• biochemical improvement
• cobalamin C defect
• high‐dose hydroxocobalamin therapy
• neurodevelopmental outcome

• Humans
• Hydroxocobalamin/administration & dosage
• Hydroxocobalamin/therapeutic use
• Male
• Female
• Infant, Newborn
• Child, Preschool
• Homocystinuria/drug therapy
• Neonatal Screening
• Infant
• Methylmalonic Acid
• Vitamin B 12/administration & dosage
• Child
• Vitamin B 12 Deficiency/drug therapy
• Vitamin B 12 Deficiency/congenital
• Amino Acid Metabolism, Inborn Errors/drug therapy
• Homocysteine/blood
• Methionine
• Treatment Outcome

• This work was supported by the Italian Ministry of Health with "Current Research funds"
• Italian Ministry of Health with "Current Research funds"

• Late-onset
• MMACHC protein
• Methylmalonic acidemia and homocystinuria
• cblC type

• Adult
• Female
• Pregnancy
• Humans
• Amino Acid Metabolism, Inborn Errors/diagnosis
• Hyperhomocysteinemia
• Homocystinuria/diagnosis
• Methylmalonic Acid
• Vitamin B 12/metabolism

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.

• MMACHC
• cobalamin
• inherited metabolic disorders
• methionine synthase
• methylmalonyl-CoA mutase
• vitamin B(12)
• vitamin B(12) deficiency

• cardiac dysfunction
• cobalamin C type
• congenital heart disease
• homocystinuria
• methylmalonic acidaemia
• pulmonary arterial hypertension

• DNA methylation
• epigenetics
• extrauterine growth restriction (EUGR)
• pulmonary arterial pressure (PAP)
• transgenerational inheritance

• neonatal screening
• methylmalonic acidemia
• mmachc gene
• cobalamin c deficiency
• prognosis
• influencing factors

• Adolescent
• Amino Acid Metabolism, Inborn Errors/genetics
• Child
• Child, Preschool
• Humans
• Infant
• Infant, Newborn
• Mutation
• Oxidoreductases/genetics
• Retrospective Studies
• Young Adult

• Endocrinological disorders
• Inborn errors of metabolism
• Obstructive lung disease
• Restrictive lung disease

• alveolar hemorrhage
• cobalamin C deficiency
• homocysteinemia
• methylmalonic acidemia
• microangiopathy
• pulmonary

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

• Metabolic disease
• Obstructive
• Pulmonary hypertension
• Restrictive

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

Cobalamin C (cblC) defect is the most common inborn error of Vitamin B12 metabolism often causing severe neurological, renal, gastrointestinal and hematological symptoms. Onset with pulmonary hypertension (PAH) and atypical hemolytic-uremic syndrome (aHUS) is rare.

We describe the case of a 2-years old child, previously in good health, admitted to the hospital with severe respiratory symptoms, rapid worsening of clinical conditions, O₂ desaturation and palmo-plantar edema. The patient showed PAH and laboratory findings compatible with aHUS. cblC defect, an inborn error of metabolism, was identified as the cause of all the symptoms described (cardiac, respiratory and renal involvement). Results of neonatal screening for inborn errors of metabolism had been negative.

Administration of IM OHCbl (intramuscular hydroxocobalamin), oral betaine and symptomatic treatment with diuretics and anti-hypertensive systemic and pulmonary drugs induced dramatic improvement of both cardiac and systemic symptoms.

In this case of cblC defect the metabolic treatment completely reverted symptoms of aHUS and PAH. The course was favorable, and the prognosis is what we foresee for the future.

• Atypical hemolytic-uremic syndrome
• Cobalamin C
• Pulmonary hypertension
• aHUS

• Cancer
• Embolie pulmonaire tumorale
• Hypertension artérielle pulmonaire
• Microangiopathie thrombotique tumorale pulmonaire
• Pulmonary hypertension
• Pulmonary tumor thrombotic microangiopathy
• Tumor pulmonary embolism

• Child, Preschool
• Hemolytic-Uremic Syndrome/etiology
• Homocystinuria/complications
• Homocystinuria/diagnosis
• Humans
• Hypertension, Pulmonary/etiology
• Male
• Vitamin B 12 Deficiency/complications
• Vitamin B 12 Deficiency/congenital
• Vitamin B 12 Deficiency/diagnosis

Combined methylmalonic acidemia (MMA) and homocysteinemia are a group of autosomal recessive disorders caused by inborn errors of cobalamin metabolism, including CblC, D, F, and J, with cblC being the most common subtype. The clinical manifestations of combined MMA and homocysteinemia vary, but typically include neurologic, developmental and hematologic abnormalities.

We report 4 children with combined MMA and homocysteinemia who presented predominantly with late-onset diffuse lung diseases (DLD). Of these, 3 accompanied by pulmonary arterial hypertension (PAH), 1 accompanied by hypertension, and 2 accompanied by renal thrombotic microangiopathy (TMA), which was confirmed by renal biopsy. This confirms combined MMA and homocysteinemia should be considered in the differential diagnosis of DLD with or without PAH or renal TMA.

• Children
• Diffuse Lung disease
• Homocysteinemia
• Homocystinuria
• Hypertension arterial pulmonary
• Methylmalonic acidemia

• Atypical hemolytic uremic syndrome
• Children
• Cobalamin C defect
• Pulmonary arterial hypertension

• Animals
• Homocysteine/genetics
• Humans
• Methionine/genetics
• Methylation/drug effects
• Methylenetetrahydrofolate Reductase (NADPH2)/deficiency
• Proto-Oncogene Proteins c-cbl/deficiency
• Vitamin B 12/pharmacology
• Vitamin B 12/therapeutic use

• European Union in the framework of the Health Program.

• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• DNA/genetics
• DNA Mutational Analysis
• Echocardiography
• Female
• Humans
• Hypertension, Pulmonary/diagnosis
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/genetics
• Infant
• Metabolism, Inborn Errors/complications
• Metabolism, Inborn Errors/genetics
• Metabolism, Inborn Errors/metabolism
• Mutation
• Oxidoreductases
• Pulmonary Wedge Pressure
• Vitamin B 12/metabolism

• Age of Onset
• Brain/pathology
• Carrier Proteins/genetics
• Child
• Child, Preschool
• Disease Progression
• Ethnicity
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Metabolism, Inborn Errors/genetics
• Metabolism, Inborn Errors/metabolism
• Metabolism, Inborn Errors/therapy
• Oxidoreductases
• Prognosis
• Proto-Oncogene Proteins c-cbl/genetics
• Surveys and Questionnaires
• Vitamin B 12/metabolism

• Mitochondrial diseases
• Persistent pulmonary neonatal hypertension
• TMEM70 defect

• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/metabolism
• Cardiomyopathy, Hypertrophic/pathology
• Child, Preschool
• Female
• Humans
• Hyperammonemia/metabolism
• Hyperammonemia/pathology
• Hypertension, Pulmonary/genetics
• Hypertension, Pulmonary/metabolism
• Hypertension, Pulmonary/pathology
• Infant
• Infant, Newborn
• Male
• Membrane Proteins/deficiency
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/metabolism
• Mitochondrial Diseases/pathology
• Mitochondrial Proteins/deficiency
• Mitochondrial Proteins/genetics
• Mitochondrial Proteins/metabolism
• Mutation
• Nitric Oxide/administration & dosage
• Piperazines/administration & dosage
• Purines/administration & dosage
• Sildenafil Citrate
• Sulfones/administration & dosage

• biomarkers
• echocardiography
• imaging
• magnetic resonance
• pediatric
• pulmonary arterial hypertension
• right ventricle