Two Rare Vitamin B12 Conditions Clinically Distinct, More Complex


The study findings support reevaluating how to treat future patients and implications for genetic counseling, according to the authors.

New research is revealed the complexity of 2 vitamin B12 diseases that affect the same genes but are clinically distant from the most common disorder, according to a Baylor College of Medicine press release. The study suggested that other genes outside of the common ones were affected, making the function and exact genes unknown.

The team analyzed mouse models and found that the genes involved in the more complex forms of the disorder not only caused the expected typical vitamin B12 disease, but also affect the generation of ribosomes, which are the protein-building machinery of the cell. The study findings support reevaluating how to treat future patients and implications for genetic counseling, according to the authors.

“Vitamin B12, or cobalamin, is a dietary nutrient essential for normal human development and health and is found in animal-based foods but not in vegetables. Mutations in the genes encoding the proteins responsible for the metabolic processes involving vitamin B12 result in rare human inborn errors of cobalamin metabolism,” said co-corresponding author Ross A. Poché, MD, associate professor of molecular physiology and biophysics at Baylor, in the press release.

The most common inherited vitamin B12 disease, cblC, causes patients to suffer from a multisystem condition that can include intrauterine growth restriction, hydrocephalus, severe cognitive impairment, intractable epilepsy, retinal degeneration, anemia, and congenital heart malformations. Further, some patients presenting with a combination of typical and non-typical cblC characteristics do not have mutations in MMACHC gene, but in genes that code for proteins called THAP11 (RONIN) and HCFC1, according to the study.

“We developed mouse models carrying the exact same mutations that the patients with cblC-like disease have in HCFC1 or RONIN genes, and recorded the animals’ characteristics,” Poché said in the press release. “We confirmed that they presented with the cobalamin syndrome as expected, but in addition we found that they had ribosome defects. This is the first time that the HCFC1 and RONIN genes have been identified as regulators of ribosome biogenesis during development.”

The research team demonstrated that this cblC-like disease affecting the function of RONIN and HCFC1 proteins is a hybrid syndrome, since it is both a cobalamin disorder and a disease of ribosomes. Therapeutic implications have occurred from this study, according to Poché.

“Some cblC-like patients may respond to some extent to cobalamin supplementation, but we anticipate that will not help the issues due to ribosome defects,” he said in the press release.

The study authors noted that their research revealed promising clinical implications.

“The beauty is in how the work in patients is symbiotic with the work in the mouse model and how each system informs the other,” said co-author David S. Rosenblatt, MD, professor in the departments of human genetics, medicine, pediatrics, and biology at McGill University and senior scientist at the Research Institute of the McGill University Health Centre, in the press release.


Unraveling the complexity of vitamin B12 diseases. Baylor College of Medicine. January 10, 2022. Accessed January 10, 2022.

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