What Is Methylmalonic Acidemia

Introduction

Methylmalonic acidemia (MMA) is an autosomal recessive disease of metabolism. It is caused by a complete or partial functional defect of the mitochondrial enzyme, methylmalonyl‐CoA mutase (MMUT gene) or by deficient synthesis of its cofactor adenosylcobalamin.^1,2,4,5 Inborn errors of metabolism are disorders caused by mutations in enzymes or co-factors that play a role in the metabolism of fats, carbohydrates and proteins.³

In the case of Methylmalonic acidemia, and methylmalonic aciduria Methylmalonic acid builds up in the blood and urine of a patient respectively. Depending on the level of build-up, this condition can manifest in a myriad of clinical symptoms. Though rare, MMA remains a contributor to morbidity and mortality secondary to acute and chronic systemic and end-organ injury.⁵

Incidence and prevalence

Recent studies reported incidence rates among newborns ranging from 0.79 per 100,000 in the Asia‐Pacific region to 6.04 per 100,000 in the Middle East and North Africa (MENA) and In Europe, 6.60 - 13.97 per 100,000, the higher values noted to be due to the increasing use of efficient newborn screening tools.¹

Forms of methylmalonic acidemia (MMA)

This condition can present in varying forms depending on the type of defect, four main forms have been identified so far:

• Isolated MMA is a result of a deficiency of methylmalonyl-CoA mutase or a functional defect of methylmalonyl-CoA epimerase³
• Isolated MMA can present as Neonatal onset form³ or Acute intermittent late‐onset MMA. The neonatal onset MMA may present within 3 days of birth while the late onset MMA may present at any age outside of the first thirty days of life (infancy, childhood, or later)¹
• Combined methylmalonic acidemia and homocystinuria are caused by defective formation of cobalamin C (cblC) enzymes; 5′-deoxyadenosylcobalamin, and methylcobalamin^2,3
• Acquired MMA which is a result of dietary Cobalamin Cbl (Vitamin B12) deficiency^5,6

In this case, methylmalonic acidemia will also be accompanied by increased levels of homocysteine in the blood.⁷

Pathophysiology

End-organ injury occurs in MMA as a result of toxicity from the build-up of primary and secondary metabolites and the deficiency of succinyl-CoA which leads to a general dysfunction in the Krebs cycle and disruption in oxidative phosphorylation.⁵

Clinical presentation

In Isolated methylmalonic acidemia, accumulating methylmalonyl-CoA is hydrolysed to methylmalonic acid which remains in the blood.⁴

The clinical course of MMA is defined by periods of stability followed by intermittent metabolic decompensation, usually associated with infections and stress. The accumulation of toxic compounds (organic acids, ammonia) can cause severe clinical symptoms including prolonged vomiting and diarrhoea, dehydration, hypotonia, irritability, and lethargy.¹

Congenital Methylmalonic Acidemia: Infants with this abnormality are ill from birth, common symptoms include vomiting, failure to thrive, severe metabolic acidosis, ketosis, and mental retardation. Anemia, if present, is normocytic and normoblastic.²

In the neonatal onset form of MMA, symptoms start within the first three days of life with acute deterioration of clinical condition, findings of metabolic acidosis, and hyperammonemia are present, progressing to coma and death if untreated.^1,4

The neonatal onset of Isolated MMA is characterized by potentially fatal progressive encephalopathy that may present as lethargy, seizures, or coma.^1,5 Long-term effects may include growth failure, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, tubulointerstitial nephritis with progressive renal failure, immune dysfunction, and optic nerve atrophy.³

Combined methylmalonic aciduria and homocystinuria usually present in the first year of life with difficulties in feeding, a global developmental delay, microcephaly, neurologic symptoms such as seizures, hypotonia, haematological findings such as megaloblastic anaemia, hemolytic uremic syndrome, cardiopulmonary manifestations, and vision loss due to a severe, progressive retinopathy and maculopathy.^2,3

Diagnosis

A proper diagnosis involves efficient history-taking, examination and laboratory examinations

• Proper History taking
• Physical examination
• Laboratory Investigations

Biochemistry: Blood tests should be done to check for levels of acylcarnitines, ammonia, homocysteine, ketones, lactate free plasmatic methylmalonic acid. Arterial blood gas (non-capillary) to assess biochemical findings of metabolic acidosis.^4,5

A full blood count and blood culture is also advised.

