Overview

Typically, our body breaks down the protein we eat into smaller constituents called amino acids. Enzymes further break down the amino acids into various forms that perform a variety of functions in the body. (Think of it like when you combine letters of the alphabet, you make different words; thus, when chains of amino acids are combined, different proteins are made). 

Amino acids perform pivotal functions in the body such as growth and repair of body tissues, synthesis of hormones and neurotransmitters, etc. However, a rare but severe condition can occur in which a specific group of amino acids called Branched-chain amino acids (BCAAs) cannot be broken down in the body. This can result in impaired and irreversible developmental effects and neurological damage. This article unravels the details about this condition and how it can affect growth and development.  

What is maple syrup urine disease and what causes it?

Maple Syrup Urine Disease (MSUD) is an autosomal recessive condition that can occur in infants and adults. It is caused by the inability to break down and metabolise the branched chain amino acids; Valine, Isoleucine and Leucine.¹ This means that levels of these amino acids, leucine in particular, build up in the blood and brain with severe impacts. MSUD gets its name from the distinctive maple odour of the affected infant's urine.   

This disease occurs due to the abnormal activity of an enzyme called branched-chain alpha-ketoacid dehydrogenase complex (BCKDH).¹ BCKDH is an enzyme complex that plays an irreversible role in the breakdown of valine, isoleucine and leucine to various by-products that can further be utilised by the body. 

The impaired ability to break the BCAAs leads to two major consequences;

• An accumulation of BCAAs especially leucine which is toxic at high concentrations
• Limited uptake of the large and neutral amino acids (tyrosine, methionine and tryptophan) in the brain. This leads to decreased synthesis of dopamine and serotonin due to low levels of the aforementioned amino acids²

The accumulation of BCAAs and their respective alpha-keto acids in the urine manifests in neonates. This leads to developmental challenges such as feeding difficulties, irritability, lethargy, seizure and eventual metabolic decompensation which can result in coma and death.³

What are the signs and symptoms?

The central nervous system is where the majority of the symptoms associated with MSUD occur.⁴ The maple syrup-like stench can also be detected in the ear wax of an affected individual. The signs and symptoms of MSUD are categorised according to the various forms of this condition. These are;

• Classic MSUD: This is the most common form and is usually present in newborns.¹ Within the first 24 to 48 hours, newborns with classic MSUD start to exhibit symptoms such as lethargy, poor breastfeeding, weight loss, irritability, encephalopathy, etc. Thereafter, the baby will display other neurological symptoms like convulsion, seizures, hypertonia, opisthotonus, central neurologic dysfunction, respiratory failure and eventually, death.⁴ In older people, high levels of leucine cause epigastric pain, anorexia, vomiting, muscle weakness, psychiatric symptoms, movement disorders, and ataxia⁵
• Intermediate MSUD: Children with intermediate MSUD are diagnosed between the ages of 5 months and 7 years. ⁶ It is also characterised by maple syrup odour of urine or cerumen, irritability, delayed developmental challenges, dystonia, and encephalopathy¹
• Intermittent MSUD: People with intermittent MSUD have normal development initially. Thus, it is not detected at newborn screening. However, when the person is under stress, has an infection or consumes excess proteinous foods, maple syrup odour appears accompanied by metabolic decompensation⁶
• Thiamine-responsive MSUD: This is similar to the intermediate form but an improved clinical presentation is observed with administration of thiamine⁶

How does MSUD impact growth and development? 

Amino acid deprivation in the brain is the main focus of the devastating effects of MSUD. Therefore, MSUD has the following potential impacts; 

Learning and memory deficits

MSUD causes decreased levels of glutamate in the brain.² Glutamate plays an essential role in the physiological functions of the nervous system. Therefore, low levels of glutamate increase the onset, severity and symptoms of obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD).⁷ Additionally, the depletion of aspartate in the brain due to MSUD can result in compromised myelin integrity. Low levels of this amino acid can also impair fatty acid synthesis, the onset of infantile epilepsy and autism.^9,10

Brain edema

MSUD can cause extensive damage to the brainstem and abnormal dendritic development.⁸ It can also induce mental retardation, brain oedema and death. 

