Introduction

Methylmalonic Acidemia (MMA) is a rare genetic disorder where the body is unable to break down certain amino acids, leading to an array of mental, heart-related, blood-related, and metabolic symptoms.^{1, 2} MMA affects around 1 in 25000 to 48000 pregnancies worldwide, and is associated with neonatal fatality and increased morbidity and mortality rates throughout life.^{1, 3}

Pathophysiology

MMA is mostly caused by mutations to the MUT (methylmalonyl-Coa mutase) gene, which encodes the enzyme responsible for the transformation of methylmalonyl-Coenzyme A (Coa) into succinyl-Coa during the oxidative metabolism of amino acids and fatty acids.^{1, 3} The exact underlying molecular mechanism inducing these symptoms is still unknown; however, it is believed to be due to the toxic nature of the methylmalonyl-Coa buildup that decreases energy production in the mitochondria and thus interferes with the metabolic processes.³ The metabolic abnormalities lead to various symptoms across multiple organ systems, usually within the 1^st year of life. These symptoms can include:

• Vomiting, lethargy, and muscle weakness that typically onset a few days after birth
• Malnutrition
• Growth failure and abnormal bone composition
• Hypoglycemia, ketonuria, and hyperammonemia, which are all products of metabolic perturbations
• Pancreatitis
• Chronic kidney disease
• Vision and hearing problems
• Neurological conditions, including cognitive impairment, stroke, seizures, and lethargy^1,3

Neurological manifestations of methylmalonic acidemia

While Methylmalonic Acidemia (MMA) affects multiple organ systems, its impact on the nervous system is particularly significant and often leads to severe complications. The neurological manifestations of MMA warrant special attention due to their profound effect on patients' quality of life and long-term outcomes.

The accumulation of toxic metabolites, primarily methylmalonic acid and propionyl-Coa, along with secondary metabolic disturbances, can have devastating effects on the developing and mature nervous system. These effects range from acute neurological crises to chronic neurodevelopmental issues. Understanding these neurological complications is crucial for early detection, appropriate management, and improved outcomes.

Among the diverse clinical features of Methylmalonic Acidemia (MMA), neurological complications stand out as particularly prevalent and impactful. The nervous system's high energy demands and sensitivity to metabolic disturbances make it especially vulnerable to the biochemical derangements seen in MMA.

Recent studies have shown that most MMA patients experience some form of neurological involvement. These manifestations can range from acute, life-threatening events to chronic, progressive impairments that significantly affect quality of life and long-term outcomes.

The neurological complications associated with MMA have unique clinical presentations, underlying mechanisms, and impact across different stages of life. This is why it is important to individually discuss diagnostic approaches, management strategies, and emerging therapies to mitigate these conditions. The major neurological correlates of MMA are as follows: 

Metabolic encephalopathy

Metabolic encephalopathy (ME) is the alteration of consciousness due to impaired cerebral metabolism. It is the most common form of diffuse or global brain dysfunction in systemic diseases and can occur due to the presence of a handful of different conditions, including: 

• Hypoxic-ischemic encephalopathy
• Hepatic encephalopathy
• Bacterial meningitis
• Seizures (as a post-seizure cognitive state)
• Drug overdose^{1, 4}

The neurologic evaluation of ME is the same, regardless of the underlying aetiology. However, we can differentiate two categories of ME based on a biochemical basis: one occurring from impaired compound delivery, like oxygen or glucose, to the brain; and the other from a pathogenic substrate that crosses the blood-brain barrier.⁴ In severe instances, this encephalopathy can transform into a complete loss of consciousness and eventually a coma.⁴

Seizures

Seizures are caused by a sudden, uncontrolled burst of electrical activity in the brain. The abnormal recruitment of neurons, present either in the pattern or the amount of brain activation, can lead to altered states, or loss of consciousness, body jerks and body spasms, and the inability to temporarily interpret the world around you.⁵ Seizures can be visualised using an Electroencephalogram (EEG), a type of graphical representation, wherein this overactivation of the brain causes highly synchronised spike-wave discharges across multiple brain areas.

