Epilepsy-aphasia spectrum

The epilepsy-aphasia spectrum is a group of childhood-onset conditions characterized by language impairment, abnormal brain electrical activity, and recurrent seizures. These disorders range from mild speech difficulties to a severe loss of previously acquired language and motor skills.

Overview

The epilepsy-aphasia spectrum is a group of conditions that have overlapping signs and symptoms. A key feature of these conditions is impairment of language skills (aphasia). The language problems can affect speaking, reading, and writing. Another feature of epilepsy-aphasia spectrum disorders is certain patterns of abnormal electrical activity in the brain, which are detected by a test called an electroencephalogram (EEG). Many people with conditions in this spectrum develop recurrent seizures (epilepsy), and some have mild to severe intellectual disability. The conditions in the epilepsy-aphasia spectrum, which all begin in childhood, include Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep syndrome (ECSWS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), intermediate epilepsy-aphasia disorder (IEAD), atypical childhood epilepsy with centrotemporal spikes (ACECTS), and childhood epilepsy with centrotemporal spikes (CECTS).

Severe Spectrum Conditions: LKS and ECSWS

LKS and ECSWS are at the severe end of the spectrum. Both usually feature a characteristic abnormal pattern of electrical activity in the brain called continuous spike and waves during slow-wave sleep (CSWS). This pattern occurs while the affected child is sleeping, specifically during deep (slow-wave) sleep.

Most children with LKS develop normally in early childhood, although some speak later than their peers. However, affected children lose language skills beginning around age 5. This loss typically begins with verbal agnosia, which is the inability to understand speech. As LKS develops, the ability to express speech is also impaired. Approximately 70 percent of children with LKS have seizures, typically of a type described as focal (or ) because the seizure activity occurs in specific regions of the brain rather than affecting the entire brain.

About half of children with ECSWS develop normally in early childhood, while others have delayed development of speech and motor skills. Although children with ECSWS typically lose a range of previously acquired skills, including those involved in language, movement, learning, or behavior, not everyone with ECSWS has aphasia. Seizures occur in approximately 80 percent of children with ECSWS and can include a variety of types, such as atypical absence seizures, which involve short periods of staring blankly; hemiclonic seizures, which cause rhythmic jerking of one side of the body; or generalized tonic-clonic seizures, which cause stiffening and rhythmic jerking of the entire body.

Mild Spectrum Condition: CECTS

CECTS is at the mild end of the epilepsy-aphasia spectrum. Affected children have rolandic seizures; these seizures are triggered by abnormal activity in an area of the brain called the rolandic region, which is part of the . The seizures, which usually occur during sleep, cause twitching, numbness, or tingling of the face or tongue, often causing drooling and impairing speech. In most people with CECTS, the seizures disappear by the end of adolescence. Most affected individuals develop normally, although some have difficulty coordinating the movements of the mouth and tongue needed for clear speech (dyspraxia) or impairment of language skills.

Intermediate Spectrum Conditions

The other conditions in the epilepsy-aphasia spectrum are less common and fall in the middle of the spectrum. Children with IEAD usually have delayed development or regression of language skills. Some have seizures and most have abnormal electrical activity in their brains during sleep, although it is not prominent enough to be classified as CSWS. ACECTS features seizures and developmental regression that can affect movement, language, and attention. Children with ACECTS have abnormal electrical activity in the brain that is sometimes classified as CSWS. ADRESD is characterized by focal seizures, speech difficulties due to dyspraxia, and learning disability.

Frequency

The prevalence of the epilepsy-aphasia spectrum is unknown. Most of the conditions in the spectrum are rare; however, CECTS is one of the most common forms of epilepsy in children, accounting for 8 to 25 percent of cases. It is estimated to occur in 1 in 5,000 children younger than 16.

Causes & Genetic Factors

Variants (also known as mutations) in the GRIN2A gene can cause conditions in the epilepsy-aphasia spectrum. These variants are more common in the more severe conditions; they are found in up to 20 percent of people with LKS or ECSWS and about 5 percent of people with CECTS. In affected people without a GRIN2A gene variant, the cause of the condition is unknown. Some affected individuals have a brain abnormality that may contribute to the condition. Researchers suspect that changes in other, unidentified genes may also be associated with epilepsy-aphasia spectrum disorders.

The GRIN2A gene provides instructions for making the GluN2A protein, which is one component (subunit) of a subset of NMDA receptors. NMDA receptors transmit signals that turn on nerve cells (neurons) in the brain. Signaling through these receptors is involved in normal brain development, changes in the brain in response to experience (synaptic plasticity), learning, and memory. The GluN2A subunit determines where in the brain the receptor is located and how it functions. Receptors containing this subunit are found in regions of the brain involved in speech and language, among other regions. These receptors also appear to play a role in brain signaling during slow-wave sleep.

