SNP Shot: Genomic Insights

Methylmalonic acidemia with homocystinuria is a metabolic disorder where the body struggles to process specific amino acids (protein building blocks), fatty acids (fat building blocks), and cholesterol. It also impairs the conversion of homocysteine to methionine. Individuals affected by this condition exhibit a combination of features associated with both methylmalonic acidemia and homocystinuria individually. There are different types of this combined condition, each with distinct genetic origins and associated signs and symptoms. The most prevalent and well-understood type, known as cblC type (or cobalamin C disease), accounts for approximately 80% of all cases.

The symptoms of methylmalonic acidemia with homocystinuria typically manifest during infancy, although they can appear at any age. In early-onset cases, affected infants often experience slower-than-expected growth, sometimes detectable before birth. These babies may also have feeding difficulties and an unusually pale complexion (pallor). Eye problems and neurological issues, such as weak muscle tone (hypotonia) and seizures, are also commonly observed. Many infants and children with this condition experience developmental delays, intellectual disability, and, in some cases, an abnormally small head size (microcephaly).

Some individuals with methylmalonic acidemia with homocystinuria develop megaloblastic anemia, a blood disorder characterized by a low red blood cell count (anemia) and abnormally large red blood cells (megaloblastic). Early-onset symptoms of methylmalonic acidemia with homocystinuria tend to worsen over time and can become life-threatening if left untreated.

When methylmalonic acidemia with homocystinuria begins during adolescence or adulthood, it can lead to behavioral and personality changes. Affected individuals may become withdrawn and experience hallucinations, delirium, and psychosis. Furthermore, they may begin to lose previously acquired mental and physical skills, resulting in decreased performance at school or work, impaired motor control, memory problems, speech difficulties, cognitive decline (dementia), or extreme fatigue (lethargy). Some individuals with later-onset methylmalonic acidemia with homocystinuria may develop subacute combined degeneration of the spinal cord, resulting in numbness and weakness in the legs, difficulty walking, and frequent falls.

Inheritance:

Methylmalonic acidemia with homocystinuria typically follows an autosomal recessive inheritance pattern. This means that both copies of the responsible gene in each cell must carry a mutation for the disorder to manifest. Parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they generally do not exhibit any symptoms of the condition. The condition caused by mutations in the HCFC1 gene follows an X-linked recessive inheritance pattern because the gene is located on the X chromosome, one of the two sex chromosomes.