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Adenosine deaminase deficiency

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Adenosine deaminase deficiency

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Adenosine deaminase deficiency

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An 18-month-old boy is brought to the emergency department for evaluation of shortness of breath and cough. Past medical history includes two episodes of pneumonia, oral thrush, chronic diarrhea and recurrent otitis media. His vaccinations are not up to date due to frequent illnesses. Family history is non-contributory. The patient is at the 2nd percentile for height and weight. Temperature is 38.7 C (101.7 F), pulse is 151/min, respirations are 36/min and blood pressure is 70/40 mmHg. Physical examination demonstrates white patches in the oral cavity and diffuse rales of the lungs bilaterally. Laboratory results are demonstrated below.

 

 Complete blood count 
 Leukocyte count  8,100 /mm3 
 Platelet count  300,000/mm3 
 Lymphocytes  5% 
 CD 19+  low 
 CD 3+  absent 
 Immunoglobulins 
 IgG  220mg/dL 
 IgA  40 mg/dL 
 IgM  15 mg/dL 

Chest X-ray demonstrates bilateral diffuse interstitial infiltrates. Which of the following is the most likely diagnosis?

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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.

Sources
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  2. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  3. "Yen & Jaffe's Reproductive Endocrinology" Saunders W.B. (2018)
  4. "Bates' Guide to Physical Examination and History Taking" LWW (2016)
  5. "Robbins Basic Pathology" Elsevier (2017)
  6. "Adenosine deaminase deficiency: Frequency and comparative pathology in autosomally recessive severe combined immunodeficiency" Clinical Immunology and Immunopathology (1979)
  7. "Educational paper" European Journal of Pediatrics (2011)
  8. "Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency" Stem Cells and Cloning: Advances and Applications (2009)
  9. "Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006)" Clinical Immunology (2007)