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2.8 — Genetic Disease: From One Wrong Letter to a Whole Illness
This page follows five diseases the whole way — from the exact base change, through the protein, through the cell, through the organ, to what the person experiences and what a doctor does about it. These five are chosen because between them they demonstrate every mechanism in Part 2, and because four of them are among the commonest inherited diseases in the world.
Sickle cell disease
The change. One base, position 6 of the beta-globin gene on chromosome 11: an A becomes a T. The codon GAG becomes GTG. Glutamic acid, which is charged and water-loving, becomes valine, which is hydrophobic.
The protein. Haemoglobin is four chains — two alpha, two beta — each holding an iron atom that binds oxygen (Chapter 1.3). The substitution puts a small greasy patch on the outside of the beta chain, where the surface should be entirely water-friendly.
The cell. When haemoglobin releases its oxygen it changes shape slightly, and in that deoxygenated shape the greasy patch on one molecule fits into a pocket on another. They stick. Then a third joins, and a fourth, and long stiff polymer fibres grow inside the red cell, deforming it into a crescent.
Two features of that mechanism decide the whole clinical picture. It only happens when oxygen is released, so the trigger is anything that increases oxygen extraction — infection, dehydration, cold, altitude, exertion, stress. And it is initially reversible: re-oxygenate the cell early and it un-sickles. After repeated cycles the membrane is permanently damaged and the cell stays sickled.
The body. Two consequences run in parallel for life.
Vaso-occlusion. Stiff cells jam in small vessels. Tissue downstream is starved of oxygen and dies, which is intensely painful — a sickle cell crisis. Bones, chest, abdomen and back are the usual sites. Pain crises are the defining experience of the disease, and they are frequently undertreated because patients presenting repeatedly requesting strong opioids are wrongly suspected of drug-seeking. The pain is real, it is ischaemic, and it is among the most severe pain medicine encounters.
Haemolysis. Damaged cells are destroyed early — a lifespan of 10 to 20 days instead of 120. The result is chronic anaemia, jaundice from the breakdown pigment, and gallstones from the same pigment.
And the organ damage accumulates. The spleen is destroyed by repeated infarction, usually by age five, which is why these children are dangerously vulnerable to certain bacteria and need penicillin prophylaxis and extra vaccination from infancy. Strokes occur in childhood, and transcranial Doppler ultrasound is used to find the children at highest risk before it happens. Acute chest syndrome — sickling within the lung — is the commonest cause of death. Kidneys, retina, hips and lungs all suffer.
Why the allele is common. Around 300 million people worldwide carry one copy. It persists because carriers are protected against falciparum malaria — parasitised red cells sickle and are cleared, and the parasite grows poorly in them. A carrier has roughly a tenfold reduction in severe malaria. In regions with intense malaria the allele's benefit to carriers outweighs its cost to the homozygotes, so it is maintained at high frequency. This is balancing selection, the textbook example of it, and the geographic map of sickle cell overlaps the historical map of malaria almost exactly (Chapter 3.3).
Treatment.
- Hydroxyurea raises the level of fetal haemoglobin, a different form that does not participate in the polymer and physically gets in its way. It reduces crises by about half and reduces mortality. Adult dose usually starts around 15 mg/kg daily and is titrated by blood counts.
- Penicillin prophylaxis from a few months old until at least five years, plus pneumococcal and meningococcal vaccination.
- Hydration, oxygen and analgesia for crises. Strong opioids are usually required and should not be withheld.
- Transfusion or exchange transfusion for stroke, acute chest syndrome, or before surgery.
- Bone marrow transplant is curative and is limited by donor availability and risk.
- Gene therapy. In late 2023, regulators in the United Kingdom and United States approved exagamglogene autotemcel (Casgevy) — the first approved CRISPR-based therapy for any disease. It edits the patient's own blood stem cells to switch fetal haemoglobin back on, and the edited cells are returned after chemotherapy has cleared the marrow. Early results show most treated patients free of crises. It costs upwards of two million dollars per patient, which is the honest problem: the disease is concentrated in exactly the parts of the world least able to pay for it.
Thalassaemia
The change. Not one mutation but hundreds, all reducing the amount of one globin chain rather than changing its shape. Beta-thalassaemia reduces beta chains, alpha-thalassaemia reduces alpha chains. Many are splicing mutations, of the kind Chapter 2.3 described.
