Adenosine deaminase deficiency

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Introduction0:00–0:01

Introduction0:01–1:43

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,. 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.

Physiology1:43–3:04

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 a autosomal recessive pattern, meaning that the disease occurs when a child receives a mutant allele from both parents.
Statistically, if two carrier parents were to have children, they’d have roughly 25% chance to have a completely healthy child with two healthy gene copies, 50% chance to have a child that’s also a carrier of one defective copy and one healthy copy, and 25% chance to have an affected child with ADA-SCID.

Pathology3:04–4:29

In individuals with adenosine deaminase deficiency, a key enzyme - adenosine deaminase is absent, and as a result, dATP cannot be degraded when no longer needed so excessive amounts of dATP pile up.
This huge excess of just one type of nucleotides slows the process the cell division immensely. Imagine that you’re assembling a pizza with four ingredients - dough, tomato sauce, cheese, and basil.
It becomes hard when you have an excess of a single ingredient. For example standing neck-deep in tomato sauce, makes it hard to find the basil, cheese, and dough, so that the pizza is made in the right proportions.
This is exactly the case here - excess of a single ingredient, dATP, makes DNA replication extremely hard. And DNA replication is vital for cell division.
This affects cells throughout the body, but particularly affects lymphocytes because they are rapidly dividing cells. As a result, B-cells, T-cells, and natural killer cells numbers go down, collapsing the immune system.
This makes affected children susceptible to any bacterial, viral, or fungal infections, starting from birth. Prognosis in such infants is extremely poor without treatment.
In terms of symptoms, because fighting infections takes a lot of energy, infants struggle to gain weight and often are diagnosed as having failure to thrive - and many die.

Treatment4:29–4:49

Treatment of adenosine deaminase deficiency usually centers on hematopoietic stem cell transplantation. The idea is to re-establish the immune system with donor immune cells that have the adenosine deaminase enzyme.
Another option is to give enzyme replacement therapy through IV infusions of adenosine deaminase, but this requires weekly infusions and isn’t curative.

Review4:49–5:23

All right, as a quick recap. Adenosine deaminase deficiency is a autosomal recessive genetic disease, resulting in a defect in genes coding for the adenosine deaminase enzyme.
The result of ADA is increased accumulation of deoxyadenosine triphosphate, which interferes with normal DNA replication and collapses our lymphocyte immune system by disabling its proliferation.
This leads to severe combined immunodeficiency, called ADA-SCID, which has a poor prognosis. Treatment options are hematopoietic stem cell transplants or lifelong enzyme replacement therapy.