RARE DISEASE
Methylmalonic acidemia with homocystinuria
Methylmalonic acidemia with homocystinuria
Methylmalonic acidemia with homocystinuria
Synonyms: Combined defect in adenosylcobalamin and methylcobalamin synthesis, Methylmalonic aciduria with homocystinuria
Synonyms: Combined defect in adenosylcobalamin and methylcobalamin synthesis, Methylmalonic aciduria with homocystinuria
Synonyms: Combined defect in adenosylcobalamin and methylcobalamin synthesis, Methylmalonic aciduria with homocystinuria
Drug discovery
3
drugs
With orphan designations
Overview
Methylmalonic acidemia with homocystinuria (MMA-HCU) is an autosomal recessive inborn error of vitamin B12 metabolism, primarily caused by mutations in MMACHC (cblC type). Impaired cobalamin processing leads to accumulation of methylmalonic acid and homocysteine, causing multisystem sequelae: developmental delay, neurological deficits, megaloblastic anemia, and renal dysfunction. Early-onset forms present with failure to thrive, seizures, and vision abnormalities; late-onset cases involve neuropsychiatric decline. Management includes hydroxocobalamin, betaine, protein-restricted diets, and metabolic monitoring [1][6][13].
Burden
Mortality: Up to 40% in untreated early-onset cases; reduced with early intervention [4][9][14].
Morbidity: Chronic kidney disease, intellectual disability, movement disorders, and retinopathy [4][9][14].
Healthcare impact: Lifelong monitoring, high treatment costs, and significant caregiver burden [4][16].
Therapies
Hydroxocobalamin injections: Restore cobalamin activity and reduce methylmalonic acid [3][13][16].
Betaine: Lowers homocysteine levels via alternative remethylation pathways [3][8][16].
Dietary management: Protein restriction, specialized formulas, and avoidance of fasting/metabolic stressors [5][8][16].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
113 drug discovery papers about Methylmalonic acidemia with homocystinuria, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
113 drug discovery papers about Methylmalonic acidemia with homocystinuria, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-05 | A Case of High Pulmonary Hypertension Associated with Methylmalonic Aciduria and Homocystinuria in a Young Child
This article describes a case of severe pulmonary hypertension in a 3-year-old boy with postmortem detection of pathogenic heterozygous variants of the MMACHC gene, which are associated with methylmalonic aciduria and homocystinuria. Awareness and timely diagnosis of this rare disorder, along with correction of metabolic disturbances associated with defects in intracellular vitamin B12 metabolism, can improve outcomes, leading to complete or partial remission of pulmonary hypertension.
2026-06-01 | Neuropsychiatric Manifestations in Methylmalonic Acidemia and Homocystinuria of Adult Presentation. A Case Report
Introduction Each neurometabolic disorder is individually rare, but their cumulative incidence is relatively high, around 1/1,500 to 1/5,000 live births. In neurometabolic diseases, there is a deficit in the transformation of a substrate that prevents the production of one or more enzymes. Common neuropsychiatric manifestations associated with vitamin B12 deficiency include motor, sensory, and autonomic symptoms, cognitive impairment, mood disorders, and psychotic symptoms. Psychiatric manifestations are considered a particular form of presentation which, precisely because of their isolated nature, make diagnostic identification difficult, given that behavioral changes in these NME generally have an insidious onset. Objectives Objective: To report the neuropsychiatric alterations associated with inborn errors of vitamin B12 metabolism in adults Methods Case report. Results 30-year-old woman who starts with anxiety, difficulty in daily organization, suspected to be reactive to active mourning and initiation of Duncan’s hyperproteic diet; 7 months later she debuts with acute encephalopathy (confusion, bradypsychia, parkinsonism), admitted to ICU for focal status epilepticus coinciding with the initiation of parenteral feeding. Brain MRI showed pericerebellar and basal ganglia hyperintensity, although LP showed no alterations, Hashimoto’s encephalopathy was initially diagnosed with minimal response to corticosteroids. The evolution in the following 4 months was torpid, persisting frontal-subcortical dysfunction, with bradypsychia, loss of skills, memory, language, gait and behavioral alterations (irritability, agitation), as well as psychotic symptoms with polymorphous delusional ideation: of harm, control and pregnancy with auditory hallucinations. She was admitted to Neurology to study the picture and was referred to Psychiatry. Due to hyperhomocysteinemia and hyperammonemia and aciduria in urine, genetic screening was performed to rule out alteration of Vitb12 metabolism, diagnosing methylmalonic aciduria with homocystinuria due to deficiency in MMACHC (cbIC) (anomaly in the synthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are coenzymes derived from Vitb12). She was treated with Vit B12 and B9 supplements, L-carnitine, betaine, and paliperidone, with significant early improvements in biochemical parameters, and later in clinical manifestations. After discharge he did not present psychosis again. Conclusions alterations in cobalamin metabolism may present psychiatric alterations. The manifestations are usually very polimorfic. Disclosure of Interest None Declared
2026-03-04 | Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting.