The mechanism, and why the imbalance is what hurts. Haemoglobin needs two alpha and two beta chains. If beta production falls, the alpha chains are still made at full rate and have no partner. Unpaired alpha chains precipitate inside the developing red cell and destroy it in the bone marrow before it is ever released. The anaemia comes as much from cells dying during production as from cells dying in circulation.
The clinical picture. Beta-thalassaemia major presents at around six months — not at birth, and the reason is instructive: a fetus makes fetal haemoglobin, which uses gamma chains instead of beta, so the defect is invisible until the switch to adult haemoglobin around three to six months. The child then becomes severely anaemic. The marrow expands enormously trying to compensate, which thins and deforms the skull and facial bones, producing the characteristic appearance seen in untreated cases. The spleen enlarges. Growth fails.
Treatment and its own complication. Regular transfusion every two to four weeks for life. And each unit of blood delivers about 200 to 250 mg of iron the body has no way to excrete. Within a few years the iron load damages the heart, liver and endocrine glands, and iron overload — not anaemia — becomes the leading cause of death. So iron chelation is mandatory, using deferasirox orally or desferrioxamine by infusion, and adherence to it is the single biggest determinant of survival. Bone marrow transplant is curative; the same CRISPR therapy approved for sickle cell is approved for transfusion-dependent beta-thalassaemia.
Carriers are common across the Mediterranean, the Middle East, South Asia and Southeast Asia, again because of malaria protection. In parts of India carrier frequency exceeds 5 percent. Cyprus reduced new cases by over 95 percent through a programme of carrier screening and counselling, which is one of the clearest public health successes attributable to genetics.
Cystic fibrosis
The change. The commonest is F508del on chromosome 7 — three bases deleted, removing a single phenylalanine at position 508 from the CFTR protein. About 70 percent of alleles in populations of northern European descent.
The protein. CFTR is a chloride channel in the membrane of cells lining airways, pancreatic ducts, sweat glands, gut and the vas deferens. As Chapter 1.3 covered, F508del does not break the channel's function — it breaks its folding, so quality control in the endoplasmic reticulum destroys it before it reaches the surface.
The consequence, organ by organ. No chloride out means no water follows, so every secretion in the body becomes thick and sticky.
- Lungs. The mucus layer that cilia normally sweep upward becomes too viscous to move. Bacteria settle permanently — Staphylococcus aureus early, then Pseudomonas aeruginosa, which is very difficult to eradicate. Repeated infection and inflammation destroy the airways. Lung disease causes the great majority of deaths.
- Pancreas. Ducts block, digestive enzymes cannot reach the gut, and fat and protein go unabsorbed. Infants fail to gain weight and pass greasy, foul stools. Later the damaged pancreas also loses its insulin-producing islets, and CF-related diabetes affects a large fraction of adults.
- Gut. Around 15 percent of newborns present with meconium ileus — the first stool is so thick it obstructs the bowel and needs surgery in the first days of life.
- Sweat glands. The salty sweat and the sweat chloride test, from Chapter 1.4.
- Reproductive tract. Around 98 percent of men with CF are infertile, because the vas deferens fails to develop.
Treatment, and a genuinely transformative development. For decades treatment was symptomatic: daily airway clearance physiotherapy, inhaled mucus-thinning drugs, aggressive antibiotics, pancreatic enzyme capsules with every meal, high-calorie diet, fat-soluble vitamins.
Then came the modulators. These are small molecules designed against the specific molecular defect. Ivacaftor opens channels that reach the surface but do not open properly. Lumacaftor, tezacaftor and elexacaftor are correctors that help the misfolded protein fold well enough to escape quality control. The triple combination elexacaftor/tezacaftor/ivacaftor, approved in 2019, works for around 90 percent of patients and produces improvements in lung function, weight and exacerbation rate of a size that had not been seen before in this disease. Median predicted survival has risen from under twenty years in the 1980s to over fifty today.
It is worth naming what made that possible: the gene was identified in 1989, the protein's behaviour was worked out over the following two decades, and the drugs were designed against a specific folding defect. That is a thirty-year path from sequence to cure, and it is the model for what genetic medicine is supposed to do.
