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Methylmalonic acidemias

Methylmalonic acidemias is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Methylmalonic acidemias rather than just read about it. In short: Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues.

Methylmalonic acidemias — main illustration
Methylmalonic acidemias — illustration

Key takeaways

  • Methylmalonic acidemias belongs to chemistry; place it in that map before memorising details.
  • Learn the definition first, then one example that makes the definition concrete.
  • Connect Methylmalonic acidemias to a quantity you can measure, compute or draw — that is where exam questions come from.
  • Reproduce the core statement of Methylmalonic acidemias from memory before moving on to harder problems.

Reference excerpt

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias. Methylmalonic acidemias have varying diagnoses, treatment requirements, and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder. The first symptoms may begin as early as the first day of life or as late as adulthood. Symptoms can range from mild to life-threatening. Some forms can result in death if undiagnosed or left untreated. Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.

Signs and symptoms Depending on the affected gene(s) and mutation, the present symptoms can range from mild to life-threatening.

Acidosis Cardiomyopathy Coma Dehydration Developmental delays Dysmorphic features Encephalopathy, progressive Failure to thrive Gastrointestinal disease Hepatomegaly Hyperammonemia Hyperglycinemia/ Hyperglycinuria Hypoglycemia Hypotonia Infections, recurrent Ketonemia/ Ketonuria Kidney failure Lethargy Low concentrations of red blood cells, white blood cells and blood platelets Memory problems Pancreatitis Respiratory distress Speech delay Seizure Stroke Vomiting As a rule, methylmalonic acidemias are not apparent at birth as symptoms do not present themselves until proteins are added to the infant's diet. Because of this, symptoms typically manifest anytime within the first year of life. However, there are also forms that only develop symptoms in adulthood.

Cause

Genetic

Methylmalonic acidemias have an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder. The exception is methylmalonic acidemia and homocystinuria, cblX type due to variants in HCFC1 gene, which is inherited in an X-linked recessive manner. The following are the known genotypes responsible for isolated methylmalonic acidemias:

The mut type can further be divided into mut0 and mut- subtypes, with mut0 characterized by a complete lack of methylmalonyl-CoA mutase and more severe symptoms and mut- characterized by a decreased amount of mutase activity. Furthermore, the following genes are also responsible for methylmalonic acidemias:

Nutritional Though not always grouped together with the inherited versions, a severe nutritional vitamin B12 deficiency can also result in syndrome with identical symptoms and treatments as the genetic methylmalonic acidemias. Methylmalonyl-CoA requires vitamin B12 to form succinyl-CoA. When the amount of B12 is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B12 deficiency in serum.

Pathophysiology

In methylmalonic acidemias, the body is unable to break down properly:

essential amino acids: methionine, valine, threonine and isoleucine propionic acid from intestinal fermentation odd-chain fatty acids cholesterol side chain As a result, methylmalonic acid builds up in liquids and tissues. Those afflicted with this disorder are either lacking functional copies or adequate levels of one or more of the following enzymes:

methylmalonyl-CoA mutase (MUT) acyl-CoA synthetase family member 3 (ACSF3) methylmalonyl-CoA epimerase (MCEE) enzymes involved in adenosylcobalamin synthesis These are briefly introduced below:

Methylmalonyl-CoA mutase

It is estimated that as many as 60% of isolated methylmalonic acidemia cases are the result of a mutated MMUT gene, which encodes the protein methylmalonyl-CoA mutase. This enzyme is responsible for the digestion of potentially toxic derivatives of the breakdown of the above-mentioned amino acids and fats, primarily cholesterol, particularly this enzyme converts methylmalonyl-CoA into succinyl-CoA. Without this enzyme, the body has no means to neutralize or remove methylmalonic acid and related compounds. The action of this enzyme can also be crippled by mutations in the MMAA, MMAB, and MMADHC genes, each of which encodes a protein required for normal functioning of methylmalonyl-CoA mutase.

Acyl-CoA synthetase family member 3 CMAMMA is probably the most common form of methylmalonic acidemias based on its allele frequency, but is rarely diagnosed due to slippage through routine newborn screening, wide symptom variety, and, in some cases, symptoms only appearing in adulthood. Pathogenic mutations of the ACSF3 gene lead to a defect of the mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3), resulting in accumulation of methylmalonic acid and malonic acid. The enzyme's dual role is the conversion of methylmalonic acid into methylmalonyl-CoA and of malonic acid into malonyl-CoA, the latter being required for mitochondrial fatty acid synthesis (mtFAS) and mitochondrial protein malonylation. CMAMMA can therefore be defined not only as an organic acidemia but also as a defect of mitochondrial fatty acid synthesis and of protein malonylation.

Methylmalonyl-CoA epimerase Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much milder form of the disorder than the related methylmalonyl-CoA mutase variant. Like the mutase, the epimerase also functions in breaking down the same substances, but to a significantly lesser extent than the mutase does. The phenotypic differences caused by a deficiency of the epimerase as opposed to the mutase are so mild that there is debate within the medical community as to whether or not this genetic deficiency can be considered a disorder or clinical syndrome.

Adenosylcobalamin Also known as vitamin B12, this form of cobalamin is a required cofactor of methylmalonyl-CoA mutase. Even with a functional version of the enzyme at physiologically normal levels, if B12 cannot be converted to this active form (due to defects in the Adenosylcobalamin synthesis system or cobalamin transporters), the mutase will be unable to function.

… excerpt ends here. Continue reading the full article.

Illustrations

Methylmalonic acidemias illustration
Methylmalonic acidemias: Methylmalonic acidemia has an autosomal recessive pattern of inheritance.
Methylmalonic acidemia has an autosomal recessive pattern of inheritance.
Methylmalonic acidemias: Propionate metabolism and mitochondrial fatty acid synthesis pathways with selected types of methylmalonic acidemias highlighted at the affected enzymes or at the cofactor adenosylcobalamin.
Propionate metabolism and mitochondrial fatty acid synthesis pathways with selected types of methylmalonic acidemias highlighted at the affected enzymes or at the cofactor adenosylcobalamin.

Worked examples

Example 1 — a first encounter with Methylmalonic acidemias

Start with the simplest possible case. Write down what Methylmalonic acidemias claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Methylmalonic acidemias before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Methylmalonic acidemias ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Methylmalonic acidemias

In research
Methylmalonic acidemias appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry
Engineering practice reuses Methylmalonic acidemias in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom
Methylmalonic acidemias is common in secondary-school and first-year university syllabi. It links to neighbouring topics Amino acid metabolism disorders, Autosomal recessive disorders, Mitochondrial diseases, so understanding it makes those chapters shorter.
In everyday life
Look for Methylmalonic acidemias outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.
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How to study Methylmalonic acidemias in 20 minutes

  1. Read the reference excerpt below once, without taking notes.
  2. Close the page and write down what Methylmalonic acidemias means in your own words.
  3. Compare your version with the excerpt and mark what you missed.
  4. Work through the three examples above with pen and paper.
  5. Explain Methylmalonic acidemias out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Methylmalonic acidemias in simple terms?

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues.

Why does Methylmalonic acidemias matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Methylmalonic acidemias?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Methylmalonic acidemias.

Tags

  • Amino acid metabolism disorders
  • Autosomal recessive disorders
  • Mitochondrial diseases
  • Rare diseases
  • Vitamin, coenzyme, and cofactor metabolism disorders

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