GLUT1 Deficiency Syndrome

GLUT1 deficiency syndrome is a rare genetic disorder affecting the nervous system that impairs brain development and function by reducing the glucose available to brain cells. This condition often leads to frequent seizures, developmental delays, and movement difficulties.

Overview and Symptoms

GLUT1 deficiency syndrome is a disorder affecting the nervous system that can have a variety of neurological signs and symptoms. The condition is generally categorized into two main forms based on the presence of epilepsy:

Common GLUT1 Deficiency Syndrome

Approximately 90 percent of affected individuals have this form of the disorder. These individuals generally experience frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be rapid and irregular involuntary eye movements. While babies with this form have a normal head size at birth, the growth of the brain and skull is often slow, which can result in an abnormally small head size (microcephaly). People with common GLUT1 deficiency syndrome may also experience:

• Developmental delay or intellectual disability
• Stiffness caused by abnormal tensing of the muscles (spasticity)
• Difficulty in coordinating movements (ataxia)
• Speech difficulties (dysarthria)
• Episodes of confusion, lack of energy (lethargy), headaches, or muscle twitches (myoclonus), particularly during periods without food (fasting)

Non-Epileptic GLUT1 Deficiency Syndrome

About 10 percent of individuals with the condition have this usually less severe form. People with non-epileptic GLUT1 deficiency syndrome do not experience seizures, but they may still have developmental delay and intellectual disability. Most experience movement problems such as ataxia or involuntary tensing of various muscles (dystonia), which may be more pronounced than in the common form.

Disease Variants

Several conditions originally given other names are now recognized as variants of GLUT1 deficiency syndrome. These include:

• Paroxysmal choreoathetosis with spasticity (dystonia 9)
• Paroxysmal exercise-induced dyskinesia and epilepsy (dystonia 18)
• Certain types of epilepsy
• Rare cases characterized by abnormal red blood cells and uncommon forms of anemia (characterized by a shortage of red blood cells)

Frequency

GLUT1 deficiency syndrome is a rare disorder. In Scotland, the incidence of the disorder has been estimated at 1 in 24,000 newborns. However, researchers suggest that the disorder may be underdiagnosed because many other neurological disorders can cause similar symptoms.

Causes

GLUT1 deficiency syndrome is caused by variants (also known as mutations) in the SLC2A1 gene. This gene provides instructions for producing a protein called the glucose transporter protein type 1 (GLUT1). The GLUT1 protein is embedded in the outer membrane of cells, where it transports a simple sugar called glucose into cells from the blood or from other cells for use as fuel.

In the brain, the GLUT1 protein is involved in moving glucose—the brain's main energy source—across the blood-brain barrier. The blood-brain barrier acts as a boundary between tiny blood vessels and the surrounding brain tissue, protecting delicate nerve tissue by preventing many other types of molecules from entering. The GLUT1 protein also moves glucose between brain cells called glia, which protect and maintain nerve cells (neurons).

Variants in the SLC2A1 gene reduce or eliminate the function of the GLUT1 protein. Having less functional GLUT1 protein reduces the amount of glucose available to brain cells, which negatively affects brain development and function.

Inheritance Pattern

This condition is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. About 90 percent of cases of GLUT1 deficiency syndrome result from new (de novo) mutations in the gene, occurring in people with no history of the disorder in their family. In other cases, an affected person inherits the variant from an affected parent.

In a small number of families, GLUT1 deficiency syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• De Vivo disease
• Encephalopathy due to GLUT1 deficiency
• G1D
• Glucose transport defect, blood-brain barrier
• Glucose transporter protein syndrome
• Glucose transporter type 1 deficiency syndrome
• Glut1 deficiency
• GLUT1 DS
• GTPS

Jervell and Lange-Nielsen Syndrome

Jervell and Lange-Nielsen syndrome is a rare genetic condition characterized by profound congenital hearing loss and a severe heart arrhythmia that increases the risk of fainting and sudden death.

Overview and Symptoms

Jervell and Lange-Nielsen syndrome is a condition that causes profound hearing loss from birth and a disruption of the heart's normal rhythm (arrhythmia). This disorder is a form of long QT syndrome, which is a heart condition that causes the cardiac muscle to take longer than usual to recharge between beats. Beginning in early childhood, these irregular heartbeats increase the risk of fainting (syncope) and sudden death.

