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 and is also unable to convert one particular amino acid to another. 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, which have different genetic causes and variable 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 have an inability to grow and gain weight at the expected rate (failure to thrive), which is sometimes recognized before birth (intrauterine growth retardation). These infants can also have difficulty feeding and an abnormally pale appearance (pallor). Eye abnormalities and neurological problems, including weak muscle tone (hypotonia) and seizures, are also common in methylmalonic acidemia with homocystinuria. Most 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 (a condition called 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 not treated.
When methylmalonic acidemia with homocystinuria begins in adolescence or adulthood, the signs and symptoms usually include psychiatric changes and cognitive problems. Affected individuals can exhibit changes in their behavior and personality; they may become less social and may experience hallucinations, delirium, and psychosis. In addition, these individuals can begin to lose previously acquired mental and movement 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.
The most common form of the condition, methylmalonic acidemia with homocystinuria, cblC type, is estimated to affect 1 in 200,000 newborns worldwide. Studies in particular populations indicate that this form of the condition may be even more common. These studies estimate the condition 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.
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. Variants in other genes cause a more severe condition that may involve methylmalonic aciduria or homocystinuria but is thought to be a separate disorder.
Except for PRDX1, each of the above-mentioned genes is involved in the processing of vitamin B12, also known as cobalamin or Cbl. The function of the PRDX1 gene is not directly related to the processing of amino acids, lipids, or cholesterol. Rather, this gene is near the MMACHC gene, and certain genetic alterations involving PRDX1 can affect MMACHC gene activity.
Processing of vitamin B12 converts it 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 the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.
Variants in the MMACHC, MMADHC, LMBRD1, ABCD4, or PRDX1 gene affect 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. This defect allows potentially toxic compounds to 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 other genes involved in vitamin B12 processing can cause related conditions. Those variants that impair only AdoCbl production lead to methylmalonic acidemia, and those that impair only MeCbl production cause homocystinuria.
Methylmalonic acidemia with homocystinuria is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.
Other Names for This Condition
- Methylmalonic acidemia and homocystinemia
- Methylmalonic acidemia and homocystinuria
- Methylmalonic aciduria and homocystinuria
- Vitamin B12 metabolic defect with combined deficiency of methylmalonyl-coA mutase and homocysteine:methyltetrahydrofolate methyltransferase
- Vitamin B12 metabolic defect with combined deficiency of methylmalonyl-coA mutase and methionine synthase activities
Additional Information & Resources
Genetic Testing Information
- Genetic Testing Registry: Methylmalonic acidemia with homocystinuria
- Genetic Testing Registry: Methylmalonic acidemia with homocystinuria cblD
- Genetic Testing Registry: Methylmalonic acidemia with homocystinuria, type cblJ
- Genetic Testing Registry: Methylmalonic aciduria and homocystinuria type cblF
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Research Studies from ClinicalTrials.gov
Scientific Articles on PubMed
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