrombotic Microangiopathies/complications
• Vitamin B 12

• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences
• 2019-I2M-5-046 CAMS Innovation Fund for Medical Sciences

• haemolytic anaemia
• megaloblastic cytopenia
• plasma exchange
• thrombotic microangiopathy
• thrombotic thrombocytopenic purpura
• vitamin B12 deficiency

• Humans
• Female
• Plasma Exchange
• Vitamin B 12 Deficiency/complications
• Purpura, Thrombotic Thrombocytopenic/therapy
• Purpura, Thrombotic Thrombocytopenic/complications
• Adult
• Young Adult
• Vitamin B 12/therapeutic use
• Vitamin B 12/blood

• P30 ES005022 NIEHS NIH HHS

• methylmalonic acid
• methylmalonic acidemia
• neuronal apoptosis
• neuroprotection
• plasma exosomes

• Animals
• Exosomes/metabolism
• Methylmalonic Acid
• Neurons/metabolism
• Neurons/drug effects
• Neuroprotective Agents/pharmacology
• Hippocampus/metabolism
• Mice
• Apoptosis/drug effects
• Apoptosis/physiology
• Male
• Mice, Inbred C57BL
• Amino Acid Metabolism, Inborn Errors

• Atypical hemolytic uremic syndrome
• Latin America
• complement inhibitors
• eculizumab
• ravulizumab

• Humans
• Latin America/epidemiology
• Atypical Hemolytic Uremic Syndrome/therapy
• Atypical Hemolytic Uremic Syndrome/diagnosis
• Atypical Hemolytic Uremic Syndrome/epidemiology
• Disease Management
• Antibodies, Monoclonal, Humanized/therapeutic use

• CKD
• Chronic kidney disease
• Inborn error of metabolism
• Metabolomics
• Pediatric

• Adult
• Adolescent
• Humans
• Child
• Diabetes Mellitus, Type 2
• Kidney/metabolism
• Renal Insufficiency, Chronic/genetics
• Metabolomics
• Biomarkers
• Metabolism, Inborn Errors/genetics

• arginine-rich pocket
• docking
• glutathione
• methylcobalamin
• molecular dynamics

• 12M111 United Arab Emirates University
• 12R107 United Arab Emirates University

• SERPINC1 gene mutation
• case report
• hereditary antithrombin III deficiency
• thrombosis
• thrombotic microangiopathy

• Hemolytic uremic syndrome
• complement
• thrombotic thrombocytopenic purpura

• Adult
• Humans
• Child
• Infant
• Purpura, Thrombotic Thrombocytopenic/diagnosis
• Purpura, Thrombotic Thrombocytopenic/therapy
• Thrombotic Microangiopathies/diagnosis
• Thrombotic Microangiopathies/etiology
• Atypical Hemolytic Uremic Syndrome/diagnosis
• Diagnosis, Differential
• Mutation

• Alternative pathway of complement
• Eculizumab
• Hemolytic uremic syndrome
• Shiga toxin
• Thrombotic microangiopathy

• Cattle
• Animals
• Humans
• Child
• Hemolytic-Uremic Syndrome/diagnosis
• Hemolytic-Uremic Syndrome/therapy
• Kidney Failure, Chronic
• Thrombocytopenia

cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investigate the clinical features of patients with late-onset cblC deficiency and explore diagnosis and management strategies around puberty.

This study included 56 patients (35 males and 21 females) with late-onset cblC deficiency who were admitted to our clinic between 2002 and September 2021. The diagnosis was confirmed by metabolic and genetic tests. The clinical and biochemical features, disease triggers, outcome, and associated genetic variants were examined. The onset age ranged from 10 to 20 years (median age, 12 years). Fifteen patients (26.8%) presented with symptoms after infection or sports training. Further, 46 patients (82.1%) had neuropsychiatric diseases; 11 patients (19.6%), cardiovascular diseases; and 6 patients (10.7%), pulmonary hypertension. Renal damage was observed in 6 cases (10.7%). Genetic analysis revealed 21 variants of the MMACHC gene in the 56 patients. The top five common variants detected in 112 alleles were c.482G > A (36.6%), c.609G > A (16.1%), c.658_660delAAG (9.8%), c.80A > G (8.0%), and c.567dupT (6.3%). Thirty-nine patients carried the c.482G > A variant. Among 13 patients who exhibited spastic paraplegia as the main manifestation, 11 patients carried c.482G > A variants. Six patients who presented with psychotic disorders and spastic paraplegia had compound heterozygotic c.482G > A and other variants. All the patients showed improvement after metabolic treatment with cobalamin, l-carnitine, and betaine, and 30 school-aged patients returned to school. Two female patients got married and had healthy babies.

