MMADHC Gene Discovery: Advancing Understanding and Treatment of Vitamin B12 Metabolism Disorders

The discovery of the MMADHC gene has significantly advanced our understanding of a rare but severe genetic disorder linked to vitamin B12 metabolism. This disorder, known as isolated and combined homocystinuria and methylmalonic aciduria (MMA) of the cblD variety, disrupts the body's ability to properly process vitamin B12, which is crucial for maintaining overall health. When vitamin B12 metabolism is impaired, it leads to a broad spectrum of debilitating symptoms, ranging from cognitive deficits to metabolic disturbances.

Vitamin B12 is essential for the synthesis of red blood cells, neurological function, and DNA synthesis. It plays a key role in regulating homocysteine levels, which, when elevated, are associated with increased risks of cardiovascular diseases such as heart attack, stroke, and dementia. Vitamin B12 is converted into two active forms in the body: methylcobalamin, which is involved in the conversion of homocysteine to methionine (an amino acid vital for many cellular processes), and adenosylcobalamin, which helps in the breakdown of certain fatty acids and amino acids. These conversions are essential for normal cellular function, and the MMADHC gene is pivotal in facilitating them.

Mutations in the MMADHC gene hinder this conversion, leading to severe health problems. The disorder typically manifests in infancy or early childhood, with symptoms including developmental delays, neurological impairments, anemia, and metabolic abnormalities. In some cases, affected individuals may experience cognitive and psychiatric issues, such as psychosis, due to the accumulation of toxic substances in the brain that are normally broken down by active vitamin B12.

The identification of the MMADHC gene has been crucial not only for diagnosing the disorder but also for exploring targeted treatments. By understanding the specific genetic mutations involved, researchers are investigating therapies that may restore normal vitamin B12 metabolism. For instance, early intervention with vitamin B12 supplements or gene-based therapies could potentially alleviate or reduce symptoms, thereby improving the long-term health outcomes for those affected. This discovery represents a significant step forward in the field of medical genetics, offering hope for more effective management of this complex disorder.
MMADHC Gene Discovery: Advancing Understanding and Treatment of Vitamin B12 Metabolism Disorders

Distinguishing Symptoms of Vitamin B12 and Folate Deficiencies

Vitamin B12 and folate deficiencies can both result in megaloblastic anemia, but they exhibit distinct symptoms due to their varying roles in the body. Here’s how they differ:

Vitamin B12 Deficiency Symptoms:

• Neurological Issues: Vitamin B12 deficiency often leads to neurological problems such as numbness and tingling in the extremities, difficulty walking, memory issues, and cognitive disturbances.
• Psychiatric Symptoms: It may also cause mood changes, including depression, irritability, and mood swings.
• Oral Symptoms: Common signs include inflammation of the tongue (glossitis) and mouth ulcers.
• General Anemia Symptoms: Fatigue, weakness, and pallor are also prevalent.

Folate Deficiency Symptoms:

• Gastrointestinal Issues: Folate deficiency typically presents with gastrointestinal symptoms like diarrhea, reduced appetite, and weight loss.
• Oral Symptoms: It can also cause mouth sores and a swollen tongue, similar to vitamin B12 deficiency.
• General Anemia Symptoms: Fatigue, weakness, and pallor are common.
• Neural Tube Defects: In pregnant women, folate deficiency poses a risk of neural tube defects in the developing fetus.

Although both deficiencies can cause fatigue and mouth sores, the presence of neurological symptoms is a distinguishing feature of vitamin B12 deficiency. Accurate diagnosis and treatment are crucial to manage these deficiencies and avoid long-term complications.
Distinguishing Symptoms of Vitamin B12 and Folate Deficiencies

Megaloblastic Anemia: Causes, Symptoms, and Treatment

Megaloblastic anemia is a type of macrocytic anemia characterized by the presence of abnormally large and immature red blood cells, known as megaloblasts, in the bone marrow and peripheral blood. This condition arises primarily due to deficiencies in vitamin B12 (cobalamin) or vitamin B9 (folate), both of which are essential for DNA synthesis and the production of healthy red blood cells.

