Fatal Case Report of Methylmalonic Acidemia: Reflections on Organic Acidemias in Colombia

Abstract

Methylmalonic acidemia (MMA) is a rare hereditary metabolic disorder caused by defects in the methylmalonyl-CoA mutase pathway, leading to toxic metabolite accumulation and severe multi-organ complications. This report presents the case of a 4-month-old Colombian female with MMA, diagnosed through whole-exome sequencing, which identified compound heterozygous pathogenic variants in the MMUT gene: c.607G>A (p.Gly203Arg) and c.1420C>T (p.Arg474Ter). Despite treatment-including a metabolic diet, L-carnitine, and hydroxocobalamin,-the patient experienced recurrent metabolic crises and ultimately succubed to multi-organ failure. This case underscores critical gaps in Colombia’s healthcare system, including the absence of universal newborn screening, limited access to specialized treatments, and significant administrative barriers that delay interventions. Expanding neonatal screening to include organic acidemias, improving access to essential medications, and establishing reference centers for metabolic diseases are crucial steps to improve outcomes for patients with rare metabolic disorders. This report highlights the urgent need for systemic changes in Colombia to address the inequities in diagnosis and treatment of rare diseases, ensuring timely intervention and comprehensive care for affected patients.

Keywords:
Methylmalonic Acidemia; Organic Acidemias; Case Report

Introduction

Organic acidemias, such as methylmalonic acidemia (MMA), represent a group of hereditary metabolic disorders resulting in the accumulation of toxic metabolites due to enzymatic defects in the degradation pathways of amino acids, fatty acids, and other compounds. MMA is one of the most common organic acidemias and is primarily caused by mutations in the MUT gene, which encodes the enzyme methylmalonyl-CoA mutase, and in genes related to cobalamin cofactor synthesis, such as MMAB and MMACHC [¹].

In Latin America, the prevalence of MMA and other inborn errors of metabolism (IEM) remains uncertain due to the lack of standardized newborn screening programs and the underestimation of these disorders in public health systems. [²] Recent studies have highlighted the importance of early and accurate diagnosis to improve clinical outcomes and reduce mortality associated with these disorders. [³] In Colombia, despite limited implementation of screening programs, the identification of critical cases has provided a basis for reflecting on the clinical and genetic characteristics and management challenges in this context [⁴].

Patients with MMA present a wide phenotypic variability, ranging from mild late-onset clinical presentations to severe neonatal forms with multi-organ involvement. [⁵] The most common manifestations include metabolic acidosis, psychomotor developmental delay, and severe neurological complications, often exacerbated by infections or increased catabolism. [⁶] The identification of specific pathogenic variants has not only improved diagnosis but also opened avenues for targeted therapeutic approaches, such as enzyme replacement therapy and the use of molecules to correct splicing in deep intronic mutations [⁷].

In this report, we present a fatal case of MMA in a Colombian patient and discuss the clinical and genetic implications of organic acidemias in the region. This case underscores the need to establish neonatal screening programs and more effective therapeutic strategies for these disorders in Latin America, while also reflecting on the diagnostic and management challenges in a resource-limited setting [⁸].

Methods

The patient was a 4-month-old female diagnosed with MMA shortly after birth. Newborn screening revealed elevated methylmalonic acid levels (247.88 μmol/L), supporting the clinical suspicion of an IEM. Further biochemical analysis showed abnormal organic acid profiles consistent with MMA.

Genetic Testing

Whole-exome sequencing (WES) was performed using the MGI DNBSEQ-G400 platform, focusing on the MMUT gene and associated genes. Two heterozygous pathogenic variants were identified: c.607G>A (p.Gly203Arg), inherited from the mother, and c.1420C>T (p.Arg474Ter), inherited from the father. Segregation analysis confirmed the compound heterozygous state.

Management and Outcome

The patient received a metabolic diet, L-carnitine, and hydroxocobalamin, but despite treatment, she experienced recurrent metabolic crises, leading to multi-organ failure. The patient passed away at 4 months and 24 days of age.

Ethics

Informed consent was obtained from the parents, and the study was approved by the Ethics Committee of Hospital Universitario San Ignacio.

