Alexander disease

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Alexander disease
Alexander autopsy.jpg
Brain of a 4-year-old boy with Alexander disease showing macroencephaly and periventricular leukomalacia (note brownish discoloration around the cerebral ventricles)
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Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins during the first two years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size and seizures. The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of Parkinson's disease or multiple sclerosis, or may present primarily as a psychiatric disorder.

Contents

According to the National Institute of Neurological Disorders and Stroke, the destruction of white matter is accompanied by the formation of Rosenthal fibers—abnormal clumps of protein that accumulate in astrocytes in the brain.

The disease occurs in both males and females, and no ethnic, racial, geographic or cultural/economic differences are seen in its distribution. Alexander disease is a progressive and often fatal disease. [1]

Presentation

Delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head (macrocephaly), seizures, spasticity, and in some cases also hydrocephalus, idiopathic intracranial hypertension, and dementia. [2]

In cases of early-onset or neonatal Alexander disease, symptoms include seizures, fluid buildup in the brain, high protein levels in cerebrospinal fluid, and severe motor and intellectual impairment. In cases of type I Alexander disease, where the condition appears before age 4, symptoms include seizures, enlarged brain and head, stiffness in the limbs, delayed intellectual and physical development, recurrent vomiting, and difficulties with gaining weight. In cases of type II Alexander disease, where the condition appears after the age of 4, symptoms include speech problems, difficulty swallowing, poor coordination, scoliosis, recurrent vomiting, and difficulties with gaining weight. [3]

Cause

Alexander disease is a genetic disorder affecting the midbrain and cerebellum of the central nervous system. It is caused by mutations in the gene for glial fibrillary acidic protein (GFAP) [4] [5] [6] that maps to chromosome 17q21. It is inherited in an autosomal dominant manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is heterozygotic. However, most cases arise de novo as the result of sporadic mutations. [2]

Alexander disease belongs to leukodystrophies, a group of diseases that affect the growth or development of the myelin sheath. The destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers. [2] [7] [8] Rosenthal fibers appear not to be present in healthy people, [7] [9] but occur in specific diseases, like some forms of cancer, Alzheimer's, Parkinson's, Huntington's, and ALS. [7] [9] [10] The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders. [7]

Pathology

Alexander disease causes the gradual loss of bodily functions and the ability to talk. It also causes an overload of long-chain fatty acids in the brain, which destroy the myelin sheath. The cause of Alexander disease is a mutation in the gene encoding GFAP. [2] [7] [4] [5] [11] [10] [ excessive citations ]

A CT scan shows:

Diagnosis

Detecting the signs of Alexander disease is possible with magnetic resonance imaging (MRI), which looks for specific changes in the brain that may be tell-tale signs for the disease. [12] [13] It is even possible to detect adult-onset Alexander disease with MRI. [11] Alexander disease may also be revealed by genetic testing for its known cause. [14] [15] A rough diagnosis may also be made through revealing of clinical symptoms, including enlarged head size, along with radiological studies, and negative tests for other leukodystrophies. [9]

Treatment

No cure or standard procedure for treatment is known, although a University of Wisconsin study shows promise with gene editing of the astrocytes. [2] [7] [10] A phase III clinical trial of an antisense therapy, sponsored by Ionis Pharmaceuticals, began in 2021. [16] A bone marrow transplant has been attempted on a child, but it made no improvement. [17] [18] Hydrocephalus may be seen in younger patients and can be relieved with surgery or by implanting a shunt to relieve pressure. [19]

Prognosis

The prognosis is generally poor. With early onset, death usually occurs within 10 years from the onset of symptoms. Individuals with the infantile form usually die before the age of seven. [20] Usually, the later the disease occurs, the slower its course. [2] [7]

Prevalence

Its occurrence is very rare. The infantile form occurs from birth to two years of age. [6] The average duration of the infantile form is usually about three years. Onset of the juvenile form presents between 2 and 12 years of age. [6] Duration of this form is in most cases about six years. The adult form occurs after 12 years. [6] In younger patients, seizures, megalencephaly, developmental delay, and spasticity are usually present. Neonatal onset is also reported. [21] Onset in adults is least frequent. In older patients, bulbar or pseudobulbar symptoms and spasticity predominate. Symptoms of the adult form may also resemble multiple sclerosis. [2] No more than 500 cases have been reported. [2]

See also

Related Research Articles

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<span class="mw-page-title-main">Glial fibrillary acidic protein</span> Type III intermediate filament protein

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<span class="mw-page-title-main">Leukodystrophy</span> Group of disorders characterised by degeneration of white matter in the brain

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<span class="mw-page-title-main">GLUT1 deficiency</span> Medical condition


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<span class="mw-page-title-main">Central nervous system disease</span> Disease of the brain or spinal cord

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<span class="mw-page-title-main">Hereditary diffuse leukoencephalopathy with spheroids</span> Medical condition

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths. It is believed that the disease arises from primary microglial dysfunction that leads to secondary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases. In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development, although genetic deficits suggest that demyelination and axonal pathology may be secondary to microglial dysfunction. The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

<span class="mw-page-title-main">Spongy degeneration of the central nervous system</span> Neurodegenerative disorder

Spongy degeneration of the central nervous system, also known as Canavan's disease, Van Bogaert-Bertrand type or Aspartoacylase (AspA) deficiency, is a rare autosomal recessive neurodegenerative disorder. It belongs to a group of genetic disorders known as leukodystrophies, where the growth and maintenance of myelin sheath in the central nervous system (CNS) are impaired. There are three types of spongy degeneration: infantile, congenital and juvenile, with juvenile being the most severe type. Common symptoms in infants include lack of motor skills, weak muscle tone, and macrocephaly. It may also be accompanied by difficulties in feeding and swallowing, seizures and sleep disturbances. Affected children typically die before the age of 10, but life expectancy can vary.