Frequency

Jervell and Lange-Nielsen syndrome is uncommon, affecting an estimated 1.6 to 6 per 1 million people worldwide. The condition has a higher prevalence in Denmark, Sweden, and Norway, where it affects at least 1 in 200,000 people.

Causes

Jervell and Lange-Nielsen syndrome is caused by mutations in the KCNE1 and KCNQ1 genes. These genes provide instructions for making proteins that work together to form a potassium channel across cell membranes. These channels transport positively charged potassium atoms (ions) out of cells. The movement of potassium ions through these channels is critical for maintaining the normal functions of the inner ear and cardiac muscle.

About 90 percent of cases of Jervell and Lange-Nielsen syndrome are caused by mutations in the KCNQ1 gene, while KCNE1 mutations are responsible for the remaining cases. Mutations in these genes alter the usual structure and function of potassium channels or prevent the assembly of normal channels. These changes disrupt the flow of potassium ions in the inner ear and in cardiac muscle, leading to the hearing loss and irregular heart rhythm characteristic of the syndrome.

Inheritance Pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of a child with an autosomal recessive disorder are not affected themselves but are carriers of one copy of the mutated gene. Some carriers of a KCNQ1 or KCNE1 mutation have a long QT interval with related heart abnormalities, but their hearing is normal.

Other Names for This Condition

• Autosomal recessive long QT syndrome (LQTS)
• Cardio-auditory-syncope syndrome
• Cardioauditory syndrome of Jervell and Lange-Nielsen
• Deafness, congenital, and functional heart disease
• Jervell-Lange Nielsen syndrome
• JLNS
• Prolonged QT interval in EKG and sudden death
• Surdo-cardiac syndrome

Pendred Syndrome

Pendred syndrome is a genetic disorder typically associated with severe-to-profound hearing loss present from birth and the development of an enlarged thyroid gland, known as a goiter.

Overview and Symptoms

Pendred syndrome is a disorder characterized by a combination of hearing loss and thyroid abnormalities. The primary features of the condition include:

• Hearing Loss: In most people with Pendred syndrome, severe to profound hearing loss caused by changes in the inner ear (sensorineural hearing loss) is evident at birth. Less commonly, hearing loss does not develop until later in infancy or early childhood.
• Goiter: Affected individuals often develop a goiter, which is an enlargement of the thyroid gland (the butterfly-shaped organ at the base of the neck that produces hormones). If a goiter develops, it usually forms between late childhood and early adulthood. In most cases, this enlargement does not cause the thyroid to malfunction.
• Balance Issues: Some affected individuals experience problems with balance caused by dysfunction of the vestibular system, the part of the inner ear that helps maintain the body's balance and orientation.
• Inner Ear Abnormalities: A characteristic feature of Pendred syndrome is an enlarged vestibular aqueduct (EVA), which is a bony canal connecting the inner ear with the inside of the skull. Some individuals also have an abnormally shaped cochlea (the snail-shaped structure in the inner ear that processes sound). The combination of an enlarged vestibular aqueduct and an abnormally shaped cochlea is known as Mondini malformation.

Pendred syndrome shares features with other hearing loss and thyroid conditions, and it is unclear whether they represent separate disorders or a spectrum of related signs and symptoms. These related conditions include DFNB4 (a form of nonsyndromic hearing loss) and, in a small number of people, a form of congenital hypothyroidism resulting from an abnormally small thyroid gland (thyroid hypoplasia). All of these conditions are caused by mutations in the same gene.

Frequency

While the exact prevalence of Pendred syndrome is unknown, researchers estimate that it accounts for 7 to 8 percent of all hearing loss present from birth (congenital hearing loss).

Causes

Mutations in the SLC26A4 gene cause about half of all cases of Pendred syndrome. The SLC26A4 gene provides instructions for making a protein called pendrin. This protein transports negatively charged particles (ions), including chloride, iodide, and bicarbonate, into and out of cells.

Although the function of pendrin is not fully understood, it is important for maintaining the proper levels of ions in the thyroid and the inner ear. Mutations in the SLC26A4 gene alter the structure or function of pendrin, disrupting ion transport. This resulting imbalance of particular ions disrupts the development and function of the thyroid gland and structures in the inner ear, leading to the characteristic features of Pendred syndrome.