Vitamin B12 deficiency can occur due to various reasons, including inadequate dietary intake, which is particularly common in individuals following a vegetarian or vegan diet, as B12 is primarily found in animal products. Additionally, malabsorption disorders such as Crohn's disease or bacterial overgrowth can interfere with B12 absorption. Pernicious anemia, an autoimmune disorder, also plays a significant role by damaging the stomach’s ability to produce intrinsic factor, a protein necessary for B12 absorption.

Folate deficiency is frequently associated with poor dietary intake, especially in individuals with diets low in fruits and vegetables. Chronic alcoholism is another contributing factor, as alcohol impairs the absorption of folate and increases its excretion. Conditions such as celiac disease or inflammatory bowel disease can also affect folate absorption, further exacerbating the risk of deficiency.

Both vitamin B12 and folate deficiencies disrupt the normal process of DNA synthesis, leading to the production of large, immature red blood cells that are less effective in transporting oxygen throughout the body. This inefficiency manifests as symptoms such as fatigue, weakness, pallor, and shortness of breath. Vitamin B12 deficiency may additionally cause neurological symptoms like numbness, tingling, and cognitive disturbances, highlighting the broader systemic impact of this condition.

Diagnosis of megaloblastic anemia typically involves blood tests to assess vitamin levels and evaluate the morphology of red blood cells. Treatment strategies focus on correcting the underlying vitamin deficiency through dietary adjustments and supplementation. Early and appropriate intervention is essential to prevent complications and improve patient outcomes. This underscores the critical role of vitamins in red blood cell production and the importance of maintaining a balanced diet to support overall health.
Megaloblastic Anemia: Causes, Symptoms, and Treatment

Vitamin B12 Sources and Bioavailability

Vitamin B12, an essential nutrient for human health, plays a vital role in various bodily functions. Its primary functions include supporting red blood cell production, maintaining nervous system health, aiding in energy metabolism, and assisting in the utilization of folate, another important B vitamin. Without sufficient intake of vitamin B12, individuals are at risk of developing vitamin B12 deficiency anemia, which can lead to various health issues.

To meet the recommended daily intake of vitamin B12—2.4 micrograms for adults, 2.6 micrograms for pregnant individuals, and 2.8 micrograms for breastfeeding individuals—it is crucial to incorporate foods rich in this nutrient into our diets. While animal products like shellfish, fish, and dairy are traditional sources of vitamin B12, there are suitable alternatives available for vegetarians and vegans.

Plant-based options such as nutritional yeast and fortified foods are excellent sources of vitamin B12 that can fulfill dietary requirements. Additionally, supplements are readily accessible for those who struggle to obtain adequate levels through food alone.

It's worth noting that the bioavailability of vitamin B12 varies depending on the source and dosage. Absorption rates decline when the body's capacity of intrinsic factor is exceeded, typically occurring at doses between 1 and 2 micrograms. Moreover, the type of food source influences bioavailability, with dairy products offering approximately three times higher bioavailability than meat, fish, and poultry. Similarly, dietary supplements provide a bioavailability roughly 50% higher than that of food sources.

In summary, ensuring an ample intake of vitamin B12 is crucial for overall health and preventing deficiency-related ailments. By diversifying our diets to include both animal and plant-based sources rich in vitamin B12, individuals can effectively meet their nutritional needs and maintain well-being.
Vitamin B12 Sources and Bioavailability

Hypervitaminosis B12

Vitamin B12, also called cobalamin, is one of 8 B vitamins. All B vitamins help the body convert food (carbohydrates) into fuel (glucose), which is used to produce energy.

The highest percentage of vitamin B12 that is required for enzymatic reactions is taken into the body through food, primarily of animal origin (offal, various types of meat, eggs, milk). Vitamin B12 is responsible for numerous functions in your body, including red blood cell formation, energy production, DNA formation, and nerve maintenance

Elevated vitamin B12 (also known as hypervitaminosis B12 or hypercobalaminemia) is most important as a diagnostic and prognostic marker for malignant disease.