<span class="mw-page-title-main">Hypomyelination-congenital cataract syndrome</span> Medical condition

Hypomyelination-congenital cataract syndrome is a rare autosomal recessive hereditary disorder that affects the brain's white matter and is characterized by congenital cataract, psychomotor development delays, and moderate intellectual disabilities. It is a type of leukoencephalopathy.

<span class="mw-page-title-main">Autosomal dominant leukodystrophy with autonomic disease</span> Medical condition

Autosomal dominant leukodystrophy with autonomic disease is a rare neurological condition of genetic origin which is characterized by gradual demyelination of the central nervous system which results in various impairments, including ataxia, mild cognitive disability and autonomic dysfunction. It is part of a group of disorders called "leukodystrophies".

References

  1. ↑ "Alexander Disease Information Page". National Institute of Neurological Disorders and Stroke. 2018.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  2. 1 2 3 4 5 6 7 8 Srivastava, Siddharth; Waldman, Amy; Naidu, Sakkubai (July 25, 1993). "Alexander Disease". In Adam, Margaret P.; Mirzaa, Ghayda M.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora JH; Gripp, Karen W.; Amemiya, Anne (eds.). GeneReviews®. University of Washington, Seattle. PMID   20301351 – via PubMed.
  3. ↑ "Alexander Disease". Children's Hospital of Philadelphia. 21 December 2017. Retrieved 23 February 2023.
  4. 1 2 Li R, Messing A, Goldman JE, Brenner M (2002). "GFAP mutations in Alexander disease". Int. J. Dev. Neurosci. 20 (3–5): 259–68. doi:10.1016/s0736-5748(02)00019-9. PMID   12175861. S2CID   13541342.
  5. 1 2 Quinlan RA, Brenner M, Goldman JE, Messing A (June 2007). "GFAP and its role in Alexander disease". Exp. Cell Res. 313 (10): 2077–87. doi:10.1016/j.yexcr.2007.04.004. PMC   2702672 . PMID   17498694.
  6. 1 2 3 4 Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE (April 2012). "Alexander disease". J. Neurosci. 32 (15): 5017–23. doi:10.1523/JNEUROSCI.5384-11.2012. PMC   3336214 . PMID   22496548.
  7. 1 2 3 4 5 6 7 Alexander Disease at NINDS
  8. ↑ "Cause of brain disease found". January 2, 2001 – via news.bbc.co.uk.
  9. 1 2 3 "Alexander Disease - United Leukodystrophy Foundation". Archived from the original on 2010-04-28. Retrieved 2010-06-14.
  10. 1 2 3 "Mutation in common protein triggers tangles, chaos inside brain cells". news.wisc.edu. Retrieved 2018-11-16.
  11. 1 2 Farina L, Pareyson D, Minati L, et al. (June 2008). "Can MR imaging diagnose adult-onset Alexander disease?". AJNR Am J Neuroradiol. 29 (6): 1190–6. doi: 10.3174/ajnr.A1060 . PMC   8118843 . PMID   18388212.
  12. ↑ Labauge P (June 2009). "Magnetic resonance findings in leucodystrophies and MS". Int MS J. 16 (2): 47–56. PMID   19671368.
  13. ↑ van der Knaap MS, Naidu S, Breiter SN, et al. (March 2001). "Alexander disease: diagnosis with MR imaging". AJNR Am J Neuroradiol. 22 (3): 541–52. PMC   7976831 . PMID   11237983.
  14. ↑ Johnson AB (2002). "Alexander disease: a review and the gene". Int. J. Dev. Neurosci. 20 (3–5): 391–4. doi:10.1016/S0736-5748(02)00045-X. PMID   12175878. S2CID   12408421.
  15. ↑ Sawaishi, Y (August 2009). "Review of Alexander disease: beyond the classical concept of leukodystrophy". Brain Dev. 31 (7): 493–8. doi:10.1016/j.braindev.2009.03.006. PMID   19386454. S2CID   206312570.
  16. ↑ "A Study to Evaluate the Safety and Efficacy of ION373 in Patients With Alexander Disease (AxD)". clinicaltrials.gov. U.S. National Library of Medicine ClinicalTrials.gov. Retrieved 2021-12-08.
  17. ↑ Staba MJ, Goldman S, Johnson FL, Huttenlocher PR (August 1997). "Allogeneic bone marrow transplantation for Alexander's disease". Bone Marrow Transplant. 20 (3): 247–9. doi: 10.1038/sj.bmt.1700871 . PMID   9257894.
  18. ↑ Messing A, LaPash Daniels CM, Hagemann TL (October 2010). "Strategies for treatment in Alexander disease". Neurotherapeutics. 7 (4): 507–15. doi:10.1016/j.nurt.2010.05.013. PMC   2948554 . PMID   20880512.
  19. ↑ "Alexander Disease - United Leukodystrophy Foundation United Leukodystrophy Foundation". ulf.org. 2 February 2016. Retrieved 2016-11-08.
  20. ↑ "Alexander Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". www.ninds.nih.gov. Archived from the original on 2012-05-14. Retrieved 2016-11-03.
  21. ↑ Singh N, Bixby C, Etienne D, Tubbs RS, Loukas M (December 2012). "Alexander's disease: reassessment of a neonatal form". Childs Nerv Syst. 28 (12): 2029–31. doi:10.1007/s00381-012-1868-8. PMID   22890470. S2CID   5851209.
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