Obtained from foods such as milk, eggs, fish and meat, B 12 is essential to human health because it helps the body convert food into fuel. It's vital to the nervous system and for making red blood cells.
Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine.
These individuals can end up having serious health problems, including developmental delay, epilepsy, anemia, stroke, psychosis and dementia.
The gene for cblC had been discovered by researchers who studied several hundred patients with similar symptoms. However, an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia recently discovered, designated cblX. The mutations in HCFC1 as the cause of the cblX disorder highlights perturbation of transcription as the cause of a classical inborn error of metabolism. Although cblC and cblX share some clinical features, cblX individuals were not documented to have the specific bulls-eye maculopathy, which is a frequent finding in cblC. Furthermore, the neurological features were more severe (e.g., brain malformation, infantile spasms, move- ment disorders) in cblX individuals, suggesting that MMACHC deficiency alone does not explain all of the clinical manifestations. The pathophysiology underlying the complex phenotype remains to be fully elucidated but most likely involves dysregulation of other HCFC1 targets. The recent discovery of variants in the regulatory regions of HCFC1 as a possible cause of nonsyndromic intellectual disability has implicated HCFC1 in brain devel- opment and function23 and, together with the data pre- sented here, suggests that the metabolic manifestations of MMACHC deficiency, along with mutation analysis of HCFC1, should be assessed in individuals with idiopathic X-linked intellectual disability.
- Whole-exome sequencing (WES)
- Sanger sequencing
- Immunoblot Analysis
The X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.