Paroxysmal nocturnal hemoglobinuria

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired (not inherited) disorder that leads to the premature death and impaired production of blood cells. The disorder affects red blood cells (erythrocytes), which carry oxygen; white blood cells (leukocytes), which protect the body from infections; and platelets (thrombocytes), which are involved in blood clotting. PNH can occur at any age, although it is most often diagnosed in young adulthood.

People with PNH have sudden, recurring episodes of symptoms (paroxysmal symptoms), which may be triggered by stresses on the body, such as infections or physical exertion. During these episodes, red blood cells are broken down earlier than they should be (hemolysis). Affected individuals may pass dark-colored urine because of the presence of hemoglobin, the oxygen-carrying protein in blood. The abnormal presence of hemoglobin in the urine is called hemoglobinuria. In many, but not all cases, hemoglobinuria is most noticeable early in the morning, upon passing urine that has accumulated in the bladder during the night (nocturnal).

The premature breakdown of red blood cells results in a shortage of these cells in the blood (hemolytic anemia), which can cause signs and symptoms such as fatigue, weakness, abnormally pale skin (pallor), shortness of breath, and an increased heart rate (tachycardia). People with PNH may also be prone to infections because of a shortage of white blood cells (leukopenia).

Abnormal platelets associated with PNH can cause problems in the blood clotting process. As a result, people with this disorder may experience abnormal blood clotting (thrombosis), especially in large abdominal veins; or, less often, episodes of severe bleeding (hemorrhage).

Individuals with PNH are at increased risk of developing cancer in blood-forming cells (leukemia). In some cases, people who have or have been treated for another blood disease called aplastic anemia may develop PNH. In a small number of affected individuals, the signs and symptoms of PNH disappear on their own.

A very rare form of PNH involves abnormal inflammation in addition to the typical features described above. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). In people with this rare form of PNH, the immune response is turned on (activated) abnormally and can cause recurrent aseptic meningitis (which is inflammation of the membranes surrounding the brain and spinal cord that is not related to infection); a red, itchy rash (known as hives or urticaria); joint pain (arthralgia); or inflammatory bowel disease. The inflammatory disorders usually begin earlier than the blood cell problems.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also known as mutations) in the PIGA gene cause almost all cases of PNH. Variants in the PIGT gene cause the rare, inflammatory form of the condition. The proteins produced from both genes are involved in a multistep process that connects particular proteins to the surface of cells. These proteins are attached to the cell by a specialized molecule called GPI anchor and are known as GPI-anchored proteins. The PIG-A protein helps produce the GPI anchor, and the PIG-T protein helps attach the GPI anchor to proteins. Anchored proteins have a variety of roles, including sticking cells to one another, relaying signals into cells, and protecting cells from destruction.

In people with PNH, variants of the PIGA gene occur during a person’s lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. In contrast, people with the inflammatory form of the condition inherit one altered copy of the PIGT gene. However, for the condition to occur, they need to also acquire a somatic variant that deletes the other copy of the PIGT gene and other genes around it.

PNH occurs when a somatic variant of the PIGA gene or PIGT gene occurs in a blood-forming cell called a hematopoietic stem cell. Hematopoietic stem cells are found mainly in the bone marrow and give rise to the various types of blood cells. These genetic variants severely reduce or eliminate the function of the PIG-A protein or PIG-T protein, respectively, in affected cells. Blood cells that arise from the abnormal stem cells also have the variant and are abnormal. As the abnormal hematopoietic stem cells multiply, more abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells.

Cells with no PIG-A protein do not produce GPI anchor, and therefore are missing GPI-anchored proteins at the surface. Cells with no PIG-T protein produce GPI anchor but cannot attach proteins to it. As a result, these cells have GPI anchor on the surface, but no attached proteins. Two important GPI-anchored proteins on red blood cells protect them from being broken down by the immune system. Without these proteins, the abnormal red blood cells are prematurely destroyed, leading to hemolytic anemia. Studies show that GPI anchors with no attached proteins trigger inflammation in the body, leading to the inflammatory features in individuals with PIGT-related PNH. It is unclear how changes in the PIGA or PIGT gene affect other types of blood cells.

