6th February 2024

Disorders of Amino Acid Metabolism

Summary of conditions

Examples

Amino acids are the building blocks of proteins which play crucial roles in various physiological processes. When their metabolism is disrupted, it can lead to a range of disorders with diverse symptoms and complications. Disorders of amino acid metabolism are a group of inherited metabolic disorders that affect the breakdown, synthesis or transportation of amino acids within the body. Many distinct disorders exist. However, only a few more commonly known examples will be discussed here:

• Phenylketonuria
• Homocystinuria
• Alkaptonuria
• Cystinosis
• Cystinuria
• Oxalosis
• Maple syrup disease

Phenylketonuria

Phenylketonuria is the most well-known amino acid metabolism disorder, affecting around 1 in 10,000 babies born in the UK. It is characterised by the inability to break down the amino acid phenylalanine due to a deficiency or complete absence of phenylalanine hydroxylase. This enzyme catabolises phenylalanine to form another amino acid, tyrosine (see pathway). Without this pathway, phenylalanine accumulates in the blood and other tissues, whilst tyrosine levels become deficient, leading to intellectual disability, seizures, behavioural problems and other neurological issues.

Clinical features

Clinical features of Phenylketonuria often appear shortly after birth when the baby consumes phenylalanine in breast milk or formula. They include:

• Intellectual disability
  • High levels of phenylalanine are toxic to the brain and interfere with its development, causing intellectual disability and cognitive impairment if left untreated. Other neurological features can include tremors, epilepsy and clonus.
• Behavioural problems
  • Children with PKU may exhibit behavioural issues such as hyperactivity, attention deficit disorder, and poor impulse control. This can present as behavioural difficulties and even self-harm.
• Skin and hair changes:
  • Some individuals with PKU have lighter skin and hair pigmentation than unaffected individuals. This is due to the role of phenylalanine in melanin production.
  • If phenylalanine levels are high, affected individuals may have a characteristic “musty odour” to their breath, skin and urine.

Diagnosis

PKU is usually diagnosed through the newborn screening programme, where a small blood sample is taken from a heel prick shortly after birth and tested for elevated phenylalanine levels (amongst other things – see later). In those with elevated levels, confirmatory tests are then performed, as well as genetic testing.

Management

Treatment involves strict dietary management with a lifelong low phenylalanine diet. Foods that are high in phenylalanine, such as meat, fish, eggs, dairy products and aspartame (which is converted to phenylalanine), must be restricted in favour of special medical formulas and low protein foods that have low or zero phenylalanine content. This helps to maintain levels within the normal range, preventing neurological damage.

Individuals with PKU require lifelong monitoring of blood phenylalanine levels to ensure they remain within a target range, with dietary adjustments indicated where levels are high. Initially, blood tests are frequent. However, they are reduced over time as the individual ages and their diet becomes stable. 

Women of childbearing age with PKU must adhere very strictly to a low phenylalanine diet to prevent pregnancy complications; elevated phenylalanine levels during pregnancy can cause harm to the developing foetus, in particular, causing developmental issues.

Whilst PKU is a lifelong disease requiring close monitoring, early diagnosis and strict dietary control ensure individuals with this condition can lead healthy and fulfilling lives, minimising the risk of intellectual disability and other associated complications.

A small proportion of patients with a mild form of PKU called hyperphenylalaninaemia may be suitable for treatment with sapropterin. This medication reduces the level of phenylalanine within the body, improving symptoms and offering neuroprotection. It allows better control of phenylalanine levels and affords patients greater dietary flexibility. However, it is not a magic bullet; patients will still require regular monitoring, and its long-term efficacy is still being determined.

Homocystinuria

Homocystinuria is a group of disorders characterised by impaired breakdown of amino acid methionine. Most typically, this is due to an autosomal recessive abnormality that results in deficiencies in the enzymes involved in methionine metabolism, such as cystathionine B synthase, methionine synthase and methylenetetrahydrofolate reductase. Cystathionine b synthase usually catalyses the breakdown of methionine by catalysing the conversion of homocysteine (an intermediary) to cystathionine. Reduced enzyme activity results in homocysteine and methionine accumulation. Elevated levels of both substances cause various complications, including eye and skeletal abnormalities, cardiovascular issues, intellectual disability and increased risk of blood clots. 

