Genes MMACHC, MMADHC, LMBRD1, ABCD4, or HCFC1 - methylmalonic with homocystinuria, cblC types, cblD, cblF, cblJ and CBLX (Methylmalonic acidemia With homocystinuria) acidemia.

Methylmalonic acidemia with homocystinuria is a disease due to an inborn error of metabolism of vitamin B12 (cobalamin) wherein the body can not properly process amino acids, some lipids, and cholesterol. Associated signs and symptoms may include megaloblastic anemia, lethargy, growth retardation and developmental, intellectual deficit, and seizures. Other signs and symptoms of the disease may include eye defects, microcephaly and blood disorders. This disease can occur between early childhood or adulthood. Patients who develop symptoms after infancy may have ataxia, dementia or psychosis. Signs and symptoms of methylmalonic acidemia with homocystinuria are progressive, and the disease can be fatal if untreated.

They described five complementation groups cobalamin defects associated with methylmalonic acidemia with homocystinuria (cblC, cblD, cblF, cblJ and CBLX). In addition to the general characteristics of the disease, individuals with type cblC with acute neurological impairment, deterioration of the retina, microcephaly, and severe brain abnormalities including hydrocephalus, white matter abnormalities and atypical lesions of the basal ganglia. Individuals with type cblD with severe learning difficulties, behavioral disorders, and abnormalities in movement and gait. People with type cblF have food problems, hypotonia, stomatitis, dysmorphic midface, cardiac malformations and rashes. Those affected with cblJ type, have delayed development, eye defects, neurological problems and blood disorders. Individuals with type CBLX, have delayed development, eye defects, neurological disorders, blood disorders and craniofacial anomalies.

This process is due to mutations in the MMACHC, MMADHC, LMBRD1, ABCD4, and HCFC1 genes. Mutations in each represent different types of cblC, cblD, cblF, cblJ, and CBLX disease, respectively.

The MMADHC genes located on the long arm of chromosome 2 (2q23.2) and MMACHC, located on the short arm of chromosome 1 (1p34.1), encode proteins that act together in the conversion of vitamin B12 in one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl required for normal function of methylmalonyl-CoA mutase enzyme. This helps break down certain amino acids, lipids and cholesterol. AdoCbl is a cofactor that helps methylmalonyl-CoA mutase to carry out its function. MeCbl is also a cofactor, but for methionine synthetase enzyme. This enzyme converts the amino acid homocysteine in the amino acid methionine. The body uses methionine to synthesize proteins and other important compounds.

Have been identified at least 3 different mutations in the gene MMADHC and dozens of mutations in the gene MMACHC can lead to methylmalonic acidemia with homocystinuria cblD and cblC respectively. A particular in MMACHC, 271dupA gene mutation represents approximately 40% of all alleles of the disease. Two common alleles are identified W203X and 658delAAG. Another mutation identified, 394C-T, is common in populations of East Asia. Mutations in both genes result in encoding a protein that can not produce AdoCbl or MeCbl. Lack of AdoCbl impairs the function of methylmalonyl-CoA mutase and methionine synthetase. As a result, certain proteins and lipids do not decompose and can not convert homocysteine to methionine. This double defect leads to accumulation of toxic compounds and homocysteine and decreased methionine production within the body. This combination of imbalances leads to the signs and symptoms of methylmalonic acidemia with homocystinuria.

The LMBRD1 gene, located on the long arm of chromosome 6 (6q13), encoding a protein of the lysosomal membrane may be involved in the transport and metabolism of cobalamin. This protein also interacts with the shape of the hepatitis delta antigen and may be necessary for the nucleocytoplasmic transport of hepatitis delta virus. At least nine mutations LMBRD1 gene have been identified as responsible for methylmalonic aciduria with homocystinuria type cblF (MMAHCF), altered metabolism of cobalamin characterized concentrations diminished of adenosylcobalamin coenzymes (AdoCbl) and methylcobalamin (MeCbl). It is due to the accumulation of free cobalamin in lysosomes, making it difficult conversion to the cofactors. Clinical features include developmental delay, stomatitis, glossitis, convulsions and sensitive aciduria methylmalonic B12.

The ABCD4 gene, located on the long arm of chromosome 14 (14q24.3), encodes a protein that is involved in the conversion of cobalamin in one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). The ABCD4 protein is found in the lysosomes, where it interacts with the LMBD1 protein encoded from LMBRD1 gene. These two proteins together vitamin B12 transport out of lysosomes, making it available for further processing in AdoCbl and MeCbl. They have identified at least five mutations in the gene responsible ABCD4 methylmalonic acidemia with homocystinuria, cblJ type. Mutations in this gene result encoding a nonfunctional protein ABCD4. ABCD4 functional deficiency protein prevents the release of vitamin B12 from the lysosomes, so the vitamin is not available for the production of AdoCbl and MeCbl.

The HCFC1 gene, located on the long arm (q) of the X chromosome (Xq28), encoding the HCF-1 protein, which helps to regulate the activity of other genes. A specific function of the HCF-1 protein is to control the activity of genes involved in processing of cobalamin in particular the MMACHC gene. Furthermore, HCF-1 helps regulate genes important in other cell, such as the progression of cells through the cell cycle processes. This protein also plays a role in the distribution of cells in tissues and organs in development, including the brain. They have identified at least six mutations in the gene HCFC1 in individuals with methylmalonic acidemia with homocystinuria, CBLX type. These mutations occur in regions of the protein that help to interact with other proteins. It is believed that changes in these regions prevent interaction of HCF-1 transcription factors, which disrupts the normal activity of the gene. In particular, the deterioration of the activity of genes MMACHC prevents processing and normal transport of vitamin B12, preventing the production of both AdoCbl as MeCbl. Neurological and developmental problems are particularly serious in individuals with type CBLX, partly due to the interruption of the activity of other genes normally regulated by protein HCF-1.

This disease is usually inherited as an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. However, when methylmalonic acidemia with homocystinuria is caused by mutations in the HCFC1 gene is inherited in an X - linked recessive pattern HCFC1 The gene is on the X chromosome, one of the two sex chromosomes. In males, an altered copy of the gene in each cell is sufficient to express the disease. In females, having two X chromosomes, a mutation would have to occur in both copies of the gene to express the alteration. Because it is unlikely that women have two altered copies of this gene, males are affected by recessive X - linked disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with methylmalonic acidemia with homocystinuria, by complete PCR amplification of the exons of MMACHC, MMADHC, LMBRD1, ABCD4 and HCFC1 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).