MMA and CBS deficiency are rare autosomal recessive metabolic disorders caused by defects in cobalamin metabolism and cystathionine-beta-synthase activity, respectively. Advanced molecular genetic techniques, have become essential for diagnosing these conditions. This study aimed to analyze the genetic variations in three MMA and four CBS deficiency cases using WES and correlate the findings with clinical, biochemical, and treatment outcomes. Clinical evaluation, biochemical testing, neuroimaging, and WES were performed. WES data were analyzed using the reference genome GRCh37, and variants were classified according to ACMG guidelines. Treatment outcomes were monitored for three months post-intervention. In MMA cases, a homozygous pathogenic variant (c.394 C > T, p.Arg132Ter) in MMACHC was identified in all three patients. Biochemical abnormalities included methylmalonic aciduria, elevated homocysteine, and megaloblastic anemia. Hydroxycobalamin therapy improved behavioral, cognitive, and dermatological symptoms, though residual neuropathy persisted in one case. In CBS deficiency, pathogenic variants in CBS (c.992 C > T, p.Ala331Val; c.862 G > A, p.Ala288Thr; c.700 G > A, p.Asp234Asn) were identified. Clinical features included developmental delayed milestones, lens dislocation, and vascular complications. Treatment outcomes varied based on early diagnosis and compliance. This study highlights the importance of newborn screening program with WES in diagnosing and managing MMA and CBS deficiency, facilitating early intervention, improving clinical outcomes, and supporting precision medicine approaches. Early newborn screening and diagnosis are critical for effective treatment and improved patient outcomes. Novel clinical and pathogenic variants will expand the current understanding of these disorders. WES enhances the diagnostic precision for MMA and CBS deficiency, facilitating timely intervention and superior clinical management. Accurate and early detection of treatable IEMs through NBS can significantly reduce disease burden and healthcare costs.
2026-03-01 | 3PC-015 Development of injectable hydroxocobalamin microcapsules for the treatment of homocystinuria and methylmalonic aciduria
Background and Importance
Methylmalonic acidemia with homocystinuria type CblC is a severe, congenital disorder caused by a defect in vitamin B12 metabolism. Treatment with hydroxocobalamin improves some symptoms but has limited effectiveness on ocular structures due to its poor permeability through the blood-ocular barrier. This results in blindness in most patients, and topical treatment is ineffective due to poor corneal absorption. Despite treatment, patients often suffer a reduced quality of life.
Aim and Objectives
In this project, a formulation is exposed to solve this problem. The formulation consists of a suspension of drug-loaded microcapsules of PEOT/PBT polymer for extended release by intravitreal administration.
Material and Methods
The methodology used to make the microcapsules was double emulsion-solvent evaporation using ultrasound. The emulsion was W/O/W sign. The microparticles presented an aqueous core with hydroxocobalamin and a sustained release polymeric shell. Scanning electron microscopy (SEM) was performed to verify the homogeneity of the outer shell. To obtain microcapsules with an adequate release profile, a rotational mathematical design consisting of 23 different tests and an ANOVA analysis was carried out. The intention was to maximise size homogeneity and encapsulation performance.
Results
The results showed a maximum microcapsule load, better release profile, and greater homogeneity with a lower weight polymer and intermediate agitation speed. Further studies will be needed to assess the in vivo ocular viability of the formulation.
Conclusion and Relevance
The studies carried out to date indicate that microcapsules have potential in the ocular treatment of this disease. Although the findings are not discouraging, much more evidence is needed to bring this formulation to the clinical setting. It would be interesting to perform longer release profiles and in vivo tests.
References and/or Acknowledgements
1. Rickes EL, Brink NG, Koniuszy FR, Wood TR, Folkers K. Crystalline vitamin B12. Science. 16 de abril de 1948;107(2781):396–7. 2. Wang Y, Liu C, Fan L, Sheng Y, Mao J, Chao G, et al. Synthesis of biodegradable poly(butylene terephthalate)/poly(ethylene glycol) (PBT/PEG) multiblock copolymers and preparation of indirubin loaded microspheres. Polym Bull. 1 de enero de 2005;53(3):147–54. 3. Cuello-Rodríguez S, Blanco-Fernández G, García-Otero X, Díaz-Tome V, Otero-Espinar FJ, Seoane-Viaño I. Long acting injectables & implants: advances in intraocular drug delivery. Int J Pharm. 2025 Oct 15;683:126058. doi: 10.1016/j.ijpharm.2025.126058.
Conflict of Interest
No conflict of interest
2025-12-24 | Incidence of Organic Acid Disorders in 13 Million Chinese Newborns: A Systematic Review and Meta-Analysis.
Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70-118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China.
proteins
2023-06-09 | Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant.
Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC (hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10 (RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
2017-06-02 | Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1
Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1–ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis. Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1–ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.
2010-12-01 | Structures of the Human GTPase MMAA and Vitamin B12-dependent Methylmalonyl-CoA Mutase and Insight into Their Complex Formation
Vitamin B12 (cobalamin, Cbl) is essential to the function of two human enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). The conversion of dietary Cbl to its cofactor forms, methyl-Cbl (MeCbl) for MS and adenosyl-Cbl (AdoCbl) for MUT, located in the cytosol and mitochondria, respectively, requires a complex pathway of intracellular processing and trafficking. One of the processing proteins, MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of AdoCbl into MUT and is defective in children from the cblA complementation group of cobalamin disorders. To characterize the functional interplay between MMAA and MUT, we have crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo, and substrate-bound ternary forms. Structures of both proteins reveal highly conserved domain architecture and catalytic machinery for ligand binding, yet they show substantially different dimeric assembly and interaction, compared with their bacterial counterparts. We show that MMAA exhibits GTPase activity that is modulated by MUT and that the two proteins interact in vitro and in vivo. Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA (GMPPNP over GDP) and apoenzyme-dependent for MUT. The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction. Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner. Vitamin B12 (cobalamin, Cbl) is essential to the function of two human enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). The conversion of dietary Cbl to its cofactor forms, methyl-Cbl (MeCbl) for MS and adenosyl-Cbl (AdoCbl) for MUT, located in the cytosol and mitochondria, respectively, requires a complex pathway of intracellular processing and trafficking. One of the processing proteins, MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of AdoCbl into MUT and is defective in children from the cblA complementation group of cobalamin disorders. To characterize the functional interplay between MMAA and MUT, we have crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo, and substrate-bound ternary forms. Structures of both proteins reveal highly conserved domain architecture and catalytic machinery for ligand binding, yet they show substantially different dimeric assembly and interaction, compared with their bacterial counterparts. We show that MMAA exhibits GTPase activity that is modulated by MUT and that the two proteins interact in vitro and in vivo. Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA (GMPPNP over GDP) and apoenzyme-dependent for MUT. The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction. Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner.
2006-06-20 | Human methionine synthase reductase is a molecular chaperone for human methionine synthase
Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR), but there have been few studies of the interactions between these two proteins. In this study, recombinant human MS (hMS) and MSR (hMSR) were expressed in baculovirus-infected insect cells and purified to homogeneity. hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K act value of 71 nM. Escherichia coli MS, however, was not activated by hMSR. Moreover, hMS was not significantly active in the presence of E. coli flavodoxin and flavodoxin reductase, which maintain the activity of E. coli MS. These results indicate that recognition of MS by their reductive partners is very strict, despite the high homology between MS from different species. The effects of hMSR on the formation of hMS holoenzyme also were examined by using crude extracts of baculovirus-infected insect cells containing hMS apoenzyme (apoMS). In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced. The observed stimulation is shown to be due to stabilization of human apoMS in the presence of MSR. Apoenzyme alone is quite unstable at 37°C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme. Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS.
small molecules
2026-09-05 | A Case of High Pulmonary Hypertension Associated with Methylmalonic Aciduria and Homocystinuria in a Young Child
This article describes a case of severe pulmonary hypertension in a 3-year-old boy with postmortem detection of pathogenic heterozygous variants of the MMACHC gene, which are associated with methylmalonic aciduria and homocystinuria. Awareness and timely diagnosis of this rare disorder, along with correction of metabolic disturbances associated with defects in intracellular vitamin B12 metabolism, can improve outcomes, leading to complete or partial remission of pulmonary hypertension.
2026-06-01 | Neuropsychiatric Manifestations in Methylmalonic Acidemia and Homocystinuria of Adult Presentation. A Case Report
Introduction Each neurometabolic disorder is individually rare, but their cumulative incidence is relatively high, around 1/1,500 to 1/5,000 live births. In neurometabolic diseases, there is a deficit in the transformation of a substrate that prevents the production of one or more enzymes. Common neuropsychiatric manifestations associated with vitamin B12 deficiency include motor, sensory, and autonomic symptoms, cognitive impairment, mood disorders, and psychotic symptoms. Psychiatric manifestations are considered a particular form of presentation which, precisely because of their isolated nature, make diagnostic identification difficult, given that behavioral changes in these NME generally have an insidious onset. Objectives Objective: To report the neuropsychiatric alterations associated with inborn errors of vitamin B12 metabolism in adults Methods Case report. Results 30-year-old woman who starts with anxiety, difficulty in daily organization, suspected to be reactive to active mourning and initiation of Duncan’s hyperproteic diet; 7 months later she debuts with acute encephalopathy (confusion, bradypsychia, parkinsonism), admitted to ICU for focal status epilepticus coinciding with the initiation of parenteral feeding. Brain MRI showed pericerebellar and basal ganglia hyperintensity, although LP showed no alterations, Hashimoto’s encephalopathy was initially diagnosed with minimal response to corticosteroids. The evolution in the following 4 months was torpid, persisting frontal-subcortical dysfunction, with bradypsychia, loss of skills, memory, language, gait and behavioral alterations (irritability, agitation), as well as psychotic symptoms with polymorphous delusional ideation: of harm, control and pregnancy with auditory hallucinations. She was admitted to Neurology to study the picture and was referred to Psychiatry. Due to hyperhomocysteinemia and hyperammonemia and aciduria in urine, genetic screening was performed to rule out alteration of Vitb12 metabolism, diagnosing methylmalonic aciduria with homocystinuria due to deficiency in MMACHC (cbIC) (anomaly in the synthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are coenzymes derived from Vitb12). She was treated with Vit B12 and B9 supplements, L-carnitine, betaine, and paliperidone, with significant early improvements in biochemical parameters, and later in clinical manifestations. After discharge he did not present psychosis again. Conclusions alterations in cobalamin metabolism may present psychiatric alterations. The manifestations are usually very polimorfic. Disclosure of Interest None Declared
2026-03-04 | Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting.
MMA and CBS deficiency are rare autosomal recessive metabolic disorders caused by defects in cobalamin metabolism and cystathionine-beta-synthase activity, respectively. Advanced molecular genetic techniques, have become essential for diagnosing these conditions. This study aimed to analyze the genetic variations in three MMA and four CBS deficiency cases using WES and correlate the findings with clinical, biochemical, and treatment outcomes. Clinical evaluation, biochemical testing, neuroimaging, and WES were performed. WES data were analyzed using the reference genome GRCh37, and variants were classified according to ACMG guidelines. Treatment outcomes were monitored for three months post-intervention. In MMA cases, a homozygous pathogenic variant (c.394 C > T, p.Arg132Ter) in MMACHC was identified in all three patients. Biochemical abnormalities included methylmalonic aciduria, elevated homocysteine, and megaloblastic anemia. Hydroxycobalamin therapy improved behavioral, cognitive, and dermatological symptoms, though residual neuropathy persisted in one case. In CBS deficiency, pathogenic variants in CBS (c.992 C > T, p.Ala331Val; c.862 G > A, p.Ala288Thr; c.700 G > A, p.Asp234Asn) were identified. Clinical features included developmental delayed milestones, lens dislocation, and vascular complications. Treatment outcomes varied based on early diagnosis and compliance. This study highlights the importance of newborn screening program with WES in diagnosing and managing MMA and CBS deficiency, facilitating early intervention, improving clinical outcomes, and supporting precision medicine approaches. Early newborn screening and diagnosis are critical for effective treatment and improved patient outcomes. Novel clinical and pathogenic variants will expand the current understanding of these disorders. WES enhances the diagnostic precision for MMA and CBS deficiency, facilitating timely intervention and superior clinical management. Accurate and early detection of treatable IEMs through NBS can significantly reduce disease burden and healthcare costs.
2026-03-01 | 3PC-015 Development of injectable hydroxocobalamin microcapsules for the treatment of homocystinuria and methylmalonic aciduria
Background and Importance
Methylmalonic acidemia with homocystinuria type CblC is a severe, congenital disorder caused by a defect in vitamin B12 metabolism. Treatment with hydroxocobalamin improves some symptoms but has limited effectiveness on ocular structures due to its poor permeability through the blood-ocular barrier. This results in blindness in most patients, and topical treatment is ineffective due to poor corneal absorption. Despite treatment, patients often suffer a reduced quality of life.
Aim and Objectives
In this project, a formulation is exposed to solve this problem. The formulation consists of a suspension of drug-loaded microcapsules of PEOT/PBT polymer for extended release by intravitreal administration.
Material and Methods
The methodology used to make the microcapsules was double emulsion-solvent evaporation using ultrasound. The emulsion was W/O/W sign. The microparticles presented an aqueous core with hydroxocobalamin and a sustained release polymeric shell. Scanning electron microscopy (SEM) was performed to verify the homogeneity of the outer shell. To obtain microcapsules with an adequate release profile, a rotational mathematical design consisting of 23 different tests and an ANOVA analysis was carried out. The intention was to maximise size homogeneity and encapsulation performance.
Results
The results showed a maximum microcapsule load, better release profile, and greater homogeneity with a lower weight polymer and intermediate agitation speed. Further studies will be needed to assess the in vivo ocular viability of the formulation.
Conclusion and Relevance
The studies carried out to date indicate that microcapsules have potential in the ocular treatment of this disease. Although the findings are not discouraging, much more evidence is needed to bring this formulation to the clinical setting. It would be interesting to perform longer release profiles and in vivo tests.
References and/or Acknowledgements
1. Rickes EL, Brink NG, Koniuszy FR, Wood TR, Folkers K. Crystalline vitamin B12. Science. 16 de abril de 1948;107(2781):396–7. 2. Wang Y, Liu C, Fan L, Sheng Y, Mao J, Chao G, et al. Synthesis of biodegradable poly(butylene terephthalate)/poly(ethylene glycol) (PBT/PEG) multiblock copolymers and preparation of indirubin loaded microspheres. Polym Bull. 1 de enero de 2005;53(3):147–54. 3. Cuello-Rodríguez S, Blanco-Fernández G, García-Otero X, Díaz-Tome V, Otero-Espinar FJ, Seoane-Viaño I. Long acting injectables & implants: advances in intraocular drug delivery. Int J Pharm. 2025 Oct 15;683:126058. doi: 10.1016/j.ijpharm.2025.126058.
Conflict of Interest
No conflict of interest
2025-12-24 | Incidence of Organic Acid Disorders in 13 Million Chinese Newborns: A Systematic Review and Meta-Analysis.
Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70-118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China.
proteins
2023-06-09 | Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant.
Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC (hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10 (RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
2017-06-02 | Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1
Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1–ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis. Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1–ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.
2010-12-01 | Structures of the Human GTPase MMAA and Vitamin B12-dependent Methylmalonyl-CoA Mutase and Insight into Their Complex Formation
Vitamin B12 (cobalamin, Cbl) is essential to the function of two human enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). The conversion of dietary Cbl to its cofactor forms, methyl-Cbl (MeCbl) for MS and adenosyl-Cbl (AdoCbl) for MUT, located in the cytosol and mitochondria, respectively, requires a complex pathway of intracellular processing and trafficking. One of the processing proteins, MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of AdoCbl into MUT and is defective in children from the cblA complementation group of cobalamin disorders. To characterize the functional interplay between MMAA and MUT, we have crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo, and substrate-bound ternary forms. Structures of both proteins reveal highly conserved domain architecture and catalytic machinery for ligand binding, yet they show substantially different dimeric assembly and interaction, compared with their bacterial counterparts. We show that MMAA exhibits GTPase activity that is modulated by MUT and that the two proteins interact in vitro and in vivo. Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA (GMPPNP over GDP) and apoenzyme-dependent for MUT. The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction. Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner. Vitamin B12 (cobalamin, Cbl) is essential to the function of two human enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). The conversion of dietary Cbl to its cofactor forms, methyl-Cbl (MeCbl) for MS and adenosyl-Cbl (AdoCbl) for MUT, located in the cytosol and mitochondria, respectively, requires a complex pathway of intracellular processing and trafficking. One of the processing proteins, MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of AdoCbl into MUT and is defective in children from the cblA complementation group of cobalamin disorders. To characterize the functional interplay between MMAA and MUT, we have crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo, and substrate-bound ternary forms. Structures of both proteins reveal highly conserved domain architecture and catalytic machinery for ligand binding, yet they show substantially different dimeric assembly and interaction, compared with their bacterial counterparts. We show that MMAA exhibits GTPase activity that is modulated by MUT and that the two proteins interact in vitro and in vivo. Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA (GMPPNP over GDP) and apoenzyme-dependent for MUT. The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction. Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner.
2006-06-20 | Human methionine synthase reductase is a molecular chaperone for human methionine synthase
Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR), but there have been few studies of the interactions between these two proteins. In this study, recombinant human MS (hMS) and MSR (hMSR) were expressed in baculovirus-infected insect cells and purified to homogeneity. hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K act value of 71 nM. Escherichia coli MS, however, was not activated by hMSR. Moreover, hMS was not significantly active in the presence of E. coli flavodoxin and flavodoxin reductase, which maintain the activity of E. coli MS. These results indicate that recognition of MS by their reductive partners is very strict, despite the high homology between MS from different species. The effects of hMSR on the formation of hMS holoenzyme also were examined by using crude extracts of baculovirus-infected insect cells containing hMS apoenzyme (apoMS). In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced. The observed stimulation is shown to be due to stabilization of human apoMS in the presence of MSR. Apoenzyme alone is quite unstable at 37°C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme. Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS.
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Drug Discovery Landscape
3 orphan drug designations for Methylmalonic acidemia with homocystinuria.
3 orphan drug designations for Methylmalonic acidemia with homocystinuria.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Hydroxocobalamin acetate | small molecules | EMA | Brancaster Pharma Ireland Limited | |
hydroxocobalamin | other | FDA | Meta Healthcare Ltd, | |
Carglumic acid [Carbaglu] | small molecules | EMA | Recordati Rare Diseases |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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