Increased concentrations of vitamin B12 are the result of excessive intake of this vitamin, increased release of vitamins from hepatic depots, or elevated concentrations of transcobalamin resulting from the increased production or reduced decomposition of this molecule.

Hematologic disorders like chronic myelogeneous leukemia, promyelocytic leukemia, polycythemia vera and also the hypereosinophilic syndrome can result in elevated levels of vitamin B12.

The increase in circulating vitamin B12 levels is predominantly caused by enhanced production of haptocorrin. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. High vitamin B12values are commonly associated with malignancies and solid tumours. Liver diseases (acute hepatitis, cirrhosis, cancer) lead to an increase in vitamin B12 levels in serum, because the liver is no longer able to store this vitamin.
Hypervitaminosis B12

Methylmalonic aciduria

Methylmalonic aciduria is a heterogeneous group of inborn errors of metabolism biochemically characterized by the accumulation of methylmalonic acid in body fluids and tissues.

Methylmalonic aciduria is clinically similar to propionic acidaemia and is due to a deficiency of methylmalonyl-CoA mutase. It can also be due to defects in its cofactor, adenosylcobalamin. Adenosylcobalamin also known as coenzyme B12, cobamamide, and dibencozide, is, along with methylcobalamin (MeCbl), one of the biologically active forms of vitamin B12.

Methylmalonyl-CoA mutase (also known as methylmalonyl-CoA isomerase) is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

The mutase enzyme requires adenosylcobalamin (Ado-Cbl) as coenzyme so that the integrity of methylmalonic acid (MMA) metabolism is inextricably linked to vitamin B12 (cobalamin), its adequate intake and correct uptake, transport and intracellular metabolism. Deficiency of Methylmalonyl-CoA mutase leads to elevated levels of MMA in body fluids.
Methylmalonic aciduria

MMACHC gene: role in Vitamin B12 metabolism

MMACHC (Methylmalonic aciduria and homocystinuria type C protein) gene is a Protein Coding gene. The MMACHC gene provides instructions for making a protein that helps convert vitamin B12 (also called cobalamin) into one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl).

AdoCbl is required for the normal function of an enzyme known as methylmalonyl CoA mutase. This enzyme helps break down certain protein building blocks (amino acids), fats (lipids), and cholesterol. AdoCbl is called a cofactor because it helps methylmalonyl CoA mutase carry out its function. Methylmalonyl CoA mutase catalyses the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin (AdoCbl) as a cofactor participating in the genera-tion of radicals that allow isomerization of the substrate.

MeCbl is also a cofactor, but for an enzyme known as methionine synthase. This enzyme converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds. Methionine is an aliphatic, sulfur-containing, essential amino acid, and a precursor of succinyl-CoA, homocysteine, cysteine, creatine, and carnitine. Recent research has demonstrated that methionine can regulate metabolic processes, the innate immune system, and digestive functioning.

Cobalamin C (cblC) deficiency, the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12.

Diseases associated with MMACHC include Methylmalonic Aciduria And Homocystinuria, Cblc Type and Methylmalonic Acidemia With Homocystinuria. Among its related pathways are Diseases of metabolism and Metabolism of water-soluble vitamins and cofactors.
MMACHC gene: role in Vitamin B12 metabolism

Vitamin B12: Structure and functions

Vitamin B12, also called cobalamin, is an indispensable molecule with a very complex structure and an intricate pathway of absorption and cellular trafficking that requires molecular escort proteins in body fluids and intracellular chaperones.

The vitamin is a cobalt-containing coordination compound generated by intestinal microbes, and a natural water-soluble vitamin of the B-complex family that must combine with Intrinsic Factor for absorption by the intestine.

Cobalamins cannot be synthesized by higher organisms and must be supplied with the diet. In humans, the lack of dietary cobalamin, or malfunctioning of absorption or of the enzymatic catalysis may provoke neurological disorders, in addition to pernicious anaemia.

However, a highly modulated absorption ability and transport through body fluids prevents any possible shortage even after many years of no intake.