Clinical features 

The clinical features of homocystinuria are varied, often dependent on the specific enzyme deficiency and severity of the condition, but include:

• Intellectual disability: 
  • Elevated homocysteine levels can affect brain development, leading to intellectual disability and learning difficulties. Some patients may also develop seizures and psychiatric conditions.
• Eye abnormalities:
  • Near-sightedness (myopia), dislocation of the lens of the eye, increased risk of glaucoma and spontaneous retinal detachment
• Skeletal abnormalities:
  • Marfanoid features include tall stature and long limbs, curvature of the spine (scoliosis), chest deformities, osteoporosis and joint problems 
• Cardiovascular complications: 
  • Increased risk of cardiovascular problems, including blood clots, heart attacks, strokes and atherosclerosis.
• Other features: 
  • Some individuals with homocystinuria may exhibit a pale complexion, thin hair, brittle bones, and a tendency to form kidney stones.

Diagnosis 

Newborns with this condition are usually diagnosed through the newborn screening programme, but cases may be suspected based on clinical symptoms. Irrespective, follow-up confirmatory tests are required, which use blood and urine samples to detect elevated homocysteine and genetic testing to characterise the specific defect causing a particular enzyme deficiency.

Management

Early detection is crucial, particularly the early testing of siblings of affected individuals. 

The mainstay of management relies on maintaining homocysteine levels within the normal range, minimising symptoms and preventing associated long-term complications. This involves adherence to a low methionine diet and restricting meat, fish, eggs, dairy products and certain grains, all of which are methionine rich. In addition, pyridoxine supplements are said to be effective in around 50% of individuals with this condition, enhancing the activity of enzymes involved in methionine metabolism. Some variants are also responsive to supplementation with folate, vitamin B12 or betaine, which support the breakdown of homocysteine.

In other cases, additional medications may be prescribed to manage the risk of complications, such as anticoagulation to prevent thromboses. Affected individuals require lifelong management with continuous monitoring of homocysteine levels and other blood markers to assess treatment efficacy with necessary adjustments to dietary and treatment regimens where levels remain high. Effective management should involve close coordination of care with a metabolic specialist, and a multidisciplinary healthcare team is crucial for optimal care and prevention of complications.

Alkaptonuria

Alkaptonuria, also known as black urine disease, is a rare genetic disorder affecting the metabolism of amino acids, tyrosine and phenylalanine. Autosomal recessively inherited mutations in the HGD gene cause defects in the enzyme homogentisate 1, 2 dioxygenase, which breaks down an intermediate of tyrosine metabolism known as homogentisic acid. Deficiency or loss of function mutations leads to the accumulation of homogentisic acid within the body.

Clinical features 

Patients with alkaptonuria classically first notice the darkening of urine, which occurs when homogentisic acid is oxidised and turns black upon exposure to air. This discolouration is not present at birth but becomes apparent by late childhood. Other body fluids, such as sweat, tears, and tissues, can also become darker and may lead to blue-black pigmentation in various body parts, such as the ears, sclerae and connective tissues.

Alkaptonuria may also affect the musculoskeletal system, with homogentisic acid accumulating in the joints, leading to ochronosis. This condition is characterised by progressive degeneration of the cartilage and connective tissues, leading to arthritis-like symptoms with stiff, painful joints that show a reduced range of motion. These features are most commonly observed in the spine, hips and knees. When they affect the ribs and thoracic spine, they can interfere with ventilatory mechanisms, leading to shortness of breath. 

Homogentisic acid can be deposited in various organs. In the urinary tract, this causes stone formation in the kidney, bladder and prostate. In the heart, deposits affect the valves, causing stenosis, whereas atherosclerotic changes can be seen in blood vessels. 

Diagnosis

Alkaptonuria is typically diagnosed with a urine test that detects homogentisic acid or a genetic test identifying a mutation in the HGD gene.

Management

Alkaptonuria requires lifelong symptom control and support with regular monitoring of joint function and pain management as the mainstays of treatment. Some medications, such as nitisinone, have shown the potential to reduce homogentisic acid levels, slowing down the progression of ochronosis. 

Genetic counselling may be recommended for affected individuals and their families to understand the inheritance pattern and assess the risk of the condition in future generations. 

Patients with pain and stiffness from alkaptonuria can benefit from regular exercise to strengthen joints and muscles. Sometimes, if joints are damaged and need replacement, or where heart valves become stenotic, there is also a role for surgery in these individuals.

Cystinosis

Cystinosis is a rare genetic disorder affecting the transport of amino acid, cystine, within cells. It is subsequently characterised by the accumulation of cystine crystals within various organs and tissues throughout the body. Cystinosis is caused by mutations in the CTNS gene, which encodes a protein called cystinosis.

