Introduction:
Cholesterol is a significant component of the body. It is received through diet and also synthesized de novo. It forms an important part of cell membranes. It is a precursor for the synthesis of vitamin D, bile acids, and steroid hormones. They are stored in the cells in the form of cholesterol esters and are transported from one cell to another with the help of lipoproteins. All the cells of the body have enzymes needed for cholesterol synthesis. The cholesterol production should be regulated properly to avoid overproduction and accumulation. The overproduction of cholesterol will lead to fat build-up around arteries leading to medical issues like atherosclerosis. So, it is important for all enzymes to function properly to prevent cholesterol accumulation.
What Is Mevalonic Aciduria?
Mevalonic aciduria is one type of mevalonate kinase deficiency, an enzyme involved in cholesterol metabolism, with frequent fever episodes starting from infancy. There are two types of mevalonate kinase deficiency: a less severe and common type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe and rare form called mevalonic aciduria (MVA). About 200 individuals are reported to have been affected by mevalonate kinase deficiency, most of which are hyperimmunoglobulinemia D syndrome.
Mevalonic aciduria is inherited as an autosomal recessive disorder.
How Is Cholesterol Synthesized in the Body?
Cholesterol production occurs in the liver and intestines. The enzymes involved in the synthesis are present in the cytoplasm, endoplasmic reticulum (microsomes), and peroxisomes of cells. The mevalonate pathway is the beginning phase of cholesterol synthesis. The biosynthesis is divided into five phases, producing cholesterol, isopentenyl pyrophosphate, and dimethylallyl pyrophosphate.
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Phase 1 - Two molecules of acetyl-CoA molecules are converted into 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) with the production of an intermediate molecule acetoacetyl CoA.
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Phase 2 - Conversion of HMG-CoA into mevalonate. It is the rate-limiting step of cholesterol synthesis.
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Phase 3 - Conversion of mevalonate to isopentenyl pyrophosphate (IPP) with the help of catalyst mevalonate 5-pyrophosphate decarboxylase.
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Phase 4 - Conversion of Isopentenyl pyrophosphate to squalene. It is the first cholesterol specific step of the pathway.
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Phase 5 - Conversion of squalene into cholesterol.
How Is Mevalonic Aciduria Caused?
A genetic mutation in the mevalonate kinase gene results in an abnormal mevalonate kinase enzyme. This enzyme converts mevalonic acid into mevalonate -5-phosphate during cholesterol synthesis. This later gets converted into other chemicals like steroid hormones and bile acids. The abnormality in the enzyme affects many functions of the body, like growth, development, and reproduction, which are mediated by steroid hormones like progesterone and testosterone, fat digestion mediated through bile acids, cell maturation, and growth and protein metabolism.
The mutation makes the enzyme fragile and distorted, which reduces mevalonate kinase enzyme activity. But people have normal cholesterol production even with deficient mevalonate kinase enzymes.
What Are the Signs and Symptoms of Mevalonic Aciduria?
It is poorly known how signs and symptoms are caused by mevalonate kinase deficiency. There are two possible theories for the pathogenesis of the syndrome. The first reason can be the accumulation of mevalonic acid, the substance metabolized by the mevalonate kinase enzyme. The second reason is the insufficient amount of substances produced from mevalonic acid. These substances help in forming normal cell structure and function. The degree of enzyme deficiency determines the severity of the disease. A percent of 1 to 20% of normal mevalonate kinase activity will result in hyperimmunoglobulinemia D syndrome, and less than 1 percent of normal enzyme will result in mevalonic aciduria. The signs and symptoms are exhibited at all times, not just during the frequent episodes of fever.
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Ataxia - A lack of coordination, balance, and speech is called ataxia due to impaired regulation of muscle movements.
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Developmental delays like learning difficulties and skill and intellectual development are seen late.
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Epilepsy - Recurrent episodes of seizures are seen due to abnormal electrical activity in the brain.
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Vision Problems - A group of eye disorders is seen:uveitis-inflammation of the eye; blue sclera- a bluish discoloration in the white portion of the eye called the sclera; cataracts-clouding of the natural lens of the eye and retinitis pigmentosa- a rare retinal disorder where the retinal cells break down and result in vision loss.
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Failure to Thrive - The child does not gain weight at the expected time like other children of the same age.
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Change in Head Shape and Size - The head size is small and elongated.
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Myopathy - The muscles become weak and do not function properly.
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Lymphadenopathy - Swelling of lymph nodes.
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Hepatosplenomegaly - Both the liver and the spleen are enlarged.
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Gastrointestinal Problems - Diarrhea and abdominal pain are seen.
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Skin Rashes.
How Is Mevalonic Aciduria Diagnosed?
A detailed patient history of symptoms and clinical evaluation of signs of the disease will suggest a more specific and sensitive test for diagnosing aciduria.
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Routine Gas Chromatography: This technique is used to measure and analyze the mixture of organic compounds.
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Organic Acid Analysis: The only diagnostic finding in mevalonic aciduria is the elevated levels of mevalonic acid in the urine, cerebrospinal fluid, and plasma.
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Mass Spectrometry: An isotope dilution mass spectrometry is done to analyze a specific substance of interest from a large sample.
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Mutational Analysis: The gene mutation of the mevalonate kinase enzyme gene is determined through genetic analysis of white blood cells and fibroblasts.
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Radiometric Assay: The activity level of enzyme-mediated reaction is measured by determining the radioactivity of different compounds involved in the reaction.
What Is the Treatment of Mevalonic Aciduria?
Mevalonic aciduria has no treatment. Since it is an inborn metabolic error, there is no cure for the condition. But the condition can be managed symptomatically. Cholesterol can be supplemented through diet to lessen the severity of the symptoms in mildly affected individuals. The fever episodes can be managed by medication like non-steroidal anti-inflammatory drugs; fevers are more frequent in infancy but reduced as the child grows. The only well-researched drug for mevalonate kinase deficiency is interleukin -1 antagonist Canakinumab. But it is expensive and not readily available. More options are Tocilizumab, Glucocorticoids, Etanercept, and Anakinra, but more evidence of these drugs' therapeutic efficiency is needed.
Conclusion
The prognosis is poor in patients with early-onset mevalonic aciduria involving multiple organ systems. The quality of life is greatly affected due to visual impairment, intellectual disabilities, difficulty walking, short stature in appearance, and progressive muscular weakness.