Cobalamin is an organometallic factor composed of a tetrapyrrolic corrinic ring with a cobalt atom coordinated to four equatorial nitrogen atoms.

Vitamin B12 in food is bound to protein and is released in the stomach by the acid environment and by proteolysis of binders by pepsin. The released vitamin B12 initially binds to R-binders, which are dietary proteins that have affinity for vitamin B12.

Cobalamin is necessary for hematopoiesis, neural metabolism, DNA and RNA production, and carbohydrate, fat, and protein metabolism. B12 improves iron functions in the metabolic cycle and assists folic acid in choline synthesis.

B12 metabolism is interconnected with that of folic acid. Vitamin B12 deficiency causes pernicious anemia, megaloblastic anemia, and neurologic lesions.
Vitamin B12: Structure and functions

Milk: Excellent source of vitamin B

Milk contains both water-soluble and fat-soluble vitamins. The nonfat portion of milk is especially plentiful in the B vitamin riboflavin, a greenish fluorescent-colored vitamin. It acts as a photosynthesizer and is readily destroyed upon exposure to sunlight.

Dairy milk contains more vitamin B than soy milk. It has 8 types of vitamin B, compared to soy milk which contains 7 types but lacking in vitamin B12.

Vitamin B12

Vitamin B12 is necessary for growth, maintenance of nerve tissues and normal blood formation, Milk provides 0.44 μg vitamin B12/100 g. Three glasses of milk would furnish all of the 2.4 μg vitamin B12 recommended for most adults.

Vitamin B12 content was measured in milk samples of 544 Dutch Holstein Friesian cows: content was 4.4 μg/L on average and varied between 1.0 and 12.9 μg/L. This variation between cows could to large extend be attributed to genetic factors.

Riboflavin or B2 vitamin is a yellow-green fluorescent compound and in addition to its role as a vitamin, it is responsible for the colour of milk serum.
Milk: Excellent source of vitamin B 

Discovery of Vitamin B12

By the late 1940s, Combs and Norris using chick growth as their bioassay procedure were fairly close to the isolation of vitamin B12.

In 1926, Vitamin B12 was discovered by two physician George Richard Minot and William Perry Murphy became inspired by George Whipple’s studies that showed daily beef liver a pound could indeed control the deadly anemia.

Minot and Murphy of Harvard showed that feeding the large amounts of raw liver, that is a quarter to half a pound per day, restored the normal level of red blood cells in cases of pernicious anemia.

Following this discovery and for the next twenty years, liver was the main source of this unknown curing factor, which has prepared, as time passed, in more and more concentrated form.

In 1929, William B. Castle of Harvard hypothesized that the liver was the organ of the body contained a factor essential for the cure of pernicious anemia.

Its chemical structure as elucidated in 1955, through the collaboration of chemists from the University of Cambridge, led by Alexander Todd, with X-ray crystallographers from the University of Oxford, led by Dorothy Hodgkin and a team from Glaxo led by Lester Smith.

However, Vitamin B12 only finally synthesize by Robert Burns Woodward in 1971.
Discovery of Vitamin B12

Deficiency of Vitamin B12

Vitamin B12 or cobalamin is a very complex chemical compound. Cobalamin is referring to the group of cobalt containing vitamer compound, this include cyanocobalamin, hydroxocobalamin, 5-deoxyadenosylcobalamin and methylcobalamin.

This vitamin required for the normal development of red blood cells, and a deficiency it causes acute pernicious anemia and a variety of other disorders. The exact requirement of Vitamin B-12 is yet unknown, since some B12 is synthesized by bacteria in the intestine. The organs of animals are excellent sources of Vitamin B12 and the muscles of warm-blooded animals and fish are good sources.

Vitamin B12 deficiency is commonly asymptomatic, but can also present as anemia characterized by enlarged blood corpuscle, so called megaloblastic anemia. However in serious case deficiency can potentially cause severe and irreversible damage to the nervous system.

Since body stores of vitamin B12 are adequate for up to five years, deficiency is generally the result of failure to absorb it. In older people, is also caused by inadequate intake of impaired absorption.