Patients with late-onset cblC deficiency present with a wide variety of neuropsychiatric symptoms and other presentations, including multiple organ damage. As a result, cb1C deficiency can easily be misdiagnosed as other conditions. Metabolic and genetic studies are important for accurate diagnosis, and metabolic treatment with cobalamin, l-carnitine, and betaine appears to be beneficial.

The online version contains supplementary material available at 10.1186/s13023-022-02471-x.

• Adolescence
• Methylmalonic aciduria
• Multiple organ damage
• Neuropsychiatric symptoms
• Puberty
• cblC

• STEC-HUS
• haemolytic uraemic syndrome
• thrombotic microangiopathy
• thrombotic thrombocytopenic purpura

• Childhood lupus
• Genetic study
• Lupus mimics
• SLC7A7
• Systemic lupus erythematous
• TREX1

• Amino Acid Transport System y+L/genetics
• Genetic Testing
• Glomerulonephritis
• Homozygote
• Humans
• Lupus Erythematosus, Systemic/diagnosis
• Lupus Erythematosus, Systemic/genetics
• Exome Sequencing

• CMRPG3H1201-3, NMRPG3G6241-3 Chang Gung Memorial Hospital, Linkou
• CMRPG3J0501-02 Chang Gung Memorial Hospital, Linkou
• MOST106-2314-B-182A-139-MY3 Ministry of Science and Technology, Taiwan

Nutritional deficiency and genetic errors that impair the transport, absorption, and utilization of vitamin B₁₂ (B₁₂) lead to hematological and neurological manifestations. The cblC disease (cobalamin complementation type C) is an autosomal recessive disorder caused by mutations and epi-mutations in the MMACHC gene and the most common inborn error of B₁₂ metabolism. Pathogenic mutations in MMACHC disrupt enzymatic processing of B₁₂, an indispensable step before micronutrient utilization by the two B₁₂-dependent enzymes methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). As a result, patients with cblC disease exhibit plasma elevation of homocysteine (Hcy, substrate of MS) and methylmalonic acid (MMA, degradation product of methylmalonyl-CoA, substrate of MUT). The cblC disorder manifests early in childhood or in late adulthood with heterogeneous multi-organ involvement. This review covers current knowledge on the cblC disease, structure–function relationships of the MMACHC protein, the genotypic and phenotypic spectra in humans, experimental disease models, and promising therapies.

• Acute kidney injury
• Cobalamin C
• Thrombotic microangiopathy
• aHUS

• Acute Kidney Injury/etiology
• Amino Acid Metabolism, Inborn Errors
• Atypical Hemolytic Uremic Syndrome/complications
• Atypical Hemolytic Uremic Syndrome/diagnosis
• Atypical Hemolytic Uremic Syndrome/genetics
• Female
• Homocysteine
• Humans
• Hyperhomocysteinemia/complications
• Infant, Newborn
• Kidney/pathology
• Methylmalonic Acid
• Oxidoreductases/genetics
• Thrombotic Microangiopathies/pathology
• Vitamin B 12
• Vitamin B 12 Deficiency/complications
• Vitamin B 12 Deficiency/diagnosis

• P30 DK079328 NIDDK NIH HHS
• R01 DK119631 NIDDK NIH HHS

• Cobalamin
• Homocysteine
• Inborn errors
• Inherited metabolic disease
• Methylmalonic acid
• Vitamin B12

Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease.

We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene.

Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.

The online version contains supplementary material available at 10.1186/s13023-022-02179-y.

