U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Alexander disease(ALXDRD)

MedGen UID:
78724
Concept ID:
C0270726
Disease or Syndrome
Synonyms: Alexander's disease; Alexanders leukodystrophy; ALXDRD; Megalencephaly in infancy accompanied by progressive spasticity and dementia
SNOMED CT: Alexander disease (81854007); Alexander's disease (81854007); Fibrinoid leukodystrophy (81854007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): GFAP (17q21.31)
 
Monarch Initiative: MONDO:0008752
OMIM®: 203450
Orphanet: ORPHA58

Disease characteristics

Excerpted from the GeneReview: Alexander Disease
Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous GFAP pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult. The neonatal form begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years. The infantile form is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form. The juvenile form typically presents in childhood or adolescence with clinical and imaging features that overlap with the other forms. Manifestations in early childhood are milder than those in the infantile form (e.g., mild language delay may be the only developmental abnormality or, with language acquisition, hypophonia or nasal speech may alter the voice, often prior to appearance of other neurologic features). Vomiting and failure to thrive as well as scoliosis and autonomic dysfunction are common. The adult form is typically characterized by bulbar or pseudobulbar findings (palatal myoclonus, dysphagia, dysphonia, dysarthria or slurred speech), motor/gait abnormalities with pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign), or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). Others may have hemiparesis or hemiplegia with a relapsing/remitting course or slowly progressive quadriparesis or quadriplegia. Other neurologic features can include sleep apnea, diplopia or disorders of extraocular motility, and autonomic dysfunction. [from GeneReviews]
Authors:
Siddharth Srivastava  |  Amy Waldman  |  Sakkubai Naidu   view full author information

Additional descriptions

From OMIM
In decreasing order of frequency, 3 forms of Alexander disease (ALXDRD) are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (Gorospe et al., 2002). All 3 forms have been shown to be caused by mutations in the GFAP gene.  http://www.omim.org/entry/203450
From MedlinePlus Genetics
Alexander disease is a rare disorder of the nervous system. It is one of a group of disorders, called leukodystrophies, that involve the destruction of myelin. Myelin is the fatty covering that insulates nerve fibers and promotes the rapid transmission of nerve impulses. If myelin is not properly maintained, the transmission of nerve impulses could be disrupted. As myelin deteriorates in leukodystrophies such as Alexander disease, nervous system functions are impaired.

Most cases of Alexander disease begin before age 2 and are described as the infantile form. Signs and symptoms of the infantile form typically include an enlarged brain and head size (megalencephaly), seizures, stiffness in the arms and/or legs (spasticity), intellectual disability, and developmental delay. Less frequently, onset occurs later in childhood (the juvenile form) or in adulthood. Common problems in juvenile and adult forms of Alexander disease include speech abnormalities, swallowing difficulties, seizures, and poor coordination (ataxia). Rarely, a neonatal form of Alexander disease occurs within the first month of life and is associated with severe intellectual disability and developmental delay, a buildup of fluid in the brain (hydrocephalus), and seizures.

Alexander disease is also characterized by abnormal protein deposits known as Rosenthal fibers. These deposits are found in specialized cells called astroglial cells, which support and nourish other cells in the brain and spinal cord (central nervous system).  https://medlineplus.gov/genetics/condition/alexander-disease