Megaloblastic anemia, Crohn's disease and other intestinal disorders are the most frequent causes of vitamin B12 deficiency.

Symptoms are attributable primarily to anemia, although glossitis, jaundice, and splenomegaly may be present. Vitamin B12 deficiency may cause decreased vibratory and positional sense, ataxia, paresthesias, confusion.

Apart from anemia due to vitamin B12 deficiency, the neurologic symptom of vitamin B12 deficiency include numbness and tingling of the arms and more commonly the legs, difficulty walking, memory loss, disorientation and dementia with or without mood changes.

Neurological or psychiatric symptoms occurs in about 40% of patents with vitamin B12 deficiency, in association with progressive damage to the spinal cord, peripheral nerves and cerebrum.
Deficiency of Vitamin B12

Gene Behind Devastating Vitamin B12-Related Disorder Discovered By Researchers

Gene Behind Devastating Vitamin B12-Related Disorder Discovered By Researchers Swiss, British and Canadian researchers have identified the gene responsible for a rare but serious genetic disorder and have simultaneously provided more clues as to how vitamin B12 works in the body. Their results will be published in the New England Journal of Medicine. Scientists at the University Children's Hospitals of Basel and Zurich in Switzerland, Brunel University in West London, England and McGill University and the McGill University Health Centre (MUHC) in Montreal, Canada, have discovered the MMADHC gene, the role it plays in the metabolism of vitamin B12, and its relationship to the vitamin B12-related disorder, isolated and combined homocystinuria and methylmalonic aciduria (MMA) of the cblD variety. 

Authors of the study include Dr. David Coelho, Dr. Terttu Suormala and Dr. Brian Fowler of the University Children's Hospital, Basel, Dr. David Rosenblatt and his graduate student Jordan Lerner-Ellis of McGill and the MUHC and colleagues at the University Children's Hospital, Zurich, the University of Zurich and Brunel University. In 2005, Dr. Rosenblatt and his McGill and MUHC colleagues made a related breakthrough involving another gene, called MMACHC. Isolated and combined homocystinuria and MMA of the cblD variety is a rare genetic inability to process vitamin B12, which is usually diagnosed in infancy or childhood. Patients may suffer from a range of debilitating health problems, including serious developmental delay, psychosis and anemia. 

Despite the variety of symptoms presented by the disorder, this research shows all of them are caused by mutations in different parts of the same gene. Vitamin B12 is an essential water-soluble vitamin found in animal-based foods -- including dairy, eggs, meat, poultry, fish and shellfish -- but not in plants. It is vital for the synthesis of red blood cells and the healthy maintenance of the nervous system, and also helps control homocysteine levels.. 

Excess homocysteine is associated with increased risk of heart disease, stroke and dementia. "Most patients with B12 problems have difficulty absorbing the vitamin, or may be vegans who don't get it in their diet," said Dr. Rosenblatt, Chair of McGill's Department Human Genetics, Director of Medical Genetics in Medicine at the MUHC, and Chief of Medical Genetics at the Jewish General Hospital. "However, this select group of patients becomes extremely sick because their bodies cannot transform the vitamin into its active forms." 

 The research relied heavily on the expertise developed at McGill and Basel as world referral centres for the diagnosis of B12-related genetic diseases, Dr. Rosenblatt said. The study was funded in part by the Canadian Institutes of Health Research (CIHR). "This important paper - published in the world's highest impact medical journal - is on-going testimony to the international leadership of Dr. Rosenblatt and his colleagues at McGill in their studies of vitamin B12 and the genetic diseases that disrupt the ability of the body to use vitamin B12," said Dr. Roderick McInnes, 

Scientific Director of CIHR's Institute of Genetics. "This research also exemplifies the outstanding genetics research done by Canadian scientists." "This discovery offers earlier diagnosis and treatment options for this serious disease, and also helps explain the mechanism of how vitamin B12 works in everyone," said Dr. Rosenblatt. 

Gene Behind Devastating Vitamin B12-Related Disorder Discovered By Researchers 

Source: medicalnewstoday.com