An Overview of Methylmalonic Acidemia With Homocystinuria

Methylmalonic acidemia with homocystinuria (MMA-HCU) is a rare, inherited metabolic disorder where the body is unable to break down and process certain amino acids. When these substances build up in the blood, they become toxic and cause symptoms.

MMA-HCU is one of a group of disorders called organic acid disorders. These disorders are usually diagnosed at birth during routine newborn screenings, but symptoms of MMA-HCU can also appear for the first time in older children and adults.

Symptoms

When MMA-HCU is diagnosed during a newborn screening, the condition may be detected before any symptoms are apparent. During a newborn screening, a tiny sample of blood is taken from the baby's foot (sometimes called a heel prick test). This blood sample is tested for a range of conditions that a baby might inherit from its parents—some of which could have serious consequences if left untreated.

Even newborns that appear completely normal and healthy are screened for certain metabolic disorders.

In newborns, children, and adults, the symptoms of MMA-HCU can range from mild to fatal. Age may also influence symptoms. For example, newborns with MMA-HCU often experience failure to thrive and older kids may display delays in development.

MMA-HCU affects the body's ability to break down certain proteins in the body. It's not uncommon for an infant with one variant of the condition to appear normal at birth, though as their diet begins to expand (particularly when protein is introduced), the symptoms will become more apparent—typically in the first year of life. In some cases, babies with MMA-HCU are born with microcephaly (an abnormally small head).

Symptoms can also be delayed into later childhood, teens, and adulthood in people with certain variants of MMA-HCU. In rare cases, research has identified individuals who were diagnosed with MMA-HCU who never had any symptoms of the condition at all.

Symptoms typically associated with MMA-HCU include:

• Vomiting
• Dehydration
• Low muscle tone
• Paleness
• Poor feeding
• Inadequate weight gain/failure to thrive
• Lethargy and weakness
• Rashes
• Vision problems
• Blood disorders, including anemias
• Infections that won't go away or keep coming back (especially fungal)

Symptom Variability With Age

In most cases, people with MMA-HCU who develop symptoms later in life have a less severe form of the disease than those who had symptoms at birth. For newborns with the condition, early diagnosis and treatment are essential to preventing long-term health complications that can affect everything from growth and development to cognitive function.

In older children, teens, and adults, symptoms may manifest with unexplained behavioral or cognitive changes, trouble walking or falls, as well as abnormal laboratory tests.

Exacerbating Factors

Symptoms of MMA-HCU can also be brought on by illness, inflammation, infection, surgery, or injury. Fasting before surgery or not eating due to illness can trigger symptoms too.

In some cases, a child's first MMA-HCU symptoms may appear after they experienced a period of reduced appetite after a viral illness.

Complications

As the condition progresses, symptoms related to critically low vitamin B12 levels may emerge. Deficiencies in B12 may be diagnosed around the same time as MMA-HCU due to the impaired cellular process.

When acidosis goes untreated it can have serious and potentially fatal complications including:

• Stroke
• Seizures
• Brain swelling
• Heart problems
• Respiratory failure
• Impaired kidney function
  

In severe cases, MMA-HCU can result in coma and sudden death. In these cases, MMA-HCU may be found during an autopsy.

Causes

MMA-HCU is a combination of two conditions: methylmalonic acidemia and homocystinuria. Both conditions affect the body's ability to break down and process amino acids.

The main trigger for the symptoms is a build-up of methylmalonic acid and homocysteine in the blood. This buildup happens because of the body's impaired ability to metabolize the amino acids. When these proteins are not properly converted, the byproducts stay in the blood and eventually reach toxic levels.

A Genetic Disease

MMA-HCA is caused by genetic mutations, meaning a person is born with the condition. The mutations are usually inherited in an autosomal recessive manner, meaning that each parent passes a mutation to their child—however, the parents do not have to have symptoms of the disorder themselves (unaffected carrier). When a child is born with two genes that do not function correctly, they develop MMA-HCU.

For families with multiple children, it's possible for an MMA-HCU-affected child to have siblings who are not affected by the mutation or who are unaffected carriers like their parents. MMA-HCU seems to affect both sexes at about the same rate. In states that screen for the condition, cases are usually diagnosed in infancy.

Diagnosis

MMA-HCU is sometimes part of routine newborn screening. However, each state's public health department decides which conditions to screen for—not every state screens for MMA-HCU.

When screening is not available, additional diagnostic tests can be run if MMA-HCU is suspected. If the condition is not detected during a newborn screening or prenatal genetic test, the diagnosis will likely not occur until symptoms develop during infancy or later in childhood, or even into adulthood.

Several laboratory tests can be used to help a doctor diagnose MMA-HCU. Usually, blood and urine samples will be needed.

Treatment

MMA-HCU needs to be managed in a number of different ways, including diet and medication. In some cases, surgery may be required. The first intervention for most people with the condition regardless of the age at which they are diagnosed with MMA-HCU is to adhere to a low-protein diet.

To help offset the body's inability to properly metabolize certain substances and prevent deficiency, many patients with MMA-HCU benefit from supplementation with cobalamin (B12) and L-Carnitine. How well a person responds to supplementation depends on the MMA-HCU variant they have. A person with MMA-HCU will work with their doctor, specialists, and dieticians to decide which (if any) of the supplements they should try.

The FDA has approved medication specifically for the homocystinuria component of MMA-HCU called Cystadane (betaine). Cystadane helps lower the levels of homocysteine in a person's blood.

Treatment for Symptoms

During periods of illness or when a person is unable to eat and drink, IV glucose and fluids can help prevent serious complications. If metabolic acidosis occurs, treatment in the hospital will also include interventions to help lower the acid in the blood.

Organ Transplant

If close monitoring, strict adherence to diet, and supplementation are not enough, MMA-HCU may eventually become severe enough that damage is done to the kidneys and liver. In these cases, people with the condition will need to have a kidney and/or liver transplant.

Organ transplantation is a very serious undertaking. A person may need to wait a long time to find a donor and the procedure itself carries serious risks for any patient.

Coping

Despite timely diagnosis and treatment, some people with MMA-HCU will continue to struggle physically and emotionally with the condition. There is no cure for MMA-HCU and each subtype of the condition will respond to available treatments differently.

However, people with MMA-HCU do not always experience life-threatening complications and may have a good overall prognosis. Many children with the condition grow up without developing other serious long-term health problems and go on to be healthy adults.

Women with the condition are often able to get pregnant and experience normal deliveries. However, couples affected by MMA-HCU may want to undergo genetic testing prior to trying to conceive to assess the chance they will pass the condition on to a child.

A Word From Verywell

MMA-HCU is a rare inherited condition that can have life-threatening consequences if not diagnosed promptly. While there is no cure and treatment can prove challenging, for people who respond to strict adherence to dietary modifications (such as low-protein diets) supplementation with vitamin B12 and other essential nutrients, and close monitoring, the outcome is generally good.

Babies born with MMA-HCU who are promptly diagnosed and treated can have a good outcome as well.