Clinical features

From HPO
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Drowsiness
MedGen UID:
4390
Concept ID:
C0013144
Finding
Abnormal feeling of sleepiness or difficulty staying awake.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Palatal tremor
MedGen UID:
45286
Concept ID:
C0030214
Sign or Symptom
Palatal tremor (PT) is an involuntary, rhythmic and oscillatory movement of the soft palate. PT is a rare type of tremor involving the soft palate. It can be unilateral or bilateral.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
Apathy is a quantitative reduction of motivation and the initiation and persistence of goal-directed behavior, where the accompanying emotions, thoughts, and social interactions are also suppressed.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Bulbar signs
MedGen UID:
347246
Concept ID:
C1856507
Finding
Abnormal dentate nucleus morphology
MedGen UID:
867758
Concept ID:
C4022148
Anatomical Abnormality
An abnormality of the dentate nucleus.
Diffuse demyelination of the cerebral white matter
MedGen UID:
870483
Concept ID:
C4024930
Anatomical Abnormality
A diffuse loss of myelin from nerve fibers in the central nervous system.
Progressive macrocephaly
MedGen UID:
395368
Concept ID:
C1859896
Finding
The progressive development of an abnormally large skull.
Pendular nystagmus
MedGen UID:
78770
Concept ID:
C0271388
Disease or Syndrome
Rhythmic, involuntary sinusoidal oscillations of one or both eyes. The waveform of pendular nystagmus may occur in any direction.
Microcoria
MedGen UID:
1372399
Concept ID:
C4476808
Anatomical Abnormality
A small pupil (typically diameter less than 2 mm) that dilates poorly or not at all in response to topically administered mydriatic drugs.

Term Hierarchy

Professional guidelines

PubMed

Holm A, Hansen SN, Klitgaard H, Kauppinen S
RNA Biol 2022;19(1):594-608. Epub 2021 Dec 31 doi: 10.1080/15476286.2022.2066334. PMID: 35482908Free PMC Article
Hagemann TL, Powers B, Mazur C, Kim A, Wheeler S, Hung G, Swayze E, Messing A
Ann Neurol 2018 Jan;83(1):27-39. Epub 2018 Jan 14 doi: 10.1002/ana.25118. PMID: 29226998Free PMC Article
Messing A, LaPash Daniels CM, Hagemann TL
Neurotherapeutics 2010 Oct;7(4):507-15. doi: 10.1016/j.nurt.2010.05.013. PMID: 20880512Free PMC Article

Curated

Leukodystrophies in Children: Diagnosis, Care, and Treatment, Pediatrics (2021) 148 (3): e2021053126.

Recent clinical studies

Etiology

Zheng X, Yang J, Hou Y, Shi X, Liu K
Eur J Med Res 2024 Jan 12;29(1):51. doi: 10.1186/s40001-023-01631-4. PMID: 38216970Free PMC Article
Holm A, Hansen SN, Klitgaard H, Kauppinen S
RNA Biol 2022;19(1):594-608. Epub 2021 Dec 31 doi: 10.1080/15476286.2022.2066334. PMID: 35482908Free PMC Article
Sabitha KR, Shetty AK, Upadhya D
Neurosci Biobehav Rev 2021 Feb;121:201-219. Epub 2020 Dec 25 doi: 10.1016/j.neubiorev.2020.12.025. PMID: 33370574Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242

Diagnosis

Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Resende LL, de Paiva ARB, Kok F, da Costa Leite C, Lucato LT
Radiographics 2019 Jan-Feb;39(1):153-168. doi: 10.1148/rg.2019180081. PMID: 30620693
Messing A
Handb Clin Neurol 2018;148:693-700. doi: 10.1016/B978-0-444-64076-5.00044-2. PMID: 29478608
Tavasoli A, Armangue T, Ho CY, Whitehead M, Bornhorst M, Rhee J, Hwang EI, Wells EM, Packer R, van der Knaap MS, Bugiani M, Vanderver A
J Child Neurol 2017 Feb;32(2):184-187. Epub 2016 Oct 10 doi: 10.1177/0883073816673263. PMID: 28112050
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242

