Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited immune disorder characterized by the overproduction and accumulation of lymphocytes, which can lead to organ enlargement and various autoimmune complications.

Overview

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which the body cannot properly regulate the number of immune system cells (lymphocytes). ALPS is characterized by the production of an abnormally large number of lymphocytes, a process known as lymphoproliferation. The accumulation of these excess lymphocytes results in the enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly), and the spleen (splenomegaly).

Symptoms & Clinical Features

ALPS can present with varying patterns of signs and symptoms. Most commonly, lymphoproliferation becomes apparent during childhood, with enlargement of the lymph nodes and spleen frequently occurring in affected individuals.

Autoimmune disorders are also common in ALPS, occurring when the immune system malfunctions and attacks the body's own tissues and organs. Most of these disorders target and damage blood cells. Examples include:

• The immune system attacking red blood cells (autoimmune hemolytic anemia)
• The immune system attacking white blood cells (autoimmune neutropenia)
• The immune system attacking platelets (autoimmune thrombocytopenia)

A combination of hemolytic anemia and thrombocytopenia is also known as Evans syndrome, which typically develops several years after the initial lymphoproliferation. Less commonly, autoimmune disorders in ALPS can affect other organs and tissues, damaging the kidneys (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), or nerves (Guillain-Barre syndrome). Skin problems, such as rashes or hives (urticaria), can also occur.

People with the classic form of ALPS generally have a near-normal lifespan, but they carry a greatly increased risk of developing cancer of the immune system cells (lymphoma) compared to the general population. Some individuals experience non-classic forms of the disorder, presenting with similar symptoms like lymphoproliferation, lymphadenopathy, splenomegaly, and low blood counts, but with different genetic causes or specific symptom patterns.

Frequency

ALPS is a rare disorder; its exact prevalence is currently unknown.

Causes & Genetic Factors

Mutations in the FAS gene cause ALPS in approximately 75 percent of affected individuals, and these mutations are associated with the classic form of the disorder. The FAS gene provides instructions for making a protein involved in cell signaling that results in the self-destruction of cells (apoptosis).

When the immune system is activated to fight infections, large numbers of lymphocytes are produced. Normally, these lymphocytes undergo apoptosis when they are no longer required. Mutations in the FAS gene lead to an abnormal protein that interferes with this self-destruction process. As a result, excess lymphocytes accumulate in the body's tissues and organs, often attacking them and leading to autoimmune disorders. This interference with apoptosis also allows cells to multiply without control, leading to the lymphomas that frequently occur in people with this disorder.

Non-classic forms of ALPS may be caused by mutations in additional genes, some of which have not yet been identified. Genes associated with Autoimmune lymphoproliferative syndrome include:

• FAS
• KRAS
• MAGT1
• NRAS
• PIK3CD
• STAT3
• CASP10
• CTLA4
• FASLG

Inheritance Pattern

In most people with ALPS, including the majority of those with FAS gene mutations, the condition is inherited in an autosomal dominant pattern. This means one copy of the altered gene in each cell is sufficient to cause the disorder. In these cases, an affected person usually inherits the mutation from one affected parent. Other autosomal dominant cases result from new mutations that occur early in embryonic development in people with no family history of the disorder.

In a small number of cases, ALPS is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

ALPS can also arise from a somatic mutation, which is a mutation in lymphocytes that is not inherited but instead occurs during an individual's lifetime.

Other Names for This Condition

• ALPS
• Canale-Smith syndrome

Capillary malformation-arteriovenous malformation syndrome

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a genetic vascular disorder characterized by small skin spots and potentially serious abnormal connections between arteries and veins.

Overview

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a disorder of the vascular system, which is the body's complex network of blood vessels. The vascular system consists of arteries, which carry oxygen-rich blood from the heart to the body's tissues; veins, which carry blood back to the heart; and capillaries, which are tiny blood vessels connecting arteries and veins.

Symptoms & Complications

CM-AVM is characterized by capillary malformations (CMs), which are composed of enlarged capillaries that increase blood flow near the surface of the skin. These malformations look like multiple small, round, pink or red spots on the skin. In most affected individuals, capillary malformations occur on the face, arms, and legs. These spots may be visible from birth or may develop during childhood. By themselves, capillary malformations usually do not cause any health problems.

While some people with CM-AVM only experience capillary malformations, others also develop more serious vascular abnormalities known as arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs). AVMs and AVFs are abnormal connections between arteries, veins, and capillaries that affect blood circulation. Depending on where they occur in the body, these abnormalities can cause complications, including:

• Abnormal bleeding
• Migraine headaches
• Seizures
• Heart failure

In some cases, these complications can be life-threatening. In people with CM-AVM, complications of AVMs and AVFs tend to appear in infancy or early childhood; however, some of these vascular abnormalities never cause any symptoms.

Some vascular abnormalities seen in CM-AVM are similar to those that occur in a condition called Parkes Weber syndrome. In addition to vascular abnormalities, Parkes Weber syndrome usually involves the overgrowth of one limb. CM-AVM and some cases of Parkes Weber syndrome share the same genetic cause.

Frequency

CM-AVM is thought to occur in at least 1 in 100,000 people of northern European origin. The prevalence of the condition in other populations is unknown.