In healthy individuals, cysteine is transported out of lysosomes, aided by cystinosis. However, impaired cystinosis function in affected individuals causes cystine accumulation within the lysosomes. Over time, excess cystine forms crystals that damage tissues and organs.

Three main types of cystinosis are described and classified based on the age of onset and severity of symptoms:

• Nephropathic infantile cystinosis
  • This is the most severe form, usually diagnosed in infancy (before age 2). It represents 95% of all cases and primarily affects the kidneys with accumulation and deposition of cystine within nephrons. If untreated, this leads to kidney dysfunction, renal Fanconi syndrome, and eventually end-stage renal disease. Patients with Fanconi syndrome exhibit impaired kidney reabsorption, resulting in excessive loss of amino acids, glucose, electrolytes and other vital molecules in the urine.
• Nephropathic juvenile cystinosis
  • Usually, later onset in childhood or adolescence shares some characteristics with nephropathic infantile cystinosis but is usually less severe and has a slower progression. Kidney dysfunction and Fanconi syndrome may still occur.
• Non Nephropathic or Ocular Cystinosis
  • This is the rarest form (representing only 1-2% of all cases), primarily affecting the eyes with deposition of cystine crystals in the cornea. Symptoms typically manifest in adulthood, including eye pain, blurred vision, and photophobia.

Clinical features

Clinical manifestation of cystinosis includes:

• Kidneys
  • Parents initially notice extreme thirst, excessive urination, vomiting, difficulty feeding, and failure to thrive in the young infant. This usually reflects Fanconi syndrome, in which the kidneys fail to absorb essential substances.
• Eyes
  • Cystine crystal deposition in the cornea can cause painful eyes, blurred vision and photophobia.
• Musculoskeletal
  • Renal failure resulting from Fanconi syndrome causes severe vitamin deficiency, ultimately resulting in rickets in the growing child. Crystal deposition can also cause weakness and wasting of the muscles; in the limbs, this can cause reduced mobility; in the chest, it may predispose to breathing difficulty; and in the larynx, it may manifest as swallowing/feeding difficulties.
• Other organs
  • Deposition of cystine crystals within the pancreas can lead to diabetes, whilst thyroid involvement can lead to an underactive thyroid with associated sequelae.

Diagnosis 

Cystinosis is diagnosed with genetic testing to identify mutations in the CTNS gene. Measurement of cystine levels in white blood cells or tissue biopsies can also play a role.

Management

Cystinosis is a chronic condition requiring lifelong management. Early diagnosis and initiation of treatment are crucial to minimise organ damage and improve long-term outcomes. 

Mainstays of management involve treating symptoms and preventing complications with cystine-depleting medications such as cysteamine. Other treatments may include supportive measures such as electrolyte replacement and nutritional support, with a role for kidney transplantation reserved for severe cases of renal failure. 

Patients must undergo regular monitoring by a multidisciplinary medical team, including nephrologists, ophthalmologists and other specialists. Genetic counselling is also crucial for individuals and families affected by cystinosis to understand the inheritance pattern and assess the risk of passing the condition on to future generations.

Cystinuria

Cystinuria is characterised by impaired reabsorption of amino acid, cystine, by the kidneys. It is a rare inherited condition (affecting 1 in 2000 in the UK) caused by mutations in the SLC3A1 and SLC7A9 genes, responsible for encoding proteins involved in transporting cystine and other amino acids in the kidney. The kidneys usually filter the blood, removing waste products and reabsorbing necessary substances into the bloodstream. However, in cystinuria, the defect prevents reabsorption, resulting in excretion in the urine. 

The main consequence of cystinuria is the formation of cystine kidney stones. Cystine is poorly soluble in urine, and when concentration is high, it crystallises and aggregates, forming stones. The stones formed vary in shape and size but often cause pain and discomfort as they pass through the urinary tract. Recurrent stone formation can lead to complications, including urinary tract obstruction, infection and kidney dysfunction.

There are three types of cystinuria, classified according to underlying genetic mutation and impact on amino acid excretion.

• Type I
  • Caused by mutations in the SLC3A1 gene, this type is characterised by defective reabsorption of cystine, arginine, lysine and ornithine.
• Type II
  • Caused by mutations in the SLC7A9 gene, this type is characterised by cystine and, to a lesser extent, dibasic amino acids like ornithine and lysine.
• Mixed type
  • Patients with mixed type may have mutations in both genes, resulting in a mixed type of cystinuria.

Clinical features

Typical features of cystinuria reflect urinary stone symptoms; they depend on the size and location of the stones. Common symptoms include flank pain, haematuria, and frequent urinary tract infections. Age of onset and severity of symptoms can be variable amongst individuals, but the defining feature is that these patients are troubled by recurrent stone episodes.

