An Overview of Methylmalonic Acidemia With Homocystinuria

A Rare, Inherited Metabolic Disorder

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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, fats, and lipids. When these substances build up in the blood, they become toxic.

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 may have underlying genetic or metabolic treatments that need treatment.

In the first hours and days of life, testing a baby's blood is the only way to be sure they are not affected.

The symptoms of MMA-HCU a person has, as well as the intensity and frequency of symptoms, will depend on which genes are affected by a mutation. Primarily, the main trigger for the cascade of symptoms is a build-up of methylmalonic acid in the blood, as well as homocysteine. 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.

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 abnormally small heads (a condition called microcephaly).

Symptoms can also be delayed into later childhood, teens, and adulthood in people with other 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)

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

In severe cases, MMA-HCU can result in coma and sudden death. In these cases, MMA-HCU may be found during an autopsy conducted in the case of unexplained death, particularly in infants and children.

Symptoms of MMA-HCU can also be brought on by illness, inflammation, or infection, having surgery or an injury, or fasting. In some cases, a child's first MMA-HCU symptoms may appear after they experienced a period of reduced appetite after a viral illness or fasting before a surgical procedure.

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

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 which can affect everything from growth and development to cognitive function.

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 certain substances in the body. As these substances (including amino acids and lipids) build up in the body, they can reach toxic levels and cause symptoms. In some cases, the buildup can cause serious complications and even be fatal.

A Genetic Disease

MMA-HCA is caused by genetic mutations, meaning a person is born with the condition (however they may not show symptoms right away). 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. Each pregnancy between a couple that carries the mutation has a 25 percent chance of passing on the defective gene, a 25 percent chance of being unaffected, and a 50 percent chance of being a carrier 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. However, it is also seen in children, teens, and adults.

The condition is rare. The most common type (cblC) occurs in about one in 200,000 newborns worldwide each year.

The other three forms are so rare that fewer than 20 cases have ever been diagnosed.

Diagnosis

MMA-HCU is part of routine newborn screenings throughout the United States. 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. As the symptoms are not necessarily present at birth, if not detected during a newborn screening or prenatal genetic test, the diagnosis will likely not occur until later in childhood or even into adulthood.

If a doctor suspects MMA-HCU, there are several steps to confirm the diagnosis. One of the first is to take a thorough history of a person's symptoms and address any that are potentially life-threatening. They may also ask questions about the health of other family members and may want them to have testing done as well.

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

Treatment

MMA-HCU needs to be managed in a number of different ways, including changes to 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 keep a person's weight up and blood sugar levels stable, people with MMA-HCU often find eating small frequent meals is a good strategy.

During periods of illness or other situations where they are unable to eat and drink, they may need to go to the hospital for IV glucose and fluids to help prevent more serious complications. If metabolic acidosis occurs, treatment in the hospital will also include interventions to help lower the acid in the blood.

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 (sold under the brand name Betaine). Cystadane helps lower the levels of homocysteine in a person's blood.

Further Treatment

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.

While transplanted organs will not have the same defect and therefore will function normally, 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. For people with MMA-HCU, the stress of surgery can trigger a serious health crisis. Even if a donor is found and the surgery goes well, the body may reject the transplanted organ.

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, even when management proves challenging, 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

Methylmalonic Acidemia With Homocystinuria (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 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 have had few complications in childhood and adolescence and even gone on to have normal pregnancies and delivered healthy children unaffected by the condition as adults.

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