Elevations of methylmalonic acid concurrently with 3‐hydroxypropionate and the presence of 2‐methylcitrate confirm a diagnosis of MMA.⁴

Also, plasma amino acid measurements may show elevated glycine levels in MMA.⁴

It is advisable to measure the levels of homocysteine and vitamin B12 in blood as this will help to differentiate between MMA and other organic acidemias caused by defects in other genes, distal or proximal in the intracellular cobalamin pathway.⁴

Urinalysis: Measurement of organic acids in urine.^4,5

• Molecular genetic testing: Molecular Analysis of the MMUT gene⁴

Treatment

A guideline was first developed by a panel of experts in 2014 on how to diagnose and treat MMA, this was revised in 2021 and is currently widely accepted as the standard.^1,4

Dietary management

We suggest a low natural protein diet under consideration of age‐appropriate total caloric and protein requirements to improve metabolic stability.^1,4,5

Research supports that the dietary protein intake should target the recommended daily allowance for protein (0.8 grams protein/kg body weight), this can be modified based on the individual patient The primary goal in MMA patients is the prevention of catabolism while allowing for normal growth, without causing obesity.⁵

Use of medical foods can be adopted based on individual symptoms and metabolic findings³ Medical foods in this case are formulated to contain zero or minimal precursors of the “toxic” dietary precursors and supply essential nutrients that may be lacking from a therapeutic diet restriction.³ This is usually administered in the form of enteral feeding with a low protein and, precursor free amino acids (PFAAs) and oral l‐arginine.^1,4

Medical management

The medications listed below are necessary to facilitate metabolic stability in MMA: Levocarnitine - to prevent secondary carnitine deficiency.^4,5 Metronidazole - to decrease the population of propiogenic gut flora^4,5 and carglumic acid (CA) and sodium benzoate may be suggested in brittle patients to treat acute and chronic hyperammonemia respectively.^1,4,5

A fraction of infants with failure of adocobalamin synthesis respond to cobalamin in large doses.^2,4 This is given parenterally and usually includes Vitamin B12 adjunctive administration in the form of hydroxycobalamin.^1,4 Patients are more or less responsive depending on the specific defect. The degree of response depends on the specific defect and varies from patient to patient.¹

Organ transplantation

Liver transplantation and combined liver kidney transplantation in MMA should be considered as they can help to improve metabolic stability.^4,5 However, injury to tissues which do not have a regenerative capacity may not be mitigated.⁵ Research has shown that transplantation decreases the number of metabolic decompensations and the number of hospital admissions during acute illness.⁴ Follow-up and constant metabolic monitoring must be sustained following organ transplantation in MMA patients.⁴

Complications

Long‐term complications include failure to thrive, intellectual disability, progressive renal disease, pancreatitis, and cardiac dysfunction.¹

In addition, more discoveries are emerging pertaining to other end organ sequelae which have remained inconclusive due to a lack of data.⁵

Prevention

Of recent, expanded neonatal screening programs (expanded newborn metabolic screening) have made possible the presymptomatic detection of MMA.¹ One method evoked in prenatal diagnoses is the measurement of methylmalonic acid in dried amniotic fluid.⁴

Another method is the use of genetic testing in neonates.⁴ Patients diagnosed in the womb have been found to have better management and better prognosis than patients diagnosed later in life.⁵

Patients found to have deteriorating kidney function should be referred promptly for further evaluation and management by a nephrologist. The use of nephrotoxic medications should also be avoided.⁵

A Dexa scan is also recommended for patients with MMA who are at increased risk for osteopenia or osteoporosis compared to their peers with or without renal disease⁵, radiographic examination is mandated for MMA patients with fractures presenting with pain.⁵

The 2021 guidelines for the diagnosis and management of MMA suggests, “age‐appropriate, standardized developmental, cognitive and behavioural testing, since developmental delay and behavioural abnormalities are known complications in MMA”.⁴

FAQs

Which foods contain cobalamin?

Dietary sources of cobalamin (Cbl) include seafood, fortified cereals, meat, poultry, eggs, and milk/dairy products.⁶

Are there any foods that must be avoided in a patient with MMA?

Following an acute metabolic decompensation, protein restriction may be ordered for a maximum of 24-48 orders, this order must come from the medical doctor.⁴

Can patients with this condition fast?

Fasting in patients with methylmalonic acidemias is not advisable. Prolonged fasting periods have been shown to increase catabolism in these patients and should be avoided to prevent metabolic instability.⁴

Can these patients take vaccines?

Yes. These patients should not miss their recommended vaccinations.

Can neonates diagnosed with MMA be breastfed?

Yes. Breastfeeding is possible keeping in view the total natural protein intake.

Summary

Methylmalonic acidemia is a rare inborn error of metabolism wherein, defects in the methylmalonyl‐CoA mutase or its coenzyme, adenosylcobalamin or other enzymes in the pathway lead to an elevation and accumulation of methylmalonic acid in the blood.

The prognosis of patients with MMA has seen tremendous improvement recently, with medical advances improving the quality of life of these patients, the prompt diagnosis and management of future complications are vital.^1,4

Most importantly, recent guidelines on diagnosis and management from a team of experts formulated from careful studies and research should be adhered to in the treatment and management of patients with methylmalonic academia.