Variants in the GRIN2A gene lead to altered NMDA receptor signaling in the brain. As a result, neurons may be abnormally turned on, which can cause seizures and other abnormal brain activity and may lead to death of the neurons. Changes in GluN2A appear to particularly affect signaling in regions of the brain involved in speech and language and disrupt brain activity during slow-wave sleep, leading to several of the signs and symptoms of this group of conditions.

It is not clear why some people with a GRIN2A gene variant have a relatively mild condition and others have more severe signs and symptoms, even within the same family. Variations in other genes and environmental factors may also play a role in development of the condition.

Inheritance Pattern

Conditions in the epilepsy-aphasia spectrum that are caused by GRIN2A gene variants are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Individuals with an epilepsy-aphasia spectrum disorder may have family members with a condition in the epilepsy-aphasia spectrum or a related disorder such as isolated seizures or speech and language problems.

In some cases, an affected person inherits the variant from . Other cases result from and occur in people with no history of the disorder in their family.

Other Names for This Condition

• Acquired aphasia with epilepsy
• DEE/EE-SWAS
• Developmental and/or epileptic encephalopathy with spike-wave activation in Sleep
• Epilepsy with continuous spike-wave in sleep
• Epilepsy with electrographic status epilepticus in sleep
• FESD
• Focal epilepsies with speech and language disorders
• Focal epilepsy with speech disorder and with or without mental retardation

Galactosialidosis

Galactosialidosis is a rare lysosomal storage disorder that impacts multiple systems of the body. It is categorized into early infantile, late infantile, and juvenile/adult forms based on the age of onset and the severity of symptoms.

Overview & Forms

Galactosialidosis is a condition that affects many areas of the body. The three forms of galactosialidosis are distinguished by the age at which symptoms develop and the pattern of features.

Early Infantile Form

The early infantile form of galactosialidosis is associated with extensive swelling caused by fluid accumulation before birth (hydrops fetalis), a soft out-pouching in the lower abdomen (), and an enlarged liver and spleen (hepatosplenomegaly). Additional features of this form include abnormal bone development (dysostosis multiplex) and Some infants have an enlarged heart (cardiomegaly), an eye abnormality called a cherry-red spot, and kidney disease that can progress to failure. Infants with this form usually are diagnosed between birth and 3 months of age; they typically live to around 6 months of age.

Late Infantile Form

The late infantile form of galactosialidosis shares some features with the early infantile form, although the signs and symptoms are somewhat less severe and begin later in infancy. This form is characterized by short stature, dysostosis multiplex, problems, hepatosplenomegaly, and "coarse" facial features. Other symptoms seen in some individuals with this type include intellectual disabilities, hearing loss, and a cherry-red spot. Children with this condition typically develop symptoms around 2 years old. The life expectancy of individuals with this type varies depending on the severity of symptoms.

Juvenile/Adult Form

The juvenile/adult form of galactosialidosis has signs and symptoms that are somewhat different from those of the other two types. This form is distinguished by difficulty coordinating movements (ataxia), muscle twitches (myoclonus), seizures, and intellectual disabilities that worsen over time. People with this form typically also have dark red spots on the skin (angiokeratomas), abnormalities in the , "coarse" facial features, a cherry-red spot, vision loss, and hearing loss. The age at which symptoms begin to develop varies widely among affected individuals, but the average age is 16. This form is typically associated with a nearly normal life expectancy.

Frequency

The prevalence of galactosialidosis is unknown; more than 100 cases have been reported. The juvenile/adult form accounts for more than half of the reported cases of galactosialidosis. Most people with this type of the condition are of Japanese descent.

Causes & Genetic Factors

Variants (also called mutations) in the CTSA gene cause all the forms of galactosialidosis. The CTSA gene provides instructions for making a protein called cathepsin A, which is active in cellular compartments called lysosomes. These compartments contain enzymes that digest and recycle materials when they are no longer needed. Cathepsin A works together with two enzymes, neuraminidase 1 and beta-galactosidase, to form a protein complex. This complex breaks down sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins) or fats (glycolipids). Cathepsin A is also found on the cell surface, where it forms a complex with neuraminidase 1 and a protein called elastin-binding protein. Elastin-binding protein plays a role in the formation of elastic fibers, which are components of the that make up the body's supportive framework.

CTSA gene variants interfere with the normal function of cathepsin A. Most of the variants that cause galactosialidosis disrupt the protein structure of cathepsin A, impairing its ability to form complexes with neuraminidase 1, beta-galactosidase, and elastin-binding protein. As a result, these other enzymes are not functional, or they break down prematurely.

