Megalencephaly: Difference between revisions
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==Prognosis== |
==Prognosis== |
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The prognosis of megalencephaly depends heavily on the underlying cause and assosciated neurological disorders.<ref name=NINDS>{{cite web|last=National Institute of Neurological Disorders and Stroke|title=NINDS Megalencephaly Information|url=http://www.ninds.nih.gov/disorders/megalencephaly/megalencephaly.htm|publisher=National Institute of Health|accessdate=11/03/2013}}</ref> Because the majority of megalencephaly cases are linked with autism, the prognosis is equivalent to the corresponding condition. |
The prognosis of megalencephaly depends heavily on the underlying cause and assosciated neurological disorders.<ref name=NINDS>{{cite web|last=National Institute of Neurological Disorders and Stroke|title=NINDS Megalencephaly Information|url=http://www.ninds.nih.gov/disorders/megalencephaly/megalencephaly.htm|publisher=National Institute of Health|accessdate=11/03/2013}}</ref> Because the majority of megalencephaly cases are linked with autism, the prognosis is equivalent to the corresponding condition. |
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Since, hemimegalencephaly is associated with severe seizures, [[hemiparesis]] and mental retardation and therefore has a poor prognosis. In most cases, those diagnosed with this type of megalencephaly usually do not survive through adulthood.<ref>{{cite |
Since, hemimegalencephaly is associated with severe seizures, [[hemiparesis]] and mental retardation and therefore has a poor prognosis. In most cases, those diagnosed with this type of megalencephaly usually do not survive through adulthood.<ref>{{cite journal|last=Nakahashi|first=M|coauthors=Sato, Yagishita, Ota, Saito, Sugai, Sasaki, Natsume, Tsushima, Amanuma, Endo|title=Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia|journal=Neuroradiology|year=2009|month=December|series=51|issue=12|pages=821-30|doi=10.1007/s00234-009-0579-7|pmid=19672585}}</ref> |
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===Future Research=== |
===Future Research=== |
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Revision as of 03:20, 26 November 2013
| Megalencephaly | |
|---|---|
| Specialty | Medical genetics, neurology, pediatrics  |
Megalencephaly (or Macrencephaly abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain that has an average weight greater than 2.5 standard deviations.[1] Megalencephaly is usually diagnosed at birth and is confirmed with an MRI. A mutation in the PI3K-AKT pathway is believed to be the primary cause of brain proliferation. This mutation has produced a classification of brain over-development that consists of two syndromes including, megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH).[2] Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly.[3] There are several neuropsychiatric disorders linked with megalencephaly, however studies have shown that autism is the most prevalent association with the malformation.[4] Although no treatment currently exists for megalencephaly, management methods are focused at reducing deficits linked with autism. Most recent research is targeted at creating inhibitors to reduce the mutational pathway.[5]
History
It is believed that megalencephaly was discovered in 1972 by neurologist in Indianapolis. Prior to diagnoses using an MRI to confirm brain overgrowth, cases of megalencephaly were diagnosed by autopsy in which the physical brain was measured and weighed.[5]
Classification
Macrocephaly
Macrocephaly is a term used to define a person who has an abnormally large head. The circumference of the head must be above the the 95th percentile or at least 2.5 standard deviations from the mean of normal weight and gender groups in the United States.[1][6] A person with macrocephaly does not necessarily indicate that megalencephaly is also present. In many cases many individuals with macrocephaly exhibit no neurodevelopment problems at all.