Causes & Genetic Factors

CM-AVM is caused by mutations in the RASA1 gene. This gene provides instructions for making a protein known as p120-RasGAP, which is involved in transmitting chemical signals from outside the cell to the nucleus. These signals help control several important cell functions, including cell growth and division (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement. The role of the p120-RasGAP protein is not fully understood, although it appears to be essential for the normal development of the vascular system.

Mutations in the RASA1 gene lead to the production of a nonfunctional version of the p120-RasGAP protein. A loss of this protein's activity disrupts tightly regulated chemical signaling during development. However, it is unclear how these changes lead to the specific vascular abnormalities seen in people with CM-AVM.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from an affected parent. Other cases result from new mutations and occur in people with no history of the disorder in their family.

Other Names for This Condition

• Capillary malformation-arteriovenous malformation
• CM-AVM

Carbamoyl phosphate synthetase I deficiency

Carbamoyl phosphate synthetase I deficiency is a rare genetic disorder that prevents the body from processing excess nitrogen, leading to a toxic accumulation of ammonia in the blood.

Overview

Carbamoyl phosphate synthetase I deficiency is an inherited disorder that causes ammonia to accumulate in the blood (hyperammonemia). Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The brain is especially sensitive to the effects of excess ammonia.

Symptoms & Clinical Features

In the first few days of life, infants with carbamoyl phosphate synthetase I deficiency typically exhibit the effects of hyperammonemia. These symptoms may include:

• Unusual sleepiness
• Poorly regulated breathing rate or body temperature
• Unwillingness to feed
• Vomiting after feeding
• Unusual body movements
• Seizures
• Coma

Affected individuals who survive the newborn period may experience a recurrence of these symptoms if their diet is not carefully managed, or if they experience infections or other stressors. They may also have delayed development and intellectual disability. In some people with carbamoyl phosphate synthetase I deficiency, signs and symptoms may be less severe and appear later in life.

Frequency

Carbamoyl phosphate synthetase I deficiency is a rare disorder; its overall incidence is unknown. Researchers in Japan have estimated that it occurs in approximately 1 in 800,000 newborns in that country.

Causes & Genetic Factors

Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. This enzyme participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys. The specific role of the carbamoyl phosphate synthetase I enzyme is to control the first step of the urea cycle, a reaction in which excess nitrogen compounds are incorporated into the cycle to be processed.

Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. In this condition, the carbamoyl phosphate synthetase I enzyme is at low levels (deficient) or absent, and the urea cycle cannot proceed normally. As a result, nitrogen accumulates in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of the condition.

Inheritance Pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Carbamoyl-phosphate synthase I deficiency disease
• Carbamyl-phosphate synthetase I deficiency disease
• Congenital hyperammonemia, type I

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Commonly known as CARASIL, this rare inherited condition causes early-onset strokes, cognitive decline, premature hair loss, and severe back pain.

Overview

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CARASIL, is an inherited condition that causes stroke and other impairments.

Symptoms & Progression

Abnormalities affecting the brain and other parts of the nervous system typically become apparent in an affected person's twenties or thirties. The progression of symptoms often follows a characteristic pattern:

• Muscle stiffness (spasticity) in the legs and problems with walking are often the first signs of the disorder.
• About half of affected individuals experience a stroke or similar episode before age 40.
• As the disease progresses, most people develop mood and personality changes, a decline in thinking ability (dementia), memory loss, and worsening problems with movement.

Other characteristic features of CARASIL include:

• Premature hair loss (alopecia) that often begins during adolescence and is limited to the scalp.
• Attacks of low back pain developing in early to mid-adulthood, resulting from the breakdown (degeneration) of the discs that separate the vertebrae.

The signs and symptoms of CARASIL worsen slowly with time. Over the course of several years, affected individuals become less able to control their emotions and communicate with others. They increasingly require help with personal care and other activities of daily living, eventually becoming unable to care for themselves. Most affected individuals die within a decade after signs and symptoms first appear, although a few people with the disease have survived for 20 to 30 years.

Frequency

CARASIL appears to be a rare condition. It has been identified in about 50 people, primarily in Japan and China.

Causes & Genetic Factors

CARASIL is caused by mutations in the HTRA1 gene. This gene provides instructions for making an enzyme that is found in many of the body's organs and tissues. One of the major functions of the HTRA1 enzyme is to regulate signaling by proteins in the transforming growth factor-beta (TGF-β) family. TGF-β signaling is essential for many critical cell functions and plays an important role in the formation of new blood vessels (angiogenesis).

In people with CARASIL, mutations in the HTRA1 gene prevent the effective regulation of TGF-β signaling. Researchers suspect that abnormally increased TGF-β signaling alters the structure of small blood vessels, particularly in the brain. These blood vessel abnormalities (described as arteriopathy) greatly increase the risk of stroke and lead to the death of nerve cells (neurons) in many areas of the brain. Dysregulation of TGF-β signaling may also underlie the hair loss and back pain seen in people with CARASIL, although the relationship between abnormal TGF-β signaling and these features is less clear.

Inheritance Pattern

This condition is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• CARASIL
• Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
• Maeda syndrome
• Nemoto disease