Case Presentation

This was the first pregnancy for a non-consanguineous couple. The mother had regular prenatal care, including routine ultrasounds, and all tests were within normal limits, including a negative screening for syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpes (STORCH). The infant was born at 39 weeks via spontaneous vaginal delivery, with a birth weight of 3,100 grams and a length of 50 cm, both appropriate for gestational age. The initial neonatal assessment was normal, and no immediate complications were noted. However, shortly after birth, the infant was noted to have poor feeding, lethargy, and occasional vomiting. She was briefly hospitalized for observation due to these symptoms and discharged after three days, as her condition appeared stable without requiring further interventions. On the third day of life, the newborn was admitted to a tertiary clinic. Due to lethargy, generalized hypotonia, and feeding difficulties. Initial laboratory findings showed severe hyperammonemia (>1060 µmol/L, reference value <50 µmol/L), metabolic acidosis, and coagulopathy, prompting suspicion of an inborn error of metabolism. Due to the critical nature of the metabolic alterations, the patient was transferred to a tertiary center with experience in metabolic diseases. Treatment included sodium benzoate (dose 300 mg/kg/day), carglumic acid (dose 200 mg/kg/day), and intravenous L-carnitine (dose 100 mg/kg/day), alongside mechanical ventilation and total parenteral nutrition. An extended amino acid profile, performed in a specialized laboratory in the United States, indicated abnormal metabolite patterns consistent with methylmalonic acidemia, contributing significantly to the diagnostic orientation (see table 1).

Table 1.
Laboratory Findings of the Patient During Clinical Evolution

Date	Test	Result	Reference Values	Interpretation
12/11/2022	Ammonia	1060 µmol/L	< 110 µmol/L	Severe hyperammonemia
12/11/2022	Blood Gas Analysis	pH 7.25, HCO3 12 mmol/L	pH 7.35-7.45, HCO3 22-26	Metabolic acidosis
13/11/2022	Lactate	5.8 mmol/L	0.5-2.2 mmol/L	Hyperlactatemia
14/11/2022	Total Bilirubin	3.2 mg/dL	0.3-1.2 mg/dL	Hyperbilirubinemia
15/11/2022	Urea	15 mg/dL	10-20 mg/dL	Normal
16/11/2022	Glucose	45 mg/dL	70-100 mg/dL	Mild hypoglycemia
17/11/2022	Liver Function Test	AST 78 U/L, ALT 65 U/L	AST < 40 U/L, ALT < 40 U/L	Mild elevation of transaminases
18/11/2022	Procalcitonin	2.5 ng/mL	< 0.5 ng/mL	Indicative of infection
20/11/2022	C-reactive Protein (CRP)	15 mg/L	< 5 mg/L	Indicative of inflammation
22/11/2022	Complete Blood Count (CBC)	WBC 15,000/µL, Hb 9.8 g/dL	WBC 4,000-11,000/µL, Hb 12-16 g/dL	Leukocytosis, anemia
24/11/2022	Renal Profile	Creatinine 0.9 mg/dL	0.6-1.1 mg/dL	Normal
25/11/2022	Blood Cultures	Positive for Klebsiella	Negative	Bacterial infection
28/11/2022	Phosphate Levels	2.1 mg/dL	2.5-4.5 mg/dL	Hypophosphatemia
30/11/2022	Organic Acid Profile	MMA 247.88 µmol/L	< 5.93 µmol/L	Compatible with methylmalonic acidemia
01/12/2022	Serum Electrolytes	Na+ 138, K+ 5.8, Cl- 104	Na+ 135-145, K+ 3.5-5.0, Cl- 98-106	Mild hyperkalemia
05/12/2022	Plasma Fatty Acids	Elevated	Normal	Altered oxidation
10/12/2022	Lactate Dehydrogenase (LDH)	720 U/L	140-280 U/L	Elevated, indicative of cell damage
14/03/2023	Hemoglobin	9.5 g/dL	12-16 g/dL	Mild anemia
20/03/2023	Arterial Blood Gases	pH 7.28, PCO2 50 mmHg	pH 7.35-7.45, PCO2 35-45 mmHg	Respiratory acidosis
25/03/2023	Carnitine Levels	22 µmol/L	25-50 µmol/L	Mild carnitine deficiency
28/03/2023	Uric Acid	8.2 mg/dL	3.5-7.2 mg/dL	Hyperuricemia
29/03/2023	Chest X-ray	Diffuse infiltrates	Normal	Indicative of pneumonitis
30/03/2023	Creatine Phosphokinase (CPK)	450 U/L	30-200 U/L	Moderate elevation
31/03/2023	Albumin	2.8 g/dL	3.5-5.0 g/dL	Hypoalbuminemia

• Legend: AST: Aspartate Aminotransferase ALT: Alanine Aminotransferase, Hb: Hemoglobin, WBC: White Blood Cells.

