CASK-Related Disorders

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Disease Profile

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Age of onset

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ICD-10

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Inheritance

CASK-related disorders are inherited in an X-linked dominant manner.^[1] This means that the gene responsible for the condition is located on the X chromosome, and having only one mutated copy of the gene is enough to cause the condition.

Because males have only one X chromosome (and one Y chromosome) and females have two X chromosomes, X-linked dominant conditions affect males and females differently. Both males and females can have an X-linked dominant condition. However, because males don't have a second, working copy of the gene (as females do), they usually have more severe disease than females.

If a father has the mutated X-linked gene:

All of his daughters will inherit the mutated gene (they will all receive his X chromosome)
None of his sons will inherit the mutated gene (they only inherit his Y chromosome)

If a mother has the mutated X-linked gene, each of her children (both male and female) has a 50% chance to inherit the mutated gene.

Rather than being inherited from a parent, the condition may also be caused by a new mutation that occurs for the first time in an affected person (a de novo mutation).

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Summary

CASK-related disorders are a group of genetic disorders that affect brain development. The two main related disorders include microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XL-ID) with or without nystagmus. Males with these disorders usually have more severe symptoms than females. The signs and symptoms may include: autism spectrum disorders, intellectual disability, epilepsy disorders, seizures, a small head size (microcephaly) with specific brain findings (pontine and cerebellar hypoplasia), delayed growth, vision and hearing issues, and low muscle tone (hypotonia).^[1]^[2]

CASK-related disorders are caused by mutations in the CASK gene and are inherited in an X-linked manner.^[1] Some researchers have suggested that a condition called FG syndrome 4 may also be caused by mutations in the CASK gene, but it seems that the only family described with this syndrome may have actually had XL-ID, with or without nystagmus.^[3]^[2] Treatment is focused on alleviating symptoms and may include medication to control seizures, nutritional support, hearing and vision aids, and physical therapy. The best management usually requires a team of specialists.^[1]

Symptoms

The two main conditions in CASK-related disorders include microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XL-ID) with or without nystagmus. The signs and symptoms associated with each condition may overlap and males are usually more severely affected than females. Symptoms appear in infancy and typically progress over time.^[1]^[3]

The signs and symptoms found in people with MICPCH may include:^[1]^[2]

An unusually small head at birth (microcephaly) that does not grow at the same rate as the rest of the body
Underdevelopment (hypoplasia) of areas of the brain called the cerebellum and the pons
Intellectual disability, which is usually severe
Sleep disturbances
Repetitive behaviors including self-biting and hand flapping
Seizures
Vision problems, such as a small (hypoplastic) nerve in the eye (optic nerve), deterioration of the retina of the eye (retinopathy), and strabismus (crossed eyes)
Hearing loss caused by nerve problems in the inner ear (sensorineural deafness)
Decreased muscle tone (hypotonia) in the torso, increased muscle tone (hypertonia), and stiffness (spasticity) in the limbs
Movement problems such as involuntary tensing of various muscles (dystonia)

Individuals with MICPCH may also have a different types of epilepsy disorders including Ohtahara syndrome, West syndrome, and myoclonic epilepsy. These disorders are more common in males with MICPCH. Other findings may include unique facial features such as arched eyebrows; a short, broad nose; a lengthened area between the nose and mouth (philtrum); a protruding upper jaw (maxilla); a short chin; and large ears. People with MICPCH do not usually develop language skills, and most do not learn to walk.^[2]

X-linked intellectual disability (XL-ID) with or without nystagmus is typically a more mild condition with signs and symptoms that may include:^[1]^[2]

Rapid, involuntary eye movements (nystagmus)
Other eye findings such as strabismus and an abnormal coloration of the optic disc (optic disc pallor)
Mild to severe intellectual disability (some females having normal intelligence)
Seizures
Hypotonia
Rhythmic shaking (tremors)

One family with FG syndrome 4 (FGS4) was found to have mutations in the CASK gene, however, some researchers suggest that this family should be included under X-linked intellectual disability (XL-ID) with or without nystagmus.^[4]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
5%-29% of people have these symptoms
Macrogyria		0007227
Nystagmus	Involuntary, rapid, rhythmic eye movements	0000639
Optic disc pallor		0000543
Optic nerve hypoplasia		0000609
Scoliosis		0002650
Seizure		0001250
Sensorineural hearing impairment		0000407
Strabismus	Cross-eyed Squint Squint eyes [ more ]	0000486
1%-4% of people have these symptoms
Feeding difficulties in infancy		0008872
Neonatal hypotonia	Low muscle tone, in neonatal onset	0001319
Prominent forehead	Pronounced forehead Protruding forehead [ more ]	0011220
Percent of people who have these symptoms is not available through HPO
Abnormally large globe	Increased size of eyes Large eyes [ more ]	0001090
Absent speech	Absent speech development Lack of language development Lack of speech No speech development No speech or language development Nonverbal [ more ]	0001344
Broad nasal tip	Broad tip of nose Broad, upturned nose Increased breadth of nasal tip Increased breadth of tip of nose Increased width of nasal tip Increased width of tip of nose Nasal tip, broad Nasal tip, wide Wide tip of nose [ more ]	0000455
Cerebellar hypoplasia	Small cerebellum Underdeveloped cerebellum [ more ]	0001321
Decreased body weight	Decreased weight Low body weight Low weight Weight less than 3rd percentile [ more ]	0004325
Dilated fourth ventricle		0002198
Epicanthus	Eye folds Prominent eye folds [ more ]	0000286
Generalized hypotonia	Decreased muscle tone Low muscle tone [ more ]	0001290
Global developmental delay		0001263
High palate	Elevated palate Increased palatal height [ more ]	0000218
Hyperreflexia	Increased reflexes	0001347
Hypertelorism	Wide-set eyes Widely spaced eyes [ more ]	0000316
Hypohidrosis	Decreased ability to sweat Decreased sweating Sweating, decreased [ more ]	0000966
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Intellectual disability, moderate	IQ between 34 and 49	0002342
Long philtrum		0000343
Macrotia	Large ears	0000400
Micrognathia	Little lower jaw Small jaw Small lower jaw [ more ]	0000347
Muscle weakness	Muscular weakness	0001324
Muscular hypotonia of the trunk	Low muscle tone in trunk	0008936
Oval face	Oval facial shape	0000300
Postnatal growth retardation	Growth delay as children	0008897
Progressive microcephaly	Progressively abnormally small cranium Progressively abnormally small skull [ more ]	0000253
Prominent nasal bridge	Elevated nasal bridge High nasal bridge Prominent bridge of nose Prominent nasal root Protruding bridge of nose Protruding nasal bridge [ more ]	0000426
Short nose	Decreased length of nose Shortened nose [ more ]	0003196
Short stature	Decreased body height Small stature [ more ]	0004322
Spasticity	Involuntary muscle stiffness, contraction, or spasm	0001257
Wide nasal bridge	Broad nasal bridge Broad nasal root Broadened nasal bridge Increased breadth of bridge of nose Increased breadth of nasal bridge Increased width of bridge of nose Increased width of nasal bridge Nasal bridge broad Wide bridge of nose Widened nasal bridge [ more ]	0000431
X-linked dominant inheritance		0001423
X-linked inheritance		0001417

Do you have updated information on this disease? We want to hear from you.

Cause

CASK-related disorders are caused by mutations in the CASK gene. This gene provides instructions for making the CASK protein, which is typically found in the nerve cells in the brain (neurons). The CASK protein is involved in controlling the activity of other genes that are involved in brain development and regulating the movement of certain necessary for signaling between neurons. Researchers suspected the protein may also be involved in development of the nerves that control eye movement.^[2]

Mutations in the CASK gene are thought to affect the role of the CASK protein in brain development and function, resulting in the associated signs and symptoms. Research indicates that the more severe symptoms associated with these disorders are caused by mutations that completely eliminate the function of the CASK protein, while more mild symptoms are caused by mutations that impair or reduce the function of the protein.^[1]^[2]

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Social Networking Websites

Visit the following Facebook groups related to CASK-Related Disorders:
CASK gene mutation management and support
CASK Gene Foundation Family and Caretaker Support

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on CASK-Related Disorders. This website is maintained by the National Library of Medicine.

In-Depth Information

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Online Mendelian Inheritance in Man (OMIM)
Online Mendelian Inheritance in Man (OMIM)

References

Moog U, Uyanik G, Kutsche K. CASK-Related Disorders. GeneReviews. November 26, 2013; https://www.ncbi.nlm.nih.gov/books/NBK169825/.
CASK-related intellectual disability. Genetics Home Reference. March 2014; https://ghr.nlm.nih.gov/condition/cask-related-intellectual-disability.
Srivastava S, McMillan R, Willis J, Clark H, Chavan V, Lian C, Zhang H, Hulver M, Mukherjee K. X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner. Acta Neuropathol Commun. March 31, 2016; 4:30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818453/.
FG syndrome. Genetics Home Reference. December 2012; https://ghr.nlm.nih.gov/condition/fg-syndrome.

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Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Summary

Symptoms

Cause

Organizations

Social Networking Websites

Learn more

Where to Start

In-Depth Information

References

Rare Nephrology & Urology News

Rare Nephrology & Urology News

#N/A

#N/A

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Summary

Symptoms

Cause

Organizations

Social Networking Websites

Learn more

Where to Start

In-Depth Information

References

Rare Nephrology
& Urology News

Rare Nephrology
& Urology News

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.