Diagnosis

Cystinuria is typically diagnosed through stone analysis or analysis of 24-hour urine samples to assess amino acid composition. 

Management

The mainstay of treatment for cystinuria is first to prevent stone formation, then to manage symptoms and reduce the risk of complications when stones are present. This involves increasing urine volume and decreasing cystine concentration, mainly by increasing fluid intake, maintaining a low-sodium diet (as sodium encourages stone formation), and alkalinising the urine (with potassium citrate). 

Cystine is made in the body from methionine. Therefore, patients with cystinuria can find it helpful to follow a diet low in methionine (i.e. a low animal protein diet) to reduce cystine burden. Patients require regular monitoring, with urine analysis, renal function tests and imaging to detect stones.

Medications, including tiopronin or alpha-mercaptopropionylglycine (α-MPG), may be prescribed to decrease cystine levels in the urine, further preventing stone formation. In some instances, surgical intervention is required to manage large stones that have caused complications.

Genetic counselling may be recommended for individuals with cystinuria and their families to understand inheritance patterns and assess the risk of passing on the condition to future generations.

Oxalosis

Oxalosis, also known as primary hyperoxaluria, is a rare genetic disorder characterised by the overproduction and accumulation of oxalate in the body. Oxalate is naturally found in many foods but is a by-product of normal metabolism. In individuals with oxalosis, a defect in the enzyme responsible for oxalate breakdown and elimination leads to its build-up in various organs and tissues.

There are three main types of primary hyperoxaluria, each caused by mutations in different genes:

• Primary Hyperoxaluria Type 1
  • Mutations in the AGXT gene cause the most common and severe form of oxalosis. It leads to a deficiency of an enzyme called alanine glyoxylate aminotransferase (AGT), which is involved in the breakdown of glyoxylate, an oxalate precursor. Excess glyoxylate accumulates and is converted to oxalate, primarily in the kidney, forming calcium oxalate crystals. Over time, these crystals cause progressive kidney damage, chronic kidney disease, and end-stage renal disease.
• Primary Hyperoxaluria Type 2
  • It is caused by mutations in the GRHPR gene, which results in a deficiency of the enzyme glyoxylate/hydoxypyruvate reductase (GRHPR). Again, as a result, oxalate accumulates in the kidneys, but this form is generally less severe with later onset compared to type 1.
• Primary Hyperoxaluria Type 3
  • It is caused by mutations in the HOGA1 gene, resulting in the deficiency of the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA1). The exact mechanisms of oxalate accumulation in this type are still being studied but appear to affect the kidneys.

Clinical features

Excessive oxalate accumulation can result in kidney stone formation and deposition of oxalate crystals in other organs and tissues, causing dysfunction. The affected organs include kidneys, urinary tract, heart, eyes, bones and central nervous system.

Diagnosis 

The diagnosis of oxalosis involves urine and blood sample analysis to measure oxalate levels, whilst genetic testing is helpful to identify the specific gene mutation involved.

Management

Treatment options for Oxalosis are limited. The mainstay of treatment is reducing oxalate levels to prevent further damage to kidneys and other organs. This involves increasing fluid intake, maintaining a low oxalate diet and using medications such as pyridoxine, which bind and eliminate excess oxalate from the body. In some cases, liver transplantation is considered to provide a functioning enzyme to help metabolise oxalate.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder affecting the body’s ability to break down certain amino acids. It is named after the characteristic sweet smell of the affected individual’s urine, which resembles maple syrup.

This condition is caused by mutations in one of several genes for enzymes involved in the metabolism of branched-chain amino acids (BCAAs), including leucine, isoleucine and valine. Usually, these amino acids are broken down by specific enzymes and converted into other molecules that the body can use for energy. However, these enzymes are deficient or defective in individuals with this condition, accumulating branched-chain amino acids and their by-products in the blood and tissues.

Clinical features

Clinical features of maple syrup urine disease depend on the location of BCAA accumulation. The severity and age of onset can also vary depending on the specific gene mutations and enzyme activity levels.

• Brain
  • Accumulation of BCAAS and their by-products in the brain is toxic and can cause brain damage and multiple other neurological sequelae, including seizures, coma and even death.
• Urine
  • The characteristic sweet smell of urine gives this condition its name.
• Other
  • Many symptoms are non-specific. Newborns with the condition may initially appear normal but develop symptoms within a few days, including irritability, vomiting, poor feeding, failure to thrive and an unusual body odour.