Hemimegalencephaly
Hemimegalencephaly is an extremely rare form of macrocephaly that is characterized by uneven development of brain hemispheres (one-half of brain is larger than other).[7] The syndrome can be presented by itself or in association with phakomatosis or hemigigantism. Additionally, hemimegalencephaly frequently will cause severe epilepsy, focal neuro-logical deficits, macrocrania, and mild to severe mental retardation.[8]
MCAP
Megalencephaly-capillary (MCAP) is one of the two major syndromes of megalencephaly. Typically MCAP and MPPH can be distinguished by somatic fatures.[9] MCAP includes many characteristics that are observed at birth including: cutaneous vascular malformations, especially capillary malformations of the face and cutis marmorata, polydactyly, connective tissue dysplasia, and focal or segmental body overgrowth.[10] Furthermore, MCAP can occassionally be linked with asymmetric brain overgrowth (hemimegalencephaly) as well as segmental overgrowth of the body (hemihypertrophy).[2]
MPPH
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) is one of the two major syndromes contributing to megalencephaly. Typically MCAP and MPPH can be distinguished by somatic fatures.[9] In differentiation to MCAP, MPPH lacks Lacks consistent somatic features other than postaxial polydactly.[10] Furthermore, brain and body development is normally symmetric in the majority of patients that appear to have MPPH symptoms.[2]
Causes
Although still very little is known as to the direct cause of megalencephaly, recent studies have begun to provide early indications of possible sources for its formation. Recent research studies have shown that there is a strong link between genetic pathways that cause brain develop and mutations in that pathway that cause and overgrowth.
PI3K-AKT
Recent studies have shown that mutations in phosphoinositide 3-kinase (PI3K) and AKT (also known as protein kinase B) pathway have been identified in MCAP and MPPH. This pathway has proven to be an integral part of brain growth and development and is an area of interest to many researchers who study the cause of megalencephaly. Mutations in this pathway have been shown to cause a gain of function an activation of the PI3K-AKT pathway.[11] This cellular pathway is critical in the regulation of diverse cell functions including, cell growth, proliferation, metabolism, survival, apoptosis, angiogenesis, tumorigenesis and most importantly in regards to megalencephaly, brain development.[12] AKT is an crucial signaling molecule part of the PI3K pathway and is also involved in many cellular functions. These include, brain development, synaptic plasticity and neurodevelopment. Loss of function in AKT can cause microcephaly in humans while inactivation of the pathway can cause hemimegalencephaly.[2] There are also several cancers linked to mutations in the AKT pathway including melanoma and lung cancer [2][13][14]
Pur-alpha
Pur-alpha (purα) is a sequence-specific singl-stranded DNA and RNA-binding protein. Studies have shown that the protein is primarily active during early development and is believed to have a role in brain enlargement.[15] Although the exact function is still controversial, it is believed that pur-alpha is responsible for neuronal proliferation as well as maturation of dendrites.[16] Thus, pur-alpha is also considered a potential root cause of megalencephaly and brain overgrowth.
Pathophysiology
One impact of megalencephaly is the complete lack of motor development. One medical study was assessed three patients presenting megalcenphaly who showed severely impaired motor and speech development as well as distinct facial abnormalities including skull bossing, a low nasal bridge and large eyes.[17]
Management
Diagnoses
Diagnoses of megalencephaly have changed over the years, however the development of more advanced equipment, physicians have been able to confirm the disorder with better accuracy. A physical exam is performed first when characteristics of megalencephaly have appeared, usually at birth or during early child development. A physician will take head measurements in order to determine the circumference. This is known as the head circumference.[6] Then a family background will be recorded in order to determine if there was a history of megalencephaly in the family.[18]
A neurological exam will then be performed using the technology of an MRI machine to confirm the diagnosis of megalencephaly. These imaging tests give detailed information regarding brain size, volume asymmetry and other irregular developments linked with MCAP, MPPH and hemimegalencephaly.[1][18]
There is also a strong correlation of Epilepsy and megalencephaly and can aid doctors in their diagnosis.[17]
If a diagnosis of megalencephaly is confirmed, the child is referred to a specialist who focuses on managing the symptoms and improving the lifestyle. Since megalencephaly is usually presented with autism, the goal of treatment is to improve deffeciencies associated with autistic causes. Addtionally, since each patient has unqiue symptoms, there is no one unique treatment method and therefore is heavily reliant on symptoms specific to an individual.
Treatment
There is