Liver And Kidney Complications In Methylmalonic Acidemia

Introduction

Methylmalonic acidemia (MMA) is a group of inherited disorders in which the body cannot properly metabolise (breakdown) proteins and fats.¹ More specifically, people with the disorder can’t metabolise a substance called methylmalonyl-CoA.^1,2

The conversion of methylmalonyl-CoA to succinyl-CoA is a key step in the metabolism of certain amino acids and odd-chain fatty acids.^1,2 As a result of improper metabolism, methylmalonic acid builds up in the body, leading to acidaemia, which can cause a series of health problems and potentially become life-threatening.^1,2 

MMA is a rare genetic disease that typically appears and is diagnosed in early infancy, affecting approximately 1 in every 50,000 to 100,000 live births.^2,3 The most common cause of the disorder is a mutation in the MUT gene, which encodes the enzyme methylmalonyl-CoA mutase, which is necessary for the conversion of methylmalonyl-CoA to succinyl-CoA.²

Pathophysiology of methylmalonic acidemia

The principal biochemical defect associated with MMA is the impaired metabolism of methylmalonyl-CoA, which pertains to mutations in the MUT genes or genes involved in metabolism of cobalamin (vitamin B12), which is a cofactor that is necessary for methylmalonyl-CoA to function.^2,4 

Mutations in the MUT gene can lead to different levels of enzyme activity.² Mutations that lead to a complete lack of enzyme activity are referred to as mut0, and those which result in partial enzyme activity are known as mut-. In the case of mut0, the complete lack of functional methylmalonyl-CoA mutase often results in severe forms of MMA, which are characterised by significantly higher levels of methylmalonic acid and its toxic derivatives in the blood. On the other hand, mut- cases typically result in milder cases, but still incur a harmful build-up of these toxic metabolites in the blood.⁵

Defects in cobalamin metabolism

Cobalamin serves a crucial role as the co-factor for methylmalonyl-CoA mutase, however, in order for it to do so, it must be converted to its active forms, known as adenosylcobalamin and methylcobalamin.⁶ Therefore, mutations in genes involved in converting cobalamin to its active forms are also causes of MMA.^3,4,6 

The most commonly associated gene mutations include MMAA, MMAB and MMADHC, which affect the transport, processing, and/or metabolism of cobalamin. 

• The MMAA gene encodes a protein that is involved in the transport and intracellular processing of cobalamin, assisting in its delivery to methylmalonyl-CoA 
• The MMAB gene encodes the enzyme adenosylcobalamin synthase, which converts cobalamin into adenosylcobalamin, one of the active forms of the cofactor which can be used by methlmalonyl-CoA mutase
• The MMADHC gene encodes a protein that is crucial in trafficking cobalamin to the appropriate cellular compartments where it can be converted into its active forms^5,6

Even if methylmalonyl-CoA mutase is structurally normal, meaning there are no mutations in the MUT gene, it cannot function properly without its necessary co-factor in the correct form, which can lead to acidaemia.^3,4,5,6

Liver complications in MMA

Individuals with MMA will often encounter various liver complications, such as hepatomegaly (enlarged liver) or liver dysfunction, which can progress and worsen to liver failure.^3,7 The toxic metabolites which accumulate in the bloodstream are able to diffuse into liver tissue, which can lead to changes in fatty acids, fibrosis and in severe cases, cirrhosis.⁷

Mechanism of liver damage 

The liver is especially vulnerable to the toxic effects elicited by accumulation of methylmalonic acid. The built-up metabolites can disrupt mitochondrial function, leading to oxidative stress and cell damage. Additionally, impaired energy metabolism in liver cells worsens the dysfunction and damage, preventing the ability of the hepatocytes (liver cells) to recover and regenerate properly. The biochemical consequences of acidemia on the liver include:^7,8,9 

Oxidative stress

The build-up of methylmalonic acid increases the production of reactive oxygen species (ROS) in hepatocytes. ROS can induce damage to cellular components, such as DNA, proteins and lipids, resulting in oxidative stress.

Mitochondrial dysfunction

Methylmalonic acid impedes mitochondrial function, which reduces the efficiency of the electron transport chain and, therefore, the efficiency of adenosine triphosphate (ATP) production. This reduction in energy impairs cellular processes which are essential for maintaining liver function and damage repair.

Disruption in lipid metabolism and hepatic steatosis 

The impaired conversion of methylmalonyl-CoA to succinyl-CoA affects the metabolism of lipids, which can result in fatty acids accumulating in liver cells. These excess fatty acids are stored as triglycerides which can result in hepatic steatosis (a build-up of fats in the liver which can lead to health problems).

Inflammation and fibrosis

The presence of toxic metabolites in the liver may trigger an inflammatory response, resulting in the release of pro-inflammatory cytokines. Chronic inflammation can induce activation of hepatic stellate cells, which are responsible for producing extracellular matrix proteins. These cells can replace normal liver tissue with scar tissue, which over time severely impair liver function.

Systemic acidosis

Acidemia contributes to metabolic acidosis, which is associated with a decrease in blood pH. At a decreased pH, the acid-base ratio required for normal physiological function is imbalanced and can disrupt liver enzyme activities.

Kidney complications in MMA

Kidney involvement is a significant concern in MMA, with chronic kidney disease (CKD) and tubulointerstitial nephritis in particular being common complications. Both of these conditions are a result of the accumulation of toxic metabolites in kidney tissue. These metabolites often build-up in renal tubules, causing tubular toxicity, inflammation and loss of kidney function. A major impact is the impaired ability to filter waste products from the blood and maintain fluid and electrolyte balance.^10,11

Mechanism of kidney damage

The consequences of acidemia on the kidney include:^10,11

Interstitial nephritis 

The kidneys continuously filter blood, exposing them to high concentrations of methylmalonic acid and other toxic byproducts in individuals with MMA. These substances can be toxic to renal tubular cells, which can cause cellular damage and impair their function. This damage can progress to interstitial nephritis, which is the inflammation of the spaces between renal tubules. Interstitial nephritis compromises kidney function and contributes to chronic kidney disease.

Oxidative stress

Similarly to damage to liver cells, renal cells can experience increased levels of oxidative stress as a result of methylmalonic acid accumulation. The oxidative stress can damage cellular components and impair kidney function.

Metabolic acidosis 

The kidney is involved in maintaining the optimal acid-base balance for physiological functions. The accumulation of methylmalonic acid exacerbates metabolic acidosis, placing an additional burden on the kidneys as they attempt to compensate for the lowered blood pH.

Compensatory mechanisms

Chronic metabolic acidosis leads to compensatory mechanisms in the kidneys, such as increased ammonia production and excretion. Over time, these mechanisms can become overwhelmed, leading to further renal impairment.^10,11

Summary

Methylmalonic acidemia (MMA) is a rare genetic disorder that disrupts the body’s ability to break down certain proteins and fats, leading to a harmful buildup of methylmalonic acid. This is most often caused by mutations in the MUT gene, or in genes involved in vitamin B12 (cobalamin) metabolism, such as MMAA, MMAB, and MMADHC.

The accumulation of toxic metabolites particularly affects the liver and kidneys. In the liver, it causes oxidative stress, mitochondrial dysfunction, and inflammation, which can lead to liver enlargement, damage, and even failure. In the kidneys, it contributes to chronic kidney disease and tubulointerstitial nephritis through similar mechanisms.