Content Reviewers:Antonia Syrnioti, MD
Three kids are brought to the clinic by three very concerned mothers.
The first one’s Carl, a 10 month old boy that, according to his mother, is always sick with bronchitis and diarrhea.
On physical examination, you notice that Carl is quite small for his age.
Laboratory studies are obtained, showing an absolute lymphocyte count of 2,000 cells per cubic millimeter.
Next comes Mark, a 2 year old boy with aggressive and self-destructive behavior, such as constantly biting his lips, tongue, and fingers.
In addition, Mark doesn’t seem to be able to walk or speak a word.
His mother tells you that her younger brother, so Mark’s uncle, was diagnosed with a rare disease that caused mental retardation, and she’s worried Mark may have it too.
Upon physical exam, you notice some orange sand-like deposits in his diapers.
Laboratory studies show elevated levels of uric acid in his blood.
Finally, you see Laura, a 4 month old girl with a history of anemia that was diagnosed some days after birth.
Since then, Laura has been on a bottle-feeding regimen with folate and vitamin B12 supplementation; however, her anemia is not getting any better.
On examination, you notice cloudy urine that left some residues on Laura’s diaper, so you ask for a urinalysis.
Results revealed that the residues are orotic acid crystals.
Based on the initial presentation, all three cases seemed to be due to purine and pyrimidine metabolism disorder.
But first, a bit of biochemistry review.
Normally, each nucleotide can be broken down into a sugar that’s either a deoxyribose in DNA or a ribose in RNA, followed by one to three phosphate groups, and a nucleobase, which can be either a purine or a pyrimidine.
There are two purine bases, adenine and guanine; and three pyrimidine bases, cytosine, thymine, and uracil.
Now, the nucleoside based on adenine and ribose is adenosine, and a nucleotide based on adenosine and one phosphate would be adenosine monophosphate, or AMP for short; whereas the same combination with a deoxyribose would be deoxyadenosine monophosphate, or dAMP; and the same naming convention applies to all the other nucleobases.
Now, there are two ways our cells can make nucleotides, one is de novo synthesis, meaning that they are made from scratch, and the other is via the salvage pathway, by recycling nucleotides.
Now, mutations in enzymes involved in these pathways lead to rare inherited disorders collectively called purine and pyrimidine metabolism disorders, the most important of which are severe combined immunodeficiency, Lesch-Nyhan syndrome, and orotic aciduria.
Starting with severe combined immunodeficiency, or SCID for short.
In fact, the immune system is so dysfunctional that it is considered almost completely absent.
Now, SCID can be caused by a variety of gene mutations.
For your exams, a very high yield one is an autosomal recessive mutation in the gene coding for the enzyme adenosine deaminase or ADA.
And this form of SCID is also called ADA-SCID.
Now, normally, in the purine salvage pathway, ADA is required to degrade adenosine and deoxyadenosine into inosine and deoxyinosine.
As a consequence, with ADA deficiency, adenosine and deoxyadenosine build up, and these can be toxic to B and T lymphocytes.
In addition, the excess deoxyadenosine can get converted into deoxyadenosine monophosphate or dAMP, then deoxyadenosine diphosphate or dADP, and finally into deoxyadenosine triphosphate or dATP.
Accumulation of dATP leads to inhibition of the enzyme ribonucleotide reductase, which mediates the conversion of ribonucleotides to deoxynucleotides, before they can get incorporated into DNA.
The end result is an impaired DNA synthesis in B and T cells, which leads to failure in their maturation and proliferation.
Now, SCID usually presents in infancy as an extreme susceptibility to all kinds of bacterial, viral, and fungal infections.
Most importantly, these include opportunistic pathogens, such as Candida albicans, nontuberculous Mycobacteria or Pneumocystis jirovecii, which don’t usually cause serious infections in individuals with a healthy immune system.
For your exams, remember that oral candidiasis typically presents with an oral thrush that’s often described as “cottage cheese-like thrush”, isn’t painful and can be scraped away with a tongue depressor, leaving behind a red mucosal base which sometimes bleeds.
In addition, individuals often present with chronic diarrhea, and a failure to thrive.
If left untreated, SCID has a high mortality rate in the first year of life.
Diagnosis of SCID in many countries is based on newborn screening tests.
These measure T-cell receptor excision circles, or TRECs, in blood.
The presence of TRECs is a biomarker for normal T-cell development, so remember that in SCID, TRECs are absent.
Laboratory tests are also required, showing an absolute lymphocyte count lower than 2500 cells per cubic millimeter, with T cells making up less than 20 percent of the total lymphocytes in flow cytometry.
Finally, a lymph node biopsy shows absence of germinal centers, which is where mature B cells would normally proliferate to fight infections.
Finally, to find the specific form of SCID, genetic testing can be performed to look for the mutated gene.
For treatment, hematopoietic stem cell transplantation is recommended before the age of 3 months.
Until then, these infants are often kept in a sterile environment to prevent infections.
Next, Lesch-Nyhan syndrome is caused by a mutation in the HPRT1 gene on the X chromosome.
So, Lesch- Nyhan syndrome is an X-linked recessive disorder, which means that all carrier males develop the disease, because they only have one X chromosome and thus one HPRT1 gene available.
On the other hand, females have two X chromosomes, so a single mutation makes them a carrier, and two mutations are needed to have the disease.
Now, the HPRT1 gene codes for an enzyme called hypoxanthine-guanine phosphoribosyl transferase or HGPRT for short.
Normally, HGPRT works in the purine salvage pathway by converting guanine to GMP, as well as hypoxanthine, which is a naturally occurring purine derivative, to IMP.
In Lesch-Nyhan syndrome, the mutated HPRT1 gene means that there’s deficiency of the HGPRT enzyme.
As a result, guanine and hypoxanthine cannot get recycled through the salvage pathway, and instead they get degraded into xanthine and then uric acid.
At the same time, to make up for the lack of recycling, the de novo purine synthesis pathway ramps up, which results in even more purines getting degraded to uric acid.
As a consequence, all that uric acid builds up in the blood, causing hyperuricemia.
Symptoms of Lesch-Nyhan syndrome typically present during the first year of life.
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