Some less severe forms of MSUD show late expression of symptoms – in late infancy, childhood or even adulthood. These intermittent forms tend to be characterised by episodes of metabolic decompensation triggered by stressors like illness or fasting.

Diagnosis

Diagnosis of MSUD tends to be made through a newborn screening programme – the heel prick test. The blood sample is tested for BCAAs and their by-products, with elevated levels indicating the presence of the disorder. Confirmatory tests are then performed to confirm the diagnosis and identify specific gene mutations responsible.

Management

Lifelong management of MSUD involves a low-protein diet, often tailored explicitly by a specialist metabolic dietitian. The role of this is to limit the intake of BCAAs, and it involves limiting high-protein foods such as meat, fish, cheese, eggs, pulses and nuts. Breast milk and baby formula need to be monitored before feeding affected babies. Regular baby formula is high in amino acid content, so it often needs to be switched to a particular formulation.

Although BCAAs are limited in the diet, some children must take isoleucine and valine supplements to maintain healthy levels within a prescribed range. Regular blood tests are required to monitor these levels.

Sometimes, liver transplantation can be used to treat MSUD, allowing patients to have a regular diet without the risk of metabolic crisis. However, liver transplantation is a significant procedure with its risks; patients have to take immunosuppressant medications for the rest of their lives, and therefore, it is not an option for all patients.

References

• Williams, R.A., Mamotte, C.D. and Burnett, J.R. (2008). ‘Phenylketonuria: An Inborn Error of Phenylalanine Metabolism’, Clinical Biochemistry Reviews, 29(1), pp. 31–41. 
• Phenylketonuria(2023) NHS Choices. Available at: https://www.nhs.uk/conditions/phenylketonuria (Accessed: 19 September 2023)
• Gerrard, A. & Dawson, C. (2022). ‘Homocystinuria diagnosis and management: it is not all classical’, Journal of Clinical Pathology, 75(11), pp. 744–750. doi:10.1136/jcp-2021-208029. 
• Morris, A.A., Kozich, V. & Chapman, K.A. (2017). ‘Guidelines for diagnosing and managing cystathionine beta-synthase deficiency’, Journal of Inherited Metabolic Disease, 40, pp. 49–74. 
• Homocystinuria(2022) NHS Choices. Available at: https://www.nhs.uk/conditions/homocystinuria (Accessed: 19 September 2023). 
• Mistry, J.B., Bukhari, M. & Taylor, A. (2013). ‘Alkaptonuria’, Rare Diseases, 27475. doi:10.4161/rdis.27475. 
• Zatkova, A., Ranganath, L. and Kadasi, L. (2020). ‘Alkaptonuria: Current Perspectives’, The Application of Clinical Genetics, Volume 13, pp. 37–47. doi:10.2147/tacg.s186773. 
• Alkaptonuria(2022) NHS Choices. Available at: https://www.nhs.uk/conditions/alkaptonuria (Accessed: 19 September 2023). 
• Elmonem, M.A., Veys, KR and Levtchenko, E. (2016). ‘Cystinosis’, Orphanet Journal of Rare Diseases, 11(47). doi:10.1186/s13023-016-0426-y. 
• What Is Cystinosis (no date) Cystinosis Foundation UK? Available at: https://www.cystinosis.org.uk/learn-more/what-is-cystinosis/ (Accessed: 19 September 2023). 
• Kowalczyk, N.S. and Zisman, A.L. (2021). ‘Cystinuria: Review of a Life-long and Frustrating Disease’, Yale Journal Biological Medicine, 94(4), pp. 681–686. 
• What is Cystinuria? Cystinuria UK. Available at: https://www.cystinuriauk.co.uk/what-is-cystinuria (Accessed: 19 September 2023). 
• Shee, K. and Stoller, M.L. (2021). ‘Perspectives in primary hyperoxaluria — historical, current and future clinical interventions’, Nature Reviews Urology, 19(3), pp. 137–146. doi:10.1038/s41585-021-00543-4. 
• Hyperoxaluria. Kidney Care UK. Available at: https://www.kidneycareuk.org/about-kidney-health/conditions/rare-conditions/hyperoxaluria/ (Accessed: 19 September 2023). 
• Blackburn, P. et al.(2017). ‘Maple syrup urine disease: mechanisms and management’, The Application of Clinical Genetics, Volume 10, pp. 57–66. doi:10.2147/tacg.s125962. 
• Maple syrup urine disease(2021) NHS Choices. Available at: https://www.nhs.uk/conditions/maple-syrup-urine-disease/ (Accessed: 19 September 2023).