Galactosialidosis belongs to a large family of lysosomal storage disorders, each caused by the deficiency of a specific lysosomal enzyme or protein. In people with galactosialidosis, impaired functioning of cathepsin A and other enzymes causes certain substances to accumulate in the lysosomes.

Inheritance Pattern

This condition is inherited in an , which means both copies of the gene in each cell must have a variant to cause the disorder. 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

• Deficiency of cathepsin A
• Goldberg syndrome
• Lysosomal protective protein deficiency
• Neuraminidase deficiency with beta-galactosidase deficiency
• PPCA deficiency

Phosphoglycerate mutase deficiency

Phosphoglycerate mutase deficiency is a rare metabolic disorder that primarily affects skeletal muscles, leading to exercise-induced muscle cramping and potentially severe muscle breakdown.

Overview & Symptoms

Phosphoglycerate mutase deficiency is a disorder that primarily affects muscles used for movement (skeletal muscles). Beginning in childhood or adolescence, affected individuals experience muscle aches or cramping following strenuous physical activity. Some people with this condition also have recurrent episodes of myoglobinuria. Myoglobinuria occurs when muscle tissue breaks down abnormally and releases a protein called myoglobin, which is processed by the kidneys and released in the urine. If untreated, myoglobinuria can lead to kidney failure.

In some cases of phosphoglycerate mutase deficiency, microscopic tube-shaped structures called tubular aggregates are seen in muscle fibers. It is unclear how tubular aggregates are associated with the signs and symptoms of the disorder.

Frequency

Phosphoglycerate mutase deficiency is a rare condition; about 15 affected people have been reported in the medical literature. Most affected individuals have been African American.

Causes & Genetic Factors

Phosphoglycerate mutase deficiency is caused by mutations in the PGAM2 gene. This gene provides instructions for making an enzyme called phosphoglycerate mutase, which is involved in a critical energy-producing process in cells known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce energy.

The version of phosphoglycerate mutase produced from the PGAM2 gene is found primarily in skeletal muscle cells. Mutations in the PGAM2 gene greatly reduce the activity of phosphoglycerate mutase, which disrupts energy production in these cells. This defect underlies the muscle cramping and myoglobinuria that occur after strenuous exercise in affected individuals.

Inheritance Pattern

This condition is inherited in an , which means both copies of the PGAM2 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. However, people who carry one altered copy of the PGAM2 gene may have some features of phosphoglycerate mutase deficiency, including episodes of exercise-induced muscle cramping and myoglobinuria.

Other Names for This Condition

• Deficiency mutase phosphoglycerate
• Glycogen storage disease X
• GSD X
• GSD10
• GSDX
• Myopathy due to phosphoglycerate mutase deficiency
• PGAM deficiency
• PGAMM deficiency

Hypophosphatasia

Hypophosphatasia is an inherited disorder that disrupts bone and tooth mineralization, leading to weakened bones, skeletal defects, and premature tooth loss.

Overview & Symptoms

Hypophosphatasia is an inherited disorder that affects the development of bones and teeth. This condition disrupts a process called mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding.

The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy.

Severe Infantile Forms

Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called . Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.

Childhood and Adult Forms

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or , enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones known as osteomalacia. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.

Odontohypophosphatasia

The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia.

Frequency

Severe forms of hypophosphatasia affect an estimated 1 in 100,000 newborns. Milder cases, such as those that appear in childhood or adulthood, probably occur more frequently.

Hypophosphatasia has been reported worldwide in people of various ethnic backgrounds. This condition appears to be most common in white populations. It is particularly frequent in a Mennonite population in Manitoba, Canada, where about 1 in 2,500 infants is born with severe features of the condition.

Causes & Genetic Factors

Mutations in the ALPL gene cause hypophosphatasia. This gene provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP), which plays an essential role in mineralization of the skeleton and teeth. Mutations in the ALPL gene lead to the production of an abnormal version of TNSALP that cannot participate effectively in the mineralization process. A shortage of TNSALP allows several other substances, which are normally processed by the enzyme, to build up abnormally in the body. Researchers believe that a buildup of one of these compounds, inorganic pyrophosphate (PPi), underlies the defective mineralization of bones and teeth in people with hypophosphatasia.

ALPL gene mutations that almost completely eliminate the activity of TNSALP usually result in the more severe forms of hypophosphatasia. Other mutations, which reduce but do not eliminate the activity of the enzyme, often cause the milder forms of the condition.

Inheritance Pattern

The severe forms of hypophosphatasia that appear early in life are inherited in an . Autosomal recessive inheritance means that two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.

Milder forms of hypophosphatasia can have either an autosomal recessive or an of inheritance. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder.

Other Names for This Condition

• Deficiency of alkaline phosphatase
• Phosphoethanolaminuria