Methylmalonic acidemia with homocystinuria is a disorder in which the body is unable to correctly process certain protein building blocks (amino acids), fat building blocks (fatty acids), and cholesterol. The body is also unable to convert the amino acid homocysteine to another amino acid, methionine. Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. There are several forms of this combined condition, and the different forms have different genetic causes and signs and symptoms. The most common and best understood form, called cblC type (or cobalamin C disease), occurs in about 80 percent of affected individuals.

The signs and symptoms of methylmalonic acidemia with homocystinuria usually develop in infancy, although they can begin at any age. When the condition begins early in life, affected individuals typically grow more slowly than expected. This sign is sometimes iedentified before the baby is born. These infants can also have difficulty feeding and have an abnormally pale appearance (pallor). Eye abnormalities and neurological problems, including weak muscle tone (hypotonia) and seizures, are also common in people with methylmalonic acidemia with homocystinuria. Many infants and children with this condition have delayed development and intellectual disability, and some have an unusually small head size (microcephaly).

Some people with methylmalonic acidemia with homocystinuria develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The signs and symptoms of early-onset methylmalonic acidemia with homocystinuria worsen over time, and the condition can be life-threatening if it is not treated.

When methylmalonic acidemia with homocystinuria begins in adolescence or adulthood, it may change an affected person's behavior and personality; the person may become less social and may experience hallucinations, delirium, and psychosis. In addition, these individuals can begin to lose previously acquired mental and physical abilities, resulting in a decline in school or work performance, difficulty controlling movements, memory problems, speech difficulties, a decline in intellectual function (dementia), or an extreme lack of energy (lethargy). Some people with methylmalonic acidemia with homocystinuria whose signs and symptoms begin later in life develop a condition called subacute combined degeneration of the spinal cord, which leads to numbness and weakness in the lower limbs, difficulty walking, and frequent falls.

Methylmalonic acidemia with homocystinuria can be caused by variants (also known as mutations) in one of several genes, including MMACHC, MMADHC, LMBRD1, and ABCD4. Variants in these genes account for the different types of the disorder: cblC, cblD, cblF, and cblJ, respectively. Another type, called epi-cblC, is caused by variants in the PRDX1 gene, usually in combination with an MMACHC gene variant.

MMACHC, MMADHC, LMBRD1, and ABCD4 are all involved in processing vitamin B12, also known as cobalamin or Cbl. The PRDX1 gene is not directly involved in processing amino acids, lipids, or cholesterol, but it is located near the MMACHC gene, and certain genetic alterations to PRDX1 can affect MMACHC gene activity.

During processing, vitamin B12 is converted to one of two molecules: adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl is required for the normal function of an enzyme that helps break down certain amino acids, lipids, and cholesterol. AdoCbl is called a cofactor because it helps the enzyme carry out its function.

MeCbl is also a cofactor, but for another enzyme that converts homocysteine to methionine. The body uses methionine to make proteins and other important compounds.

Variants in the MMACHC, MMADHC, LMBRD1, ABCD4, or PRDX1 gene affect the early steps of vitamin B12 processing, resulting in a shortage of both AdoCbl and MeCbl. Without AdoCbl, proteins and lipids are not broken down properly. As a result, potentially toxic compounds build up in the body's organs and tissues, causing methylmalonic acidemia.

Without MeCbl, homocysteine is not converted to methionine. As a result, homocysteine builds up in the bloodstream and methionine is depleted. Some of the excess homocysteine is excreted in urine (homocystinuria).

Variants in the HCFC1 gene are the most common cause of a condition called methylmalonic acidemia with homocystinuria, cblX type. This gene provides instructions for making a protein that helps regulate the activity of other genes, including the MMACHC gene. Variants in the HCFC1 gene (and, less commonly, other related genes) likely disrupt the normal activity of the MMACHC gene, impairing vitamin B12 processing and leading to methylmalonic acidemia or homocystinuria. However, variants in the HCFC1 gene likely also disrupt the normal activity of other genes, resulting in additional signs and symptoms that are more serious. Many researchers consider cblX a separate disorder from methylmalonic acidemia with homocystinuria.

Variants in other genes involved in vitamin B12 processing can cause related conditions. Variants that impair only AdoCbl production lead to methylmalonic acidemia, and variants that impair only MeCbl production cause homocystinuria.

Methylmalonic acidemia with homocystinuria is a genetic condition. Babies inherit it from their biological (birth) parents.

• Methylmalonic acidemia with homocystinuria is usually an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes methylmalonic acidemia with homocystinuria (MMACHC, MMADHC, LMBRD1, or ABCD4) to their baby. Only babies with two matching nonworking genes—for example, one nonworking MMACHC from the mom and one nonworking MMACHC from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking MMACHC from the mom and one nonworking LMBRD1 from the dad—will not have this condition.
• People with one working copy and one nonworking copy of the MMACHC, MMADHC, LMBRD1, or ABCD4 gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the MMACHC, MMADHC, LMBRD1, or ABCD4 gene, they have a 1 in 4 chance of having a child with methylmalonic acidemia with homocystinuria.
  • Carriers for methylmalonic acidemia with homocystinuria often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with methylmalonic acidemia with homocystinuria.
  • Parents who already have a child with methylmalonic acidemia with homocystinuria due to a change in the MMACHC, MMADHC,LMBRD1, or ABCD4 gene still have a 1 in 4 chance of having another child with methylmalonic acidemia with homocystinuria. This 1 in 4 chance stays the same for all future children.
• In some cases, methylmalonic acidemia with homocystinuria is inherited in an X-linked recessive pattern. Babies inherit the condition on the X chromosome, which is one of the two sex chromosomes.
  • When boys (who only have one X chromosome) receive one nonworking copy of the HCFC1 gene from their mom, they have this condition. Dads cannot pass on this condition to their sons.
  • Because this condition is linked to the X chromosome, it is much more common in boys than girls. The condition is also usually more severe in boys than in girls.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of methylmalonic acidemia with homocystinuria vary. Depending on the condition type, they can appear anytime between the first few days of life up to 14 years of age.

Signs of the condition may include the following:

• Delayed growth and weight gain
• Difficulty feeding
• Small head size
• Skin rash
• Vomiting
• Poor appetite
• Fever
• Sleeping longer or more often
• Floppy arms and legs (hypotonia)

Newborn screening for methylmalonic acidemia with homocystinuria is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. Your body makes these substances when it breaks down food. Babies with high levels of these substances might have methylmalonic acidemia with homocystinuria.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for methylmalonic acidemia with homocystinuria is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample
• Small skin sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen.

Babies who are given carnitine or who have a lot of bilirubin in their blood may have a false-positive newborn screening result for methylmalonic acidemia with homocystinuria.

Moms with low levels of vitamin B-12 can also have babies with false-positive newborn screening results.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Vitamin B-12 treatments
• L-carnitine supplements
• Betaine supplements
• Low-protein diet
• Special formulas
• Frequent feedings to avoid long periods without food

Children who receive early and ongoing treatment for methylmalonic acidemia with homocystinuria can have healthy growth and development.

The most common form of the condition, methylmalonic acidemia with homocystinuria, cblC type, is estimated to affect 1 in 200,000 newborns worldwide. This form of the condition may be even more common in certain populations; some studies estimate that it occurs in 1 in 100,000 people in New York and 1 in 60,000 people in California.

Other types of methylmalonic acidemia with homocystinuria are much less common. Fewer than 20 cases of each of the other types have been reported in the medical literature.