In individuals with Pendred syndrome who do not have mutations in the SLC26A4 gene, the cause of the condition is currently unknown. Researchers suspect that other genetic and environmental factors may influence the development 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

• Autosomal recessive sensorineural hearing impairment, enlarged vestibular aqueduct, and goiter
• Deafness with goiter
• Goiter-deafness syndrome
• Pendred's syndrome

Nonsyndromic Dilated Cardiomyopathy

Nonsyndromic dilated cardiomyopathy is a genetic heart condition where the cardiac muscle becomes thin and enlarged, severely impairing the heart's ability to pump blood and increasing the risk of heart failure.

Overview and Symptoms

Dilated cardiomyopathy is a form of heart disease in which the heart muscle becomes thin and enlarged (dilated). This dilation typically begins in the lower left chamber of the heart (left ventricle), making it harder for the heart to pump blood to the rest of the body.

The condition is classified as nonsyndromic dilated cardiomyopathy when it cannot be explained by other causes—such as a heart attack or damage to the heart valves—and is not associated with signs and symptoms that affect other parts of the body.

The signs and symptoms of nonsyndromic dilated cardiomyopathy vary among affected individuals, even within the same family. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Symptoms may include:

• A sensation of fluttering or pounding in the chest (palpitations)
• Shortness of breath, especially when lying down or during physical activity
• Fatigue
• Swelling of the legs and feet
• Episodes of dizziness or fainting (syncope)

Over time, individuals with nonsyndromic dilated cardiomyopathy may develop life-threatening complications, including abnormal heart rhythms (arrhythmias) and heart failure. Although uncommon, sudden death can occur, even in individuals who have no other symptoms of the condition.

Frequency

Dilated cardiomyopathy may affect as many as 1 in 250 people. In approximately 30 to 50 percent of these cases, there is a family history of the condition.

Causes

Variants (also called mutations) in more than 20 genes have been found to cause nonsyndromic dilated cardiomyopathy. These genes provide instructions for making proteins found in cardiac muscle cells called cardiomyocytes.

Many of these proteins play important roles in the contraction of the heart muscle through their association with structures called sarcomeres. Sarcomeres are the basic units of contraction, made of proteins that generate the mechanical force needed for muscles to contract. Other proteins associated with the condition make up the structural framework (the cytoskeleton) of cardiomyocytes, while the remaining proteins ensure proper cellular function.

A genetic cause is identified in approximately 25 to 35 percent of people with dilated cardiomyopathy, and is more likely to be found in individuals who have affected family members.

The Role of the TTN Gene

Variants in one gene, TTN, account for approximately 15 to 20 percent of all cases of dilated cardiomyopathy. The TTN gene provides instructions for making a protein called titin, which is found in the sarcomeres of cardiomyocytes and other muscle cells. Titin provides structure, flexibility, and stability to sarcomeres, and plays a role in chemical signaling and sarcomere assembly. Many of the TTN gene variants in affected individuals cause cells to produce an abnormally short version of the titin protein, which likely impairs sarcomere function and disrupts chemical signaling.

Syndromic and Acquired Forms

Dilated cardiomyopathy can also occur as part of a syndrome affecting other organs and tissues (described as "syndromic" and caused by variants in other genes). Additionally, some cases are acquired during a person's lifetime. Causes of acquired dilated cardiomyopathy include damage to the heart valves, or damage to the cardiac muscle caused by a heart attack, infections, or certain medications.

Inheritance Pattern

Nonsyndromic dilated cardiomyopathy has different inheritance patterns depending on the specific gene involved. When the condition is present in multiple family members, it is often called familial dilated cardiomyopathy.

• Autosomal Dominant: The condition is usually inherited in an autosomal dominant pattern, meaning one copy of an altered gene in each cell is sufficient to cause the disorder. However, some people with the altered gene never develop features of the condition, a phenomenon known as reduced penetrance. While many individuals have an affected parent, some cases result from new (de novo) variants that occur during the formation of reproductive cells or during early embryonic development.
• Autosomal Recessive: Less commonly, the condition can be inherited in an autosomal recessive pattern, meaning both copies of a gene in each cell must have a variant. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Syndromic dilated cardiomyopathy follows the inheritance pattern of its associated syndrome.

Other Names for This Condition

• DCM
• Familial dilated cardiomyopathy
• Idiopathic dilated cardiomyopathy