Methylmalonic acidemia with homocystinuria

Alternate Names

Methylmalonic acidemia and homocystinemia

Definition

Methylmalonic acidemia with homocystinuria is an inherited disorder in which the body is unable to properly process protein building blocks (amino acids), certain fats (lipids), and a waxy fat-like substance called cholesterol.

Summary

• Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. The signs and symptoms of the combined condition, methylmalonic acidemia with homocystinuria, usually develop in infancy, although they can begin at any age.
• When the condition begins early in life, babies have difficulty gaining weight (failure to thrive), feeding difficulties, and a pale appearance. Babies may also have weak muscle tone (hypotonia) and seizures.
• Most babies and children with this condition have an unusually small head size (microcephaly), intellectual disability and developmental delay. Less common features of the condition include eye problems and a blood disorder called megaloblastic anemia.
• When the disorder begins in adolescence or adulthood, the signs and symptoms usually include behavior and personality changes and cognitive problems (issues with learning, memory, perception etc).
• In some cases, abilities are lost, resulting in a decline of performance, memory and speech problems, dementia and lethargy.

Cause

• Methylmalonic acidemia with homocystinuria can be caused by mutations in one of several genes: MMACHC, MMADHC, LMBRD1, ABCD4, or HCFC1.
• Mutations in these genes account for the different types of the disorder, which are known as complementation groups: cblC, cblD, cblF, cblJ, and cblX, respectively.
• Each of the above-mentioned genes is involved in the processing of vitamin B12, also known as cobalamin or Cbl.
• Processing of the vitamin 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.

Gene mutations

• Mutations in the MMACHC, MMADHC, LMBRD1, ABCD4, or HCFC1 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). Researchers have not determined how altered levels of homocysteine and methionine lead to the health problems associated with homocystinuria.

Inheritance

Autosomal recessive inheritance, a 25% chance

• Methylmalonic acidemia with homocystinuria is usually inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

X-linked recessive inheritance

• When caused by mutations in the HCFC1 gene, the condition is inherited in an X-linked recessive pattern.

Diagnosis

Diagnostic methods Measurement of organic acids and amino acids, in particular evidence of increased total plasma homocysteine (tHcy), is suggestive of the disease. Diagnosis is confirmed by complementation analysis of cultured patient fibroblasts or by identification of mutations in the MMACHC, MMADHC, LMBRD1 or ABCD4 genes.

Differential diagnosis

Differential diagnoses include acquired vitamin B12 deficiency, vitamin B12-responsive methylmalonic aciduria, and homocystinuria without methylmalonic aciduria (see these terms). The combination of methylmalonic aciduria, homocystinuria and normal serum cobalamin concentrations is required to distinguish patients.

Antenatal diagnosis

Antenatal diagnosis is possible by measurement of methylmalonate and homocysteine in amniotic fluid and maternal urine at mid-trimester and by studies of cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible when the affected gene and the mutation(s) segregating in the family are known. Prenatal therapy (treating the mother with hydroxycobalamin during pregnancy) has been reported in two cases with apparent success.

Genetic counseling

All four forms of the disorder are transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families.

Treatment

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Betaine (Brand name: Cystadane)Treatment of homocystinuria to decrease elevated homocysteine blood levels.

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