Haemophilia
The change. X-linked recessive (Chapter 2.6). Haemophilia A is a deficiency of clotting factor VIII, haemophilia B of factor IX. Roughly 1 in 5,000 male births for A, 1 in 30,000 for B. About 45 percent of severe haemophilia A is caused by a single specific event: an inversion within the factor VIII gene.
The mechanism. Clotting is a cascade — one activated factor activates the next, amplifying at each step, ending in a fibrin mesh (Chapter 7.1). Remove one step and the cascade cannot reach its end. Platelets still work, which is why the bleeding pattern is characteristic: small cuts stop normally because platelets plug them, but the plug is never reinforced with fibrin, so bleeding restarts hours later, and deep bleeding into joints and muscles is the real problem.
Severity tracks factor level precisely. Below 1 percent of normal is severe, with spontaneous bleeding. One to 5 percent is moderate. Five to 40 percent is mild, with bleeding only after injury or surgery.
Bleeding into joints — haemarthrosis — is the defining injury. Blood in a joint is intensely painful and inflammatory, and repeated bleeds destroy the cartilage. Untreated, this produced the crippling arthritis that defined the disease historically. Knees, ankles and elbows are the usual sites.
Treatment.
- Factor replacement, given prophylactically two or three times a week rather than only after bleeds, which prevents joint destruction. Modern products are recombinant, avoiding the contaminated-plasma disaster of the 1980s in which thousands of haemophilia patients were infected with HIV and hepatitis C — one of the worst treatment injuries in the history of medicine.
- Emicizumab, an engineered antibody that physically bridges two clotting factors and does the job factor VIII normally does. Given by subcutaneous injection weekly to monthly rather than by vein several times a week, which is a very large change in daily life.
- Gene therapy using a viral vector to deliver a working factor gene to liver cells has been approved for both types, producing durable factor levels in many patients from a single infusion. Long-term durability is still being established.
- Desmopressin for mild haemophilia A, which releases stored factor VIII from the vessel lining.
Huntington's disease
The change. A CAG repeat expansion in the huntingtin gene on chromosome 4, autosomal dominant. Under 27 repeats normal; 27 to 35 not itself causing disease but unstable when passed on; 36 to 39 reduced penetrance; 40 or more causes disease with certainty.
The mechanism. CAG codes for glutamine, so the expanded gene produces a protein with a long tail of glutamines. This is a gain of function, not a loss — the abnormal protein does something toxic rather than failing to do its job. It misfolds, aggregates inside neurons, and progressively kills them, starting in a deep brain region called the striatum that controls the smoothness of movement.
Age of onset tracks repeat length, inversely and quite tightly: 40 to 45 repeats typically gives onset in middle age, over 60 repeats gives juvenile onset. And the repeat expands further when transmitted, especially through the father, which produces the anticipation of Chapter 2.5 — successive generations affected earlier.
The course. Usually onset between 30 and 50, after most people have had children. Three domains deteriorate together over 15 to 20 years:
- Movement — chorea, meaning involuntary flowing movements, later rigidity and difficulty swallowing.
- Cognition — loss of planning, judgement and flexibility, progressing to dementia.
- Psychiatric — depression, irritability and apathy, often the earliest change, and the suicide rate is several times the general population.
Treatment is symptomatic only. Tetrabenazine and deutetrabenazine reduce chorea. Antidepressants and antipsychotics manage mood and behaviour. Nothing yet slows the disease, though gene-silencing approaches aimed at reducing production of the abnormal protein are in trials, and one large trial was halted in 2021 when the treated group did worse than placebo — a reminder that plausible mechanisms are not results.
And Huntington's raises the hardest question in genetics. A predictive test is available and completely accurate; you can know decades in advance whether you will develop an untreatable fatal illness. Only about 5 to 20 percent of people at risk choose to be tested. Those who test are counselled at length before and after, and testing of children is not offered, because the child cannot consent and the information is not actionable. The right to not know is taken as seriously as the right to know, and this is the case that established that principle.
What the next page fixes
Every disease above was found by decades of painstaking work on one gene at a time. That is not how it is done now. Chapter 2.9 covers what has changed: sequencing an entire genome, what direct-to-consumer tests actually measure and what they do not, how gene therapy works, what CRISPR can and cannot do, and where the honest boundaries of the technology sit.