The recurrence of seizures is when we talk about epilepsy, which is due to genetic as well as sporadic causes, for instance, due to a tumour or brain injury. Cause and the area of origin in the brain differentiate the various types of seizures.⁵ Many seizure types can be present in patients with methylmalonic acidemia (MMA), including:  

• Partial seizures (only local spread)
• Generalised tonic–clonic seizures, affecting both hemispheres and featuring both body stiffness and spasms 
• Tonic seizures (featuring body stiffness only)
• Myoclonic seizures (featuring sudden, uncontrollable muscle movement)
• Epileptic spasms
• Convulsive status epilepticus 
• Combination of multiple seizure types (seizure lasting over 5 minutes, or multiple seizures without regaining normal consciousness in between)^{5, 6}

Stroke

It is believed that the accumulation of methylmalonic acid and fatty acids can induce neurotoxicity that affects the function of neurons and glial cells in the nervous system. This toxicity impairs the metabolism of substrates in the brain, leading to infarction, most likely due to the lack of oxygen or blood supply.

Another theory argues that these metabolic strokes might occur upon the administration of a synthetic B12 compound called Cyanocobalamin, which is used for treating some aspects of the MMA, but was also associated with potential neurotoxicity.^{1, 2, 7}

Interestingly, the damage is specific to a brain area, primarily affecting the globus pallidus (responsible for risk-reward-associated behaviour), located in the basal ganglia.^{2, 7}

Myelination deficits

Impaired metabolism affects a type of glia, named an oligodendrocyte. These glial cells produce myelin, a fatty substrate that wraps around axons, insulates them, and facilitates a so-called saltatory signal conduction. It is noteworthy that saltatory conduction increases the communication speed between neurons.⁸ 

During MMA, the metabolic pathways supplying oligodendrocytes are impaired, which leads to them producing myelin sheaths more slowly and less efficiently. This results in delayed and under-myelination of the nervous system, which disrupts the normal communication between different brain areas.

MRI scans screen altered myelination, which visualises the white matter integrity (which is essentially myelinated fibres) through the brain.^{1, 8}

Intellectual and learning disabilities

Unfortunately, even if the condition is diagnosed early, many MMA patients experience intellectual and learning difficulties.¹ Mental abnormalities are especially prevalent where MMA is caused by 5-deoxy-adenosyl-cobalamin (cblA) deficiency. CblA is another enzyme associated with the metabolic process of amino acids.^{2, 9} This subtype accounts for roughly 30-38% of MMA patients.⁹

Meanwhile, patients with MMA stemming from the mutation of MCM enzymes do not show any form of cognitive deficits, and usually, their other organ systems are more functional as well.⁹ The intellectual deficits of the cblA cohort are especially particular and usually include poor visual attention, neurological deterioration (partially due to myelination deficits), reduced working memory, as well as irritability and lethargy.^{3, 10}

Diagnosis and management of methylmalonic acidemia symptoms

Diagnosis and neuroimaging correlates

Early and accurate diagnosis of methylmalonic acidemia (MMA) is essential to monitor and manage associated conditions before they worsen. However, the disease's non-specific presentation across individuals often complicates the evaluation process.¹

Given the strong genetic component of MMA, it is critical to conduct prenatal and neonatal testing, especially in families with a history of the disease. Potential patients should also be screened if they exhibit signs such as:

• Abnormal muscle tone
• Cardiac problems
• High susceptibility to infectious diseases
• Vascular abnormalities
• Metabolic issues and feeding difficulties
• Cognitive abnormalities, seizures, or stroke-like events
• Vitamin B12 deficiency ^{1, 10}

Metabolic strokes are among the most severe clinical manifestations of MMA, necessitating a comprehensive diagnostic approach. This typically includes blood tests, imaging studies, and cardiac evaluations when a stroke is suspected. Blood tests screen for abnormal ammonia levels and amino acid compositions in patients.^{1, 7}

