Adenosine deaminase deficiency

Adenosine deaminase deficiency


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Adenosine deaminase deficiency

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Most of the cases of adenosine deaminase deficiency manifest in the (first month/second year) of life.


USMLE® Step 1 style questions USMLE

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USMLE® Step 2 style questions USMLE

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A 6-month-old girl is brought to her pediatrician for pneumonia that has been worsening over the past three days. Her medical history is significant for two prior pneumonias, frequent infections since birth, failure to thrive, and chronic diarrhea. Her lymphocyte count is 100/mm3. Molecular genetic analysis is mostly likely to reveal a mutation causing impaired function of which of the following enzymes?

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Adenosine deaminase deficiency, or ADA deficiency, is a rare genetic disease, that results in severe combined immunodeficiency, or SCID for short.

SCID can be caused by a number of causes, so this particular variation is called ADA-SCID.

Let’s take a step back. Our cells have all the instructions on how to live and behave written on their own copy of DNA.

DNA is made out of four nucleotides, which can also do all kinds of cool stuff in their free time, like provide energy to various processes in the cell.

Nucleotides are made out of a sugar, in this case deoxyribose, one to three phosphate groups, and a nucleobase, which can be adenine, thymine, cytosine, or guanine.

So, the name of a deoxyribose-containing, triphosphatic nucleotide, based on adenine, that makes up DNA would be deoxyadenosine triphosphate, or dATP, for short.

These nucleotides are needed in equal proportions in order to make cellular division run smoothly.

Now, nucleotides have a functional lifetime of their own, and our body has mechanisms on how to break them up into their building blocks, to be either excreted or recycled.

Let’s focus on deoxyadenosine triphosphate.

First the enzyme adenosine deaminase removes an amine group from it, turning it into deoxyinosine monophosphate, or dIMP.

Then purine nucleoside phosphorylase comes in and removes the phosphate and the deoxyribose from dIMP, making hypoxanthine.

Hypoxanthine is then oxidised twice by xanthine oxidase - first to become xanthine, and then finally, to uric acid.

Uric acid can then be excreted by the kidneys, in the form of urine.

Now one class of cells that divides quickly and therefore relies heavily on cell division to work smoothly are lymphocytes.

Lymphocytes protect the body from pathogens, like bacteria and viruses in two ways.

First, B lymphocytes, or B cells, produce immune proteins called antibodies, which seek out and latch on onto an invader, marking it for destruction by other cells.

Second, cytotoxic T lymphocytes, or cytotoxic T cells, as well as lymphocytes called natural killer cells, go cell to cell, looking for virally-infected cells or cells that look like they’ve started dividing uncontrollably - like a cancer cell.

If they find a cell like that, they destroy it.

Simultaneous breakdown of both of these pathways makes the immunodeficiency combined, and severe.

Hence the name, severe combined immunodeficiency.

Adenosine deaminase is encoded by a gene on chromosome 20, and typically mutations are inherited through an autosomal recessive pattern, meaning that the disease occurs when a child receives a mutant allele from both parents.