In individuals with either form of PNH, the proportion of abnormal blood cells can vary. It is unclear why the population of cells that grow from the hematopoietic stem cell with a PIGA gene variant may be larger than the population of normal cells in some affected individuals and smaller in others. Research suggests that certain abnormal white blood cells that are also part of the immune system may mistakenly attack normal blood-forming cells, in a malfunction called an autoimmune process. In addition, abnormal hematopoietic stem cells in people with PNH may be less susceptible than normal cells to a process called apoptosis, which causes cells to self-destruct when they are damaged or unneeded.

In abnormal blood cells with PIGT gene variants, the somatic variant in the PIGT gene deletes other nearby genes that control cell growth and development. Researchers suggest that loss of these genes allows the abnormal cells to grow or survive better than normal cells, increasing the proportion of abnormal blood cells in the body. The proportion of abnormal blood cells affects the severity of the signs and symptoms of PNH, including the risk of hemoglobinuria and thrombosis.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

PNH is acquired, rather than inherited. Most cases result from new variants in the PIGA gene, and generally occur in people with no previous history of the disorder in their family. This form of the condition is not passed down to children of affected individuals.

The PIGA gene is located on the X chromosome, which is one of the two sex chromosomes. Males have only one X chromosome, and a variant in the only copy of the PIGA gene in each cell is sufficient to cause the condition. Females have two X chromosomes. However, early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). This process, called X-inactivation, ensures that females, like males, have only one active copy of the X chromosome in each body cell. In females, a variant in the active copy of the PIGA gene is sufficient to cause the condition.

The risk of developing PIGT-related PNH follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase a person’s chance of developing the condition. Affected individuals inherit one altered copy of the PIGT gene from a parent. However, the condition is acquired when a second alteration occurs in the other copy of the PIGT gene.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

PNH is a rare disorder, estimated to affect between 1 and 5 per million people. The inflammatory form of the disorder is extremely rare and has been identified in a very small number of individuals.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal erythrocyte enzyme activity · Obligate (100%)

An altered level of any enzyme to act as catalysts within erythrocytes. This term includes changes due to altered activity of an enzyme.

Anemia · Very frequent (99-80%)

A reduction in erythrocytes volume or hemoglobin concentration.

Asthenia · Very frequent (99-80%)

A state characterized by a feeling of weakness and loss of strength leading to a generalized weakness of the body.

Hemoglobinuria · Very frequent (99-80%)

The presence of free hemoglobin in the urine.

Hemolytic anemia · Very frequent (99-80%)

A type of anemia caused by premature destruction of red blood cells (hemolysis).

Chest pain · Frequent (79-30%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.

Chronic kidney disease · Frequent (79-30%)

Functional anomaly of the kidney persisting for at least three months.

Conjunctival icterus · Frequent (79-30%)

Conjunctival icterus is a condition where there is yellowing of the whites of the eyes. This is most commonly seen in patients who have liver disease.

Other findings in the same source

From: Orphanet

Additional reported features include Decreased serum iron (Frequent (79-30%)); Deep venous thrombosis (Frequent (79-30%)); Dyspnea (Frequent (79-30%)); Episodic abdominal pain (Frequent (79-30%)); Erythromelalgia (Frequent (79-30%)); Headache (Frequent (79-30%)); Hemosiderinuria (Frequent (79-30%)); Increased blood urea nitrogen (Frequent (79-30%)); Increased circulating lactate dehydrogenase concentration (Frequent (79-30%)); Reduced haptoglobin level (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Paroxysmal nocturnal hemoglobinuria is Haematology, with a haematologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which blood-cell, marrow, bleeding or clotting finding matters most?
• Does the diagnosis need confirmation or a more precise subtype?
• Which symptoms or laboratory changes should trigger earlier review?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.