• Adult-onset
• CblC
• Cobalamin C deficiency
• Homocysteine
• Methylmalonic aciduria and homocystinuria
• Neuropsychiatric presentation
• Renal function decline
• aHUS

• MMACHC gene
• cblC
• renal complications
• thrombotic microangiopathy (TMA)
• variant c.80A>G

• case report
• cobalamin C defect
• coronary artery ectasia
• homocystinemia
• methylmalonic academia

• Cobalamin C
• Homocystinuria
• MMACHC
• Methylmalonic aciduria
• Pulmonary arterial hypertension

• Acute renal failure
• Complement system
• Thrombotic micronangiopathy
• cobalamin C defeciency

• Kim-1
• NGAL
• Opana ER
• Polyethylene oxide (PEO)
• acute kidney injury
• guinea pig
• hemolytic uremic syndrome (HUS)
• intravascular cell-free hemoglobin (Hb)
• intravascular hemolysis
• red blood cell (RBC)
• thrombotic microangiopathy (TMA)

Thrombotic microangiopathy (TMA) is a rare and potentially life-threatening condition that can be caused by a heterogeneous group of diseases, often affecting the brain and kidneys. TMAs should be classified according to etiology to indicate targets for treatment. Complement dysregulation is an important cause of TMA that defines cases not related to coexisting conditions, that is, primary atypical hemolytic uremic syndrome (HUS). Ever since the approval of therapeutic complement inhibition, the approach of TMA has focused on the recognition of primary atypical HUS. Recent advances, however, demonstrated the pivotal role of complement dysregulation in specific subtypes of patients considered to have secondary atypical HUS. This is particularly the case in patients presenting with coexisting hypertensive emergency, pregnancy, and kidney transplantation, shifting the paradigm of disease. In contrast, complement dysregulation is uncommon in patients with other coexisting conditions, such as bacterial infection, drug use, cancer, and autoimmunity, among other disorders. In this review, we performed a critical appraisal on complement dysregulation and the use of therapeutic complement inhibition in TMAs associated with coexisting conditions and outline a pragmatic approach to diagnosis and treatment. For future studies, we advocate the term complement-mediated TMA as opposed to the traditional atypical HUS-type classification.

• atypical hemolytic uremic syndrome
• complement
• eculizumab
• hypertensive emergency
• kidney transplantation
• pregnancy
• thrombotic microangiopathy

• IL-6
• TAFRO syndrome
• VEGF
• idiopathic multicentric Castleman disease (MCD)
• renal thrombotic microangiopathy

• Animals
• Castleman Disease/complications
• Castleman Disease/physiopathology
• Castleman Disease/therapy
• Humans
• Kidney/pathology
• Thrombotic Microangiopathies/complications
• Thrombotic Microangiopathies/physiopathology
• Thrombotic Microangiopathies/therapy

Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli–induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment.

Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors.

This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies.

Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli–induced hemolytic uremic syndrome, also known as “typical” HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA.

The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

• STEC-induced hemolytic uremic syndrome
• atypical hemolytic uremic syndrome
• thrombotic microangiopathy
• thrombotic thrombocytopenic purpura

Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.

• cobalamic C defect
• early-onset cblC deficit
• hemolytic uremic syndrome
• methylmalonic acidemia and homocystinuria
• thrombotic microangiopathy

• Thrombotic microangiopathy (TMA)
• hyperhomocysteinemia
• methylene tetrahydrofolate reductase (MTHFR)
• methylmalonic aciduria and homocystinuria type C protein (MMACHC)

Die thrombotische Mikroangiopathie (TMA) zeichnet sich durch eine endothelschadenassoziierte Bildung von Plättchenthromben in arteriellen und venösen Mikrogefäßen aus. Die damit einhergehende Ischämie führt zu schwerwiegenden Organdysfunktionen und kann akut lebensbedrohlich sein. Ätiologisch verbirgt sich hinter der TMA ein sehr heterogenes Erkrankungsspektrum. Neben der thrombotisch-thrombozytopenischen Purpura, die durch eine stark reduzierte ADAMTS13(„a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13“)-Aktivität gekennzeichnet ist, dem infektassoziierten klassischen hämolytisch-urämischen Syndrom (HUS) sowie dem komplementvermittelten atypischen HUS (aHUS) können weitere sehr seltene Erkrankungen oder sekundäre Formen vorliegen. Die differenzialdiagnostische Einteilung ist aufgrund unterschiedlicher therapeutischer Ansätze erforderlich. Der Einsatz neuer spezifischer medikamentöser Behandlungsmethoden hat die Prognose der TMA deutlich verbessert.