Metabolic decompensation

Metabolic decompensation occurs due to the failure of the body’s metabolic processes which can lead to a rapid decline in health. It can be triggered by injury or exercise, infections, or surgery and can lead to life-threatening conditions. MSUD can lead to metabolic decompensation due to impaired metabolism of BCAAs. 

Decreased synthesis of neurotransmitters dopamine, norepinephrine, epinephrine, and serotonin

Low levels of neurotransmitters have a direct correlation to the onset of psychiatric and movement disorders.² Neurotransmitters are endogenous chemicals that are essential in shaping our lives and performing a variety of functions in the body. 

Increased oxidative stress

One of the depleted amino acids in MSUD methionine is vital for the synthesis of cysteine and glutathione. These are essential antioxidants that protect against reactive oxygen species (ROS). This can impair learning, and cognitive ability and induce chronic inflammation which can trigger other health conditions.²

What treatment options/management are available?

Effective treatment and management of MSUD encompasses addressing the nutritional needs and reducing the severity of the neurological manifestations of this disease. The following treatment/management options are available;

• Adoption of a BCAA-restricted diet: This involves strict minimal supplies of nutrients devoid of branched-chain amino acids throughout a lifetime. The aim is to minimise neurological damage and maintain adequate plasma levels of amino acids that will not trigger metabolic crises
• Prevention of primary and secondary manifestations: Orthotopic liver transplantation has been studied to be an effective therapy for individuals with MSUD.¹¹ It supplies adequate enzyme activity to break down unrestricted protein diets and maintain amino acid homeostasis. Although the child still has MSUD genetically, there is a reduced risk of developing neuropsychiatric disorders. Thiamine can also be administered to people who have thiamine-responsive MSUD
• Management in pregnancy: Metabolic control should be critically monitored throughout the gestation period. This is because as the foetus is developing, the need for protein and BCAAs increases.¹ Therefore, regular measurement of plasma amino acid concentrations and foetal growth is imperative to avoid nutritional deficiencies.¹ The sources of metabolic decompensation for the mother could be the stress of labour, internal sequestration of blood should also be monitored
• Genetic counselling: Many reproductive options are available for couples who are both carriers of the same MSUD gene. Parents can choose natural conception with no genetic testing, consider adoption, sperm or egg donation. Additionally, if the carrier status has been confirmed molecularly, parents can also consider prenatal testing. This can be done through chorionic villus sampling or amniocentesis.¹² Also, young adults with MSUD may face barriers to communicating their condition with their peers, have social anxiety due to dietary restrictions or challenges dealing with mental health disorders. A mental health professional can help such individuals cope with the disease¹²

Can MSUD be prevented?

Babies with two faulty copies of the BCKDH gene cannot be treated to stop the pathology of MSUD from showing up. Newborn screening can be done for the condition. Couples may speak with genetic counsellors and undergo DNA testing through the methods listed above. If the condition is detected, adequate measures can be taken to reduce the occurrence of associated symptoms. 

FAQs

How is MSUD diagnosed? 

Newborn screening is done on neonates to check for the amount of some amino acids in the blood. For adults exhibiting symptoms of MSUD, the most informative test is the identification of alloisoleucine using plasma amino acid analysis. Gas chromatography-mass spectrometry can also be used to detect branched-chain keto acids and other organic acids. 

How common is MSUD?

Since MSUD is a rare condition, the estimated incidence of this disease is between one in 100,000 to one in 300,000 births.¹

Does a positive screening result for a newborn mean that the baby has MSUD?

A positive screening result does not automatically mean that your baby has MSUD. It means that more testing needs to be done because your baby might have MSUD. Babies with MSUD are healthier if treatment begins early, hence, it is important to have follow-up testing done quickly to find out if your baby has MSUD and rule out false positives. 

Summary

• Maple syrup urine disease (MSUD) is a rare metabolic disorder brought about by a problem with the branched-chain ketoacid dehydrogenase enzyme complex (BCKDH). The signs and symptoms of this disease vary depending on the form of MSUD the patient has
• BCKDH plays an irreversible role in the breakdown of branched-chain amino acids and prevents their accumulation which can be harmful to the body
• MSUD leads to low levels of essential amino acids in the brain which plays a role in brain development and various neurological functions
• Various treatment options are available as well as management strategies depending on the severity of symptoms and age of individuals with MSUD