WES identified two pathogenic variants in the MMUT gene: c.607G>A (p.Gly203Arg) and c.1420C>T (p.Arg474Ter). According to the ACMG criteria, both variants were classified as pathogenic. Sanger sequencing of the parents confirmed that these variants were inherited in a compound heterozygous state; the c.607G>A variant was maternally inherited, and the c.1420C>T variant was paternally inherited. The genetic study was performed when the patient was 1 month and 18 days old, and the result was obtained postmortem at 4 months and 27 days of age. The patient’s clinical course was characterized by recurrent metabolic decompensations with hyperammonemia, severe respiratory failure, and profound neurological impairment. She required multiple hospitalizations at Fundación Cardioinfantil, where she received intensive care, including invasive mechanical ventilation, continuous metabolic management with ammonia-lowering therapies, and broad-spectrum antibiotics for recurrent bacterial infections-most notably, pneumonia caused by Klebsiella pneumoniae resistant to standard treatments. Neurological evaluations and imaging revealed hypoxic-ischemic encephalopathy with multiple acute and subacute infarcts, further complicating her prognosis (see Figure 1 for a chronological timeline of clinical events).

Figure 1.
Chronological Timeline of Clinical Events and Management in a Case of Methylmalonic Acidemia.

At 4 months of age, the patient developed a viral infection that led to severe metabolic decompensation. Despite receiving mechanical ventilation, hemodialysis, and intensive metabolic support, she rapidly progressed to multi-organ failure. The patient succumbed to her illness at 4 months and 24 days of age, highlighting the severe, life-limiting nature of her condition despite comprehensive care.

Following the patient's passing, the parents received genetic counseling session where they were informed about the genetic risks associated with MMA, the autosomal recessive inheritance pattern, and the 25% risk of recurrence in future pregnancies. Reproductive options, including preimplantation genetic diagnosis (PGD) and prenatal testing, were discussed to help them make informed decisions about future family planning.

Discussion

MMA is a severe hereditary metabolic disorder classified as an organic acidemia , characterized by the accumulation of methylmalonic acid due to deficiencies in the enzyme methylmalonyl-CoA mutase or in the synthesis of its cofactor, adenosylcobalamin [¹, ²]. This condition leads to the toxic accumulation of metabolites, causing severe Multisystemic alterations, primarily affecting the nervous, renal, and gastrointestinal systems. Symptoms can vary from lethargy, vomiting, and metabolic acidosis in neonates to seizures, developmental delays, and chronic renal failure in more advanced stages [⁹]. In Colombia, the lack of universal neonatal screening and limited access to advanced diagnostic services significantly worsen the prognosis of these patients, as observed in this case [³].

Although Colombia passed Law 1980 of 2019 to establish a Neonatal Screening Program for early detection of congenital diseases, organic acidemias like MMA were not included among the six mandatory metabolic diseases for screening [¹⁰]. Moreover, Resolution No 207 of 2024, which issued new guidelines for the Neonatal Screening Program, focused exclusively on congenital hypothyroidism, once again excluding organic acidemias [¹¹]. This reflects a significant disconnect between clinical needs and regulations, highlighting the challenges faced by patients and their families in receiving early diagnosis and proper management of these conditions in Colombia.

Early diagnosis is essential for improving outcomes, as it enables intervention before severe symptoms emerge. In many developed countries, MMA is detected through neonatal screening using tandem mass spectrometry, allowing for early identification and targeted treatment [¹²]. In Colombia, however, the absence of a universal screening program means that many cases are not detected until patients present with advanced clinical symptoms. In this patient’s case, although the genetic diagnosis was performed in a Colombian laboratory, the metabolic study that helped confirm the severity of the condition was conducted in a U.S. laboratory, contributing to delays in appropriate management [¹³].

MMA treatment focuses on preventing metabolic decompensations through a low-protein diet, L-carnitine supplementation to facilitate organic acid excretion, and specific drugs such as carglumic acid (Carbaglu) to control hyperammonemia [¹⁴, ¹⁵]. Although these medications are authorized by the National Institute for Food and Drug Surveillance (INVIMA)in Colombia and are part of the health plan, administrative processes and limited availability can result in critical delays in delivery, affecting treatment continuity [¹⁶]. In this case, these administrative barriers further complicated the patient's management, who experienced multiple metabolic decompensations requiring prolonged hospitalizations and intensive management.

Studies have shown that early and aggressive management of MMA significantly improves the quality of life and prognosis of patients [¹⁷]. However, limitations in access to medications and inadequate infrastructure in Colombia result in many patients not receiving continuous and effective treatment, leading to progressive deterioration. Despite efforts to manage the condition with available resources, the outcome was fatal, reflecting the reality faced by many patients in the country.