Additionally, genetic analyses of DNA can be used to identify potential gene mutations responsible for the disease, or metabolomic analyses of urine samples with mass spectrometry (MS) can be used to provide a chemical diagnosis.^{1, 7, 10}

Another important screening method, specifically for diagnosing the neurological manifestations of MMA, is neuroimaging. Since imaging can point out potential brain injuries and developmental or physical abnormalities, it can be a useful tool to guide the diagnosis and the treatment of patients.¹⁰

Out of the imaging techniques, ultrasound can be used for brain examination on infants and newborns, which is a non-invasive and low-cost method; however, the volume of tissue it can assess is limited. Thus, magnetic resonance imaging (MRI) is the gold standard used in most individuals, which can visualise injuries and brain tissue integrity with greater detail. It can also accurately detect white matter abnormalities, which are also common in MMA patients and are associated with declined cognitive abilities.^{9, 10}

Finally, computed tomography (CT) provides a great resolution; however, the technique uses ionising radiation, thus its application is fairly limited in patients.¹⁰ It is important to mention that while these techniques are important for evaluating the physical appearance of the brain, the electrical activity within is measured by EEG. Especially for those with seizures, EEG findings are a crucial part of evaluating the seizure subtype.⁷

Regardless of the technique used, these imaging findings help clinicians understand the neurological impact of the disease and guide appropriate management strategies. Healthcare providers, by focusing on these critical diagnostic measures, can better manage the diverse and potentially severe complications associated with MMA. 

Management of cognitive MMA symptoms 

In the initial, acute phase of the disease, the most important aspect is management of the underlying cause that led to acidosis in the patient. Acidosis itself must also be accounted for, which can be done by dietary modifications to restrict protein intake, carnitine, and cobalamin supplementation. Although the outcome depends on the disease subtype, as patients possessing the cblA subtype usually present with worse clinical outcomes.¹

In severe cases, dialysis can be performed, a treatment where excess water and waste are removed from the blood, usually counterbalancing inadequate kidney function.¹ Liver and kidney transplantations have also been attempted, but usually failed to prevent further pathophysiologies, especially neurological symptoms that arise pre- or post-transplantation. 

In case of seizures, dysarthria, or stroke, a neurologist must be consulted, by whom genetic and dietary counselling can be accessed. Neural correlates and other symptoms associated with the condition, including cardiac and metabolic abnormalities, should be treated with appropriate medications (anti-seizure drugs, vasodilators, etc.) promptly to improve the clinical outcome of MMA for these patients.^{1, 10}

Summary

Methylmalonic Acidemia (MMA) is a rare genetic disorder affecting 1 in 25,000 to 48,000 pregnancies worldwide. It results from mutations in the MUT gene, leading to the body's inability to break down certain amino acids. This causes a buildup of toxic metabolites, primarily affecting the nervous system.

The neurological manifestations of MMA are diverse and can be severe, including:

• Metabolic encephalopathy: Altered consciousness due to impaired cerebral metabolism
• Seizures: Various types, from partial to generalised tonic-clonic seizures
• Stroke: Often affecting the globus pallidus, possibly due to neurotoxicity
• Myelination deficits: Impaired myelin production affecting neural communication
• Intellectual and learning disabilities: Particularly prevalent in patients with cblA deficiency

Diagnosis involves prenatal and neonatal testing, blood tests, genetic analyses, and neuroimaging techniques such as MRI and CT scans. EEG is crucial for evaluating seizure activity.

Management strategies include dietary modifications, carnitine and cobalamin supplementation, and in severe cases, dialysis or organ transplantation. Neurological symptoms require specialised treatment and ongoing monitoring.

Early detection and appropriate management are crucial for improving outcomes and quality of life for MMA patients, as the condition can lead to significant morbidity and mortality throughout life.