• atypical hemolytic uremic syndrome
• cortical necrosis
• glomerular sclerosis
• interstitial fibrosis
• prognosis
• thrombotic microangiopathy
• tubular atrophy

• Atypical Hemolytic Uremic Syndrome/diagnosis
• Atypical Hemolytic Uremic Syndrome/mortality
• Atypical Hemolytic Uremic Syndrome/pathology
• Atypical Hemolytic Uremic Syndrome/physiopathology
• Biopsy
• Child
• Child, Preschool
• Female
• Follow-Up Studies
• Humans
• Infant
• Kidney/pathology
• Logistic Models
• Male
• Prognosis
• Registries
• Renal Insufficiency, Chronic/diagnosis
• Renal Insufficiency, Chronic/etiology
• Renal Insufficiency, Chronic/mortality
• Renal Insufficiency, Chronic/therapy
• Retrospective Studies

Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention.

We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019.

Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group.

Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.

• C.609G > A
• Cobalamin C deficiency (cblC)
• Methylmalonic acidemia and homocysteinemia
• The MMACHC gene

• atypical hemolytic uremic syndrome
• diacylglycerol kinase ε
• membranoproliferative glomerulonephritis
• thrombotic microangiopathy

• Atypical Hemolytic Uremic Syndrome/drug therapy
• Atypical Hemolytic Uremic Syndrome/epidemiology
• Atypical Hemolytic Uremic Syndrome/genetics
• Child, Preschool
• Diacylglycerol Kinase/genetics
• Humans
• Prospective Studies
• Retrospective Studies
• United Kingdom

• Wellcome Trust
• MR/K023519/1 Medical Research Council
• MR/R000913/1 Medical Research Council
• MR/R001359/1 Medical Research Council

• Adult
• Alcohol Drinking/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Complement Inactivating Agents/therapeutic use
• Hemolytic-Uremic Syndrome/drug therapy
• Hemolytic-Uremic Syndrome/etiology
• Humans
• Male
• Pancreatitis/complications
• Recurrence

Pulmonary hypertension (PH) causes significant morbidity and mortality in diverse childhood diseases. However, limited information has been reported to obtain a good understanding of pediatric PH. Gaps exist between genome sequencing and metabolic assessments and lead to misinterpretations of the complicated symptoms of PH. Here, we report a rare case of a patient who presented with severe PH as the first manifestation without significant cardiovascular malformation and was finally diagnosed with methylmalonic aciduria (MMA) after metabolic and genomic assessments.

An 11-year-old female presented with an aggressive reduction in activity capability and shortness of breath for only 4 mo and suffered from unexplained PH. A series of examinations was performed to evaluate any possible malformations or abnormalities of the cardiovascular system and lungs, but negative results were obtained. The blood tests were normal except for manifestations of microcytic anemia and elevated total homocysteine. Computed tomography and magnetic resonance imaging failed to identify any pulmonary diseases. Cardiac catheterization examination identified a small right coronary artery to pulmonary artery shunt and severe PH. During the follow-up, PH progressed rapidly. Then, genome sequencing and metabolic disorder screening were performed, which confirmed a diagnosis of MMA with MMACHC c.80A > G/c and 609G > A mutations. Vitamin B12, betaine and bosentan were then administered as the main treatments. During the 6-mo follow-up, the pulmonary artery pressure dropped to 45 mmHg, while the right ventricle structure recovered. The patient’s heart function recovered to NYHA class II. Metabolic disorder analysis failed to identify significant abnormalities.

As emerging types of metabolic dysfunction have been shown to present as the first manifestation of PH, and taking advantage of next generation sequencing technology, genome sequencing and metabolic disorder screening are recommended to have a more superior role when attempting to understand unclear or aggressive PH.

• Pulmonary hypertension
• Methylmalonic acidemia
• Genomic sequence
• Metabolic disorder
• Case report

Thrombotic microangiopathy (TMA) syndromes are characterized by the association of hemolytic anemia, thrombocytopenia and organ injury due to arteriolar and capillary thrombosis.