Therapy

Schoenmakers DH, Leferink PS, Vanderver A, Bonkowsky JL, Krägeloh-Mann I, Bernard G, Bertini E, Fatemi A, Fogel BL, Wolf NI, Skwirut D, Buck A, Holberg B, Saunier-Vivar EF, Rauner R, Dekker H, van Bokhoven P, Stellingwerff MD, Berkhof J, van der Knaap MS
BMC Neurol 2023 Aug 17;23(1):305. doi: 10.1186/s12883-023-03354-9. PMID: 37592248Free PMC Article
Holm A, Hansen SN, Klitgaard H, Kauppinen S
RNA Biol 2022;19(1):594-608. Epub 2021 Dec 31 doi: 10.1080/15476286.2022.2066334. PMID: 35482908Free PMC Article
Olivera-Bravo S, Isasi E, Fernández A, Casanova G, Rosillo JC, Barbeito L
Adv Exp Med Biol 2016;949:227-243. doi: 10.1007/978-3-319-40764-7_11. PMID: 27714692
Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, Almass R, Al-Harazi OS, Al-Hindi H, Malibari OI, Almutari FB, Tulbah S, Alhadeq F, Al-Sheddi T, Alamro R, AlAsmari A, Almuntashri M, Alshaalan H, Al-Mohanna FA, Colak D, Kaya N
J Med Genet 2015 Mar;52(3):186-94. Epub 2014 Dec 24 doi: 10.1136/jmedgenet-2014-102592. PMID: 25539947
Kingsley PB, Shah TC, Woldenberg R
NMR Biomed 2006 Jun;19(4):435-62. doi: 10.1002/nbm.1039. PMID: 16763970

Prognosis

Zheng X, Yang J, Hou Y, Shi X, Liu K
Eur J Med Res 2024 Jan 12;29(1):51. doi: 10.1186/s40001-023-01631-4. PMID: 38216970Free PMC Article
Vaia Y, Mura E, Tonduti D
Mol Genet Metab 2023 Mar;138(3):107540. Epub 2023 Feb 10 doi: 10.1016/j.ymgme.2023.107540. PMID: 36804850
Rodriguez D
Handb Clin Neurol 2013;113:1619-28. doi: 10.1016/B978-0-444-59565-2.00030-7. PMID: 23622383
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242
Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K, Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A, Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A
Neurology 2011 Sep 27;77(13):1287-94. Epub 2011 Sep 14 doi: 10.1212/WNL.0b013e3182309f72. PMID: 21917775Free PMC Article

Clinical prediction guides

Adang LA, Sevagamoorthy A, Sherbini O, Fraser JL, Bonkowsky JL, Gavazzi F, D'Aiello R, Modesti NB, Yu E, Mutua S, Kotes E, Shults J, Vincent A, Emrick LT, Keller S, Van Haren KP, Woidill S, Barcelos I, Pizzino A, Schmidt JL, Eichler F, Fatemi A, Vanderver A
Mol Genet Metab 2024 May;142(1):108453. Epub 2024 Mar 18 doi: 10.1016/j.ymgme.2024.108453. PMID: 38522179Free PMC Article
Zarekiani P, Breur M, Wolf NI, de Vries HE, van der Knaap MS, Bugiani M
Acta Neuropathol Commun 2021 Jun 3;9(1):103. doi: 10.1186/s40478-021-01206-6. PMID: 34082828Free PMC Article
Resende LL, de Paiva ARB, Kok F, da Costa Leite C, Lucato LT
Radiographics 2019 Jan-Feb;39(1):153-168. doi: 10.1148/rg.2019180081. PMID: 30620693
Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K, Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A, Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A
Neurology 2011 Sep 27;77(13):1287-94. Epub 2011 Sep 14 doi: 10.1212/WNL.0b013e3182309f72. PMID: 21917775Free PMC Article
Namekawa M, Takiyama Y, Honda J, Shimazaki H, Sakoe K, Nakano I
BMC Neurol 2010 Apr 1;10:21. doi: 10.1186/1471-2377-10-21. PMID: 20359319Free PMC Article

Recent systematic reviews

Balbi P, Salvini S, Fundarò C, Frazzitta G, Maestri R, Mosah D, Uggetti C, Sechi G
J Neurol 2010 Dec;257(12):1955-62. Epub 2010 Aug 20 doi: 10.1007/s00415-010-5706-1. PMID: 20721574

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • AAP, 2021
      Leukodystrophies in Children: Diagnosis, Care, and Treatment, Pediatrics (2021) 148 (3): e2021053126.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...