National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Alexander disease

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Other Names:
Alexanders leukodystrophy; Megalencephaly in infancy accompanied by progressive spasticity and dementia
Categories:
This disease is grouped under:
Alexander disease is a type of leukodystrophy characterized by the destruction of  the myelin sheath (the fatty covering that acts as an insulator around nerve fiber) and abnormal protein deposits known as Rosenthal fibers. Most cases of Alexander disease begin before age 2 years (the infantile form). Symptoms of the infantile form include an enlarged brain and head, seizures, stiffness in the arms and/or legs, intellectual disability, and delayed physical development. Less frequently, onset occurs later in childhood (the juvenile form) or adulthood. Common problems in juvenile and adult forms of Alexander disease include speech abnormalities, swallowing difficulties, and poor coordination.[1][2] Alexander disease is caused by mutations in the GFAP gene. While this condition is inherited in an autosomal dominant fashion, most cases result from new mutations in the gene.[1]
Last updated: 12/29/2015
The symptoms of Alexander disease vary depending on the form of the condition (neonatal, infantile, juvenile, and adult). Even within the different forms there may be huge differences in respect to symptoms and severity:[3][2][4][1]
  • Neonatal form - Leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability.
  • Infantile form - The most common type of Alexander disease. It has an onset during the first two years of life. Usually there are both mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size, and seizures.
  • Juvenile form - Less common and has an onset between the ages of two and thirteen. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.
  • Adult form - Rare and is generally the most mild. Onset can be anywhere from the late teens to very late in life. In some cases the symptoms mimic those of Parkinson disease or multiple sclerosis.

The United Leukodystrophy Foundation provides additional details related to the symptoms of this condition.

Last updated: 12/29/2015

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.

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Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal pyramidal sign 0007256
Agenesis of corpus callosum 0001274
Clonus 0002169
EEG abnormality 0002353
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Frontal bossing 0002007
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Large face
Big face
0100729
Macrocephaly
Increased size of skull
Large head
Large head circumference
[ more ] 		0000256
Megalencephaly 0001355
Nausea and vomiting 0002017
Scoliosis 0002650
Seizure 0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
30%-79% of people have these symptoms
Ataxia 0001251
Cerebral calcification
Abnormal deposits of calcium in the brain
0002514
Constipation 0002019
Depressivity
Depression
0000716
Diplopia
Double vision
0000651
Dysarthria
Difficulty articulating speech
0001260
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty
[ more ] 		0002015
Dysphasia 0002357
Dysphonia
Inability to produce voice sounds
0001618
Emotional lability
Emotional instability
0000712
Facial palsy
Bell's palsy
0010628
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait
[ more ] 		0001288
Hyperhidrosis
Excessive sweating
Increased sweating
Profuse sweating
Sweating
Sweating profusely
Sweating, increased
[ more ] 		0000975
Hypotension
Low blood pressure
0002615
Hypothermia
Abnormally low body temperature
0002045
Kyphosis
Hunched back
Round back
[ more ] 		0002808
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Ptosis
Drooping upper eyelid
0000508
Recurrent singultus
Recurrent hiccup
0100247
Sleep apnea
Pauses in breathing while sleeping
0010535
Tetraplegia
Paralysis of all four limbs
0002445
Tremor 0001337
5%-29% of people have these symptoms
Abnormal autonomic nervous system physiology 0012332
Aqueductal stenosis 0002410
Bowel incontinence
Loss of bowel control
0002607
Chorea 0002072
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood
[ more ] 		0002376
Diabetes mellitus 0000819
Encephalitis
Brain inflammation
0002383
High palate
Elevated palate
Increased palatal height
[ more ] 		0000218
Hydrocephalus
Too much cerebrospinal fluid in the brain
0000238
Hyperlordosis
Prominent swayback
0003307
Hyperpigmented nevi 0007481
Hypertension 0000822
Hypothyroidism
Underactive thyroid
0000821
Muscular hypotonia
Low or weak muscle tone
0001252
Osteopenia 0000938
Precocious puberty
Early onset of puberty
Early puberty
[ more ] 		0000826
Respiratory insufficiency
Respiratory impairment
0002093
Self-injurious behavior
Self-injurious behaviour
0100716
Short neck
Decreased length of neck
0000470
Sudden cardiac death
Premature sudden cardiac death
0001645
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance 0000006
Bulbar signs 0002483
Diffuse demyelination of the cerebral white matter 0007162
Increased CSF protein 0002922
Infantile onset
Onset in first year of life
Onset in infancy
[ more ] 		0003593
Progressive macrocephaly
Progressively abnormally enlarging cranium
Progressively abnormally enlarging skull
[ more ] 		0004481
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Last updated: 7/1/2020
The disease is caused by changes (mutations in the GFAP gene in about 90% of cases. This gene provides the instructions for making a protein called glial fibrillary acidic protein (GFAP). GFAP is a normal part of the brain, but it is not clear how mutations in the gene cause the disease. In most cases, the mutations are new in the family (de novo) and are not inherited from the parents. A small number of people who are thought to have Alexander disease are not found to have a mutation in the GFAP gene, which suggests that there may be other causes of Alexander disease that have yet to be identified.[1]
Last updated: 1/4/2016
No specific therapy is currently available for Alexander disease. Management is supportive and includes attention to general care, physical and occupational therapy, nutritional requirements, antibiotic treatment for any infection, and antiepileptic drugs (AED) for seizure control.[4]

Physical and occupational therapy and speech therapy may be recommended depending on the specific signs and symptoms present. Physical and occupational therapy may be indicated in people with developmental and language delays.
Last updated: 12/29/2015

Management Guidelines

The prognosis for individuals with Alexander disease is generally poor and typically depends of the specific form. People with the neonatal form usually have the worst prognosis. Most children with the infantile form do not survive past the age of 6. The juvenile and adult forms of the disorder have a slower, more lengthy course. The adult form varies greatly and, in some cases, there are no symptoms.[2]
Last updated: 12/29/2015

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Alexander disease. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Patient Registry

  • A registry supports research by collecting of information about patients that share something in common, such as being diagnosed with Alexander disease. The type of data collected can vary from registry to registry and is based on the goals and purpose of that registry. Some registries collect contact information while others collect more detailed medical information. Learn more about registries.

    Registries for Alexander disease:
    Myelin Disorders Bioregistry Project
     

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.

Organizations Supporting this Disease

Organizations Providing General Support

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

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.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • 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. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Alexander disease. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Alexander disease. Genetics Home Reference. October, 2015; http://ghr.nlm.nih.gov/condition=alexanderdisease. Accessed 10/31/2015.
  2. Alexander disease. National Institute of Neurological Disorders and Stroke (NINDS). October, 22, 2012; http://www.ninds.nih.gov/disorders/alexander_disease/alexander_disease.htm. Accessed 10/31/2015.
  3. Alexander Disease. United Leukodystrophy Foundation. http://ulf.org/alexander-disease#. Accessed 10/31/2015.
  4. Gorospe JR. Alexander Disease. GeneReviews. January 8, 2015; http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alexander. Accessed 10/31/2015.