We report the first case of adult onset cobalamin C (Cbl C) disease associated with anti-factor H antibody-associated hemolytic uremic syndrome (HUS).

A 19-year-old woman was admitted to the nephrology department owing to acute kidney failure, proteinuria, and hemolytic anemia with schizocytes.

TMA was diagnosed and plasma exchanges were started in emergency.

Exhaustive analyses showed 1) circulating anti factor H antibody and 2) hyperhomocysteinemia, hypomethioninemia and high levels of methylmalonic aciduria pointing towards Clb C disease. Cbl C disease has been confirmed by methylmalonic aciduria and homocystinuria type C protein gene sequencing revealing two heterozygous pathogenic variants.

The kidney biopsy showed 1) intraglomerular and intravascular thrombi 2) noticeable thickening of the capillary wall with a duplication aspect of the glomerular basement membrane and a glomerular capillary wall IgM associated with Cbl C disease related TMA.

We initiated treatment including hydroxycobalamin, folinic acid, betaine and levocarnitine and Eculizumab. Rituximab infusions were performed allowing a high decrease in anti-factor H antibody rate.

Six month after the disease onset, Eculizumab was weaning and vitaminotherapy continued. Outcome was favorable with a dramatic improvement in kidney function.

TMA with renal involvement can have a complex combination of risk factors including anti-FH autoantibody in the presence of cblC deficiency.

• Anti-factor H antibody
• Atypical hemolytic uremic syndrome
• Cobalamin C (Cbl C) disease
• Thrombotic microangiopathy

• Homocystinuria
• Left pulmonary vein ectopic drainage to coronary sinus
• Methylmalonic academia
• Noncompaction of the ventricular myocardium
• Pulmonary arterial hypertension

• Cobalamin
• MM-TMA
• Plasmic score
• Thrombotic microangiopathy
• Vitamin B12

• cobalamin C defect
• cyanosis
• pulmonary hypertension
• thrombotic microangiopathy

The thrombotic microangiopathies (TMAs) are a group of diseases characterised by microangiopathic haemolysis, thrombocytopenia, and thrombus formation leading to tissue injury. Traditionally, TMAs have been classified as either thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS) based on the clinical presentation, with neurological involvement predominating in the former and acute kidney injury in the latter. However, as our understanding of the pathogenesis of these conditions has increased, it has become clear that this is an over-simplification; there is significant overlap in the clinical presentation of TTP and HUS, there are different forms of HUS, and TMAs can occur in other, diverse clinical scenarios. This review will discuss recent developments in the diagnosis of HUS, focusing on the different forms of HUS and how to diagnose and manage these potentially life-threatening diseases.

• Complement
• Haemolytic Uraemic Syndrome
• Thrombotic microangiopathy

• early onset cobalamin metabolism defects
• hemolytic‐uremic syndrome
• homocysteine
• methylmalonic aciduria
• methylmalonic aciduria with homocystinuria
• parenteral hydroxocobalamin dose intensification
• subcutaneous injection port

• Anti-factor H antibodies
• Complement
• Plasma exchange
• Thrombotic microangiopathy

• Imerslund-Gräsbeck
• cobalamin
• folate
• intrinsic factor
• transcobalamin
• vitamin B12

• Folic Acid/metabolism
• Folic Acid Deficiency/etiology
• Folic Acid Deficiency/genetics
• Homocystinuria/etiology
• Homocystinuria/genetics
• Humans
• Infant, Newborn
• Metabolic Networks and Pathways
• Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism
• Methylenetetrahydrofolate Reductase (NADPH2)/deficiency
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Muscle Spasticity/etiology
• Muscle Spasticity/genetics
• Psychotic Disorders/etiology
• Psychotic Disorders/genetics
• Vitamin B 12/metabolism
• Vitamin B 12 Deficiency/etiology
• Vitamin B 12 Deficiency/genetics

• Cobalamin C deficiency
• Congenital nephropathy
• Déficit en cobalamine C
• Microangiopathie thrombotique
• Néphropathie congénitale
• Thrombotic microangiopathy