Rare Pulmonology News

Disease Profile

CASK-Related Disorders

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

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Inheritance

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

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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

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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.

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

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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.

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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.

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Not applicable

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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

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

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

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

  1. Moog U, Uyanik G, Kutsche K. CASK-Related Disorders. GeneReviews. November 26, 2013; https://www.ncbi.nlm.nih.gov/books/NBK169825/.
  2. CASK-related intellectual disability. Genetics Home Reference. March 2014; https://ghr.nlm.nih.gov/condition/cask-related-intellectual-disability.
  3. 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/.
  4. FG syndrome. Genetics Home Reference. December 2012; https://ghr.nlm.nih.gov/condition/fg-syndrome.

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