Internationally, patients with MMA in countries with more developed health systems have access to comprehensive management that includes not only immediate medical intervention but also long-term multidisciplinary follow-up [¹⁸]. These systems allow for faster access to treatments, specialized management, and standardized protocols that improve clinical outcomes. In Colombia, the centralization of resources in major cities creates significant disparities in access, particularly for patients in rural areas who face greater obstacles in receiving timely care [¹⁹].

Training of healthcare professionals is another critical area that needs strengthening in Colombia. Early identification of MMA symptoms and other organic acidemias requires a high level of knowledge and preparation, which is currently not uniformly distributed across the country [²⁰]. In many cases, patients are not adequately diagnosed until the disease has progressed considerably, and the lack of access to specialists in genetics and metabolic disorders further limits treatment and management options.

In addition to improving detection and management, it is crucial for Colombia to invest in the creation of specialized reference centers for metabolic diseases. These centers could provide comprehensive care that includes not only medical treatment but also psychological and social support for affected families [²¹]. International experience has shown that specialized centers significantly improve outcomes for patients with MMA, reducing mortality and enhancing quality of life through more coordinated and specialized management.

Ensuring equitable access to medications is another critical challenge. Although Carbaglu and L-carnitine are available within the health system, administrative barriers and lack of immediate availability limit their effective use [²², ²³]. Improvements in administrative processes are needed to ensure that patients receive treatments without delays, especially during metabolic crises that can be life-threatening if not managed immediately [²⁴]. Creating a more efficient distribution system for these medications is essential to improve the care of patients with MMA.

Finally, implementing a more accessible genetic counseling program for affected families is crucial. In the presented case, the parents received genetic counseling following the diagnosis of their daughter, which allowed them to understand the risks of recurrence in future pregnancies and explore available reproductive options [²⁵]. However, such services are limited and not available to all families in the country. Expanding access to genetic counseling can help families make informed decisions and reduce the incidence of severe MMA cases in the future.

Conclusion

This case of methylmalonic acidemia (MMA) highlights the critical challenges faced in Colombia due to the lack of early diagnosis, limited access to specialized treatments, and significant administrative barriers. The fatal outcome of the patient underscores the urgent need to improve neonatal screening programs, incorporate a broader range of metabolic disorders, and streamline access to essential medications like carglumic acid and L-carnitine, which are crucial in managing this condition.

Despite existing regulations, such as Law 1980 of 2019 and Resolution No 207 of 2024, there remains a disconnection between policy and clinical practice, particularly in the management of rare metabolic disorders. Expanding screening capabilities and implementing comprehensive guidelines that include organic acidemias are essential steps toward reducing diagnostic delays and improving outcomes for patients.

Furthermore, the establishment of specialized centers for metabolic diseases in Colombia could provide a more coordinated and multidisciplinary approach, enhancing care delivery and supporting affected families. Enhancing healthcare professional training, increasing awareness of these conditions, and integrating genetic counseling into standard care are also crucial strategies to ensure that patients and their families receive the support they need.

Overall, this case serves as a stark reminder of the systemic challenges in the management of rare metabolic disorders in Colombia and the need for urgent, targeted interventions to prevent similar outcomes in the future. Improved infrastructure, equitable access to treatments, and comprehensive public health policies will be fundamental in addressing the current gaps in care and ensuring better prognoses for all patients with MMA and other similar conditions.

Acknowledgments

We would like to express our gratitude to Fundación Cardioinfantil and Hospital Universitario San Ignacio for their invaluable support and care provided throughout the patient's clinical management. Special thanks to the Pontificia Universidad Javeriana and the Instituto de Genética Humana for their academic and technical contributions that made this case study possible.

We extend our heartfelt appreciation to the patient, whom God has in His glory, for being a brave fighter, and to her parents for their strength, dedication, and cooperation during this difficult journey. Their courage and commitment have been a source of inspiration throughout this work.

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• Funding
  This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
• Data Availability
  The dataset generated and analysed during the current study contains personal health information that cannot be made publicly available to protect patient privacy. De-identified data may be obtained from the corresponding author upon reasonable request and with prior approval of the Ethics Committee of Hospital Universitario San Ignacio.

Data availability

The dataset generated and analysed during the current study contains personal health information that cannot be made publicly available to protect patient privacy. De-identified data may be obtained from the corresponding author upon reasonable request and with prior approval of the Ethics Committee of Hospital Universitario San Ignacio.

Publication Dates

• Publication in this collection
  13 June 2025
• Date of issue
  2025

History

• Received
  27 Dec 2024
• Accepted
  16 May 2025