RARE DISEASE
Malonic aciduria
Malonic aciduria
Malonic aciduria
Synonyms: Deficiency of malonyl-CoA decarboxylase, MLYCD deficiency, Malonic acidemia, Malonyl-CoA decarboxylase deficiency
Synonyms: Deficiency of malonyl-CoA decarboxylase, MLYCD deficiency, Malonic acidemia, Malonyl-CoA decarboxylase deficiency
Synonyms: Deficiency of malonyl-CoA decarboxylase, MLYCD deficiency, Malonic acidemia, Malonyl-CoA decarboxylase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Malonic Aciduria is a rare autosomal recessive disorder caused by MLYCD gene mutations, resulting in malonyl-CoA decarboxylase deficiency. This disrupts fatty acid oxidation, leading to accumulation of malonic acid and malonylcarnitine. Key clinical features include developmental delay, cardiomyopathy, metabolic acidosis, hypoglycemia, seizures, and failure to thrive [1][6][16]. Diagnosis relies on elevated urinary malonic acid, plasma C3DC levels, and genetic confirmation [6][12][16].
Therapies
Dietary: High-carbohydrate, low-long-chain-fat diet with medium-chain triglyceride (MCT) supplementation [2][6][13].
Pharmacologic: Carnitine supplementation, anticonvulsants, and cardiomyopathy management (e.g., ACE inhibitors) [2][8][13].
Monitoring: Regular metabolic profiling and cardiac surveillance [12][16][19].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
46 drug discovery papers about Malonic aciduria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
46 drug discovery papers about Malonic aciduria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-02-27 | Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects.
2025-09-11 | Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation
Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable. This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family's index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation. These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.
2024-11-12 | Abstract 4143142: Lost to Follow Up: A Rare Case of Malonyl-CoA Decarboxylase Deficiency Induced Cardiomyopathy in an Adult Spanish Speaking Hispanic Male
Introduction: Malonyl-CoA decarboxylase deficiency (MLYCDD) is a rare inherited metabolic disorder with multi-organ involvement, causing cognitive impairment, cardiomyopathy, seizures, hypotonia, and acidosis. Variants in MLYCCD, the gene for malonyl-CoA decarboxylase, disrupt long chain fatty acid synthesis in cardiac tissue. Prevalence is estimated to be less than 1 in 1,000,000, with cardiomyopathy being the leading cause of morbidity and mortality. Less than 40 cases have been documented, the majority of which detail newborns. No guidelines exist for treatment. A high-carbohydrate, low-fat diet, and levocarnitine reportedly improve cardiac function. Presentation: A 30-year-old Spanish-speaking male with MLYCDD, with resultant heart failure with reduced ejection fraction (EF) and cognitive delay, presented to a community hospital with malaise. He was diagnosed at age 9 and followed with an interdisciplinary team, receiving care in Spanish and English since diagnosis. His treatment consisted of levocarnitine and dietary restrictions that had led to cardiac recovery. At 24, his doctor retired, his insurance changed, and he was lost to follow-up, leading to dietary liberalization. On presentation, he was diagnosed with pneumonia complicated by atrial fibrillation (AF). AF was treated with a diltiazem infusion, resulting in cardiogenic shock with an EF of 15% from 39%. He was transferred to an academic center where diltiazem was stopped, inotropes started, and impella placed. He started enteral nutrition with liquid protein, dextrose infusion, medium-chain triglyceride (MCT) oil, and levocarnitine, along with supportive care for pneumonia. Given persistent shock he was transferred to our center for advanced therapies evaluation. Notable changes included replacing MCT oil with triheptanoin and stopping the dextrose infusion. A repeat echocardiogram showed recovery of EF to 40% Conclusions: MLYCDD exhibits a range of phenotypes, with limited data on long-term outcomes. This presentation is atypical: an adult with cardiomyopathy diagnosed in adolescence, successfully treated, who decompensated after stopping a modified diet in the setting of pneumonia and diltiazem. This case offers several clinical insights: (1) Restrictive diets with levocarnitine supplementation are instrumental in treating MLYCDD. (2) Avoid diltiazem in heart failure to prevent iatrogenic shock. (3) Language-concordant care ensures patients understanding and supports seamless care transitions.
2024-09-07 | Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease. Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents. Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes. A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.
2023-12-16 | Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review.
Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.
small molecules
2026-02-27 | Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects.
2025-09-11 | Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation
Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable. This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family's index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation. These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.
2024-11-12 | Abstract 4143142: Lost to Follow Up: A Rare Case of Malonyl-CoA Decarboxylase Deficiency Induced Cardiomyopathy in an Adult Spanish Speaking Hispanic Male
Introduction: Malonyl-CoA decarboxylase deficiency (MLYCDD) is a rare inherited metabolic disorder with multi-organ involvement, causing cognitive impairment, cardiomyopathy, seizures, hypotonia, and acidosis. Variants in MLYCCD, the gene for malonyl-CoA decarboxylase, disrupt long chain fatty acid synthesis in cardiac tissue. Prevalence is estimated to be less than 1 in 1,000,000, with cardiomyopathy being the leading cause of morbidity and mortality. Less than 40 cases have been documented, the majority of which detail newborns. No guidelines exist for treatment. A high-carbohydrate, low-fat diet, and levocarnitine reportedly improve cardiac function. Presentation: A 30-year-old Spanish-speaking male with MLYCDD, with resultant heart failure with reduced ejection fraction (EF) and cognitive delay, presented to a community hospital with malaise. He was diagnosed at age 9 and followed with an interdisciplinary team, receiving care in Spanish and English since diagnosis. His treatment consisted of levocarnitine and dietary restrictions that had led to cardiac recovery. At 24, his doctor retired, his insurance changed, and he was lost to follow-up, leading to dietary liberalization. On presentation, he was diagnosed with pneumonia complicated by atrial fibrillation (AF). AF was treated with a diltiazem infusion, resulting in cardiogenic shock with an EF of 15% from 39%. He was transferred to an academic center where diltiazem was stopped, inotropes started, and impella placed. He started enteral nutrition with liquid protein, dextrose infusion, medium-chain triglyceride (MCT) oil, and levocarnitine, along with supportive care for pneumonia. Given persistent shock he was transferred to our center for advanced therapies evaluation. Notable changes included replacing MCT oil with triheptanoin and stopping the dextrose infusion. A repeat echocardiogram showed recovery of EF to 40% Conclusions: MLYCDD exhibits a range of phenotypes, with limited data on long-term outcomes. This presentation is atypical: an adult with cardiomyopathy diagnosed in adolescence, successfully treated, who decompensated after stopping a modified diet in the setting of pneumonia and diltiazem. This case offers several clinical insights: (1) Restrictive diets with levocarnitine supplementation are instrumental in treating MLYCDD. (2) Avoid diltiazem in heart failure to prevent iatrogenic shock. (3) Language-concordant care ensures patients understanding and supports seamless care transitions.
2024-09-07 | Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease. Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents. Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes. A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.
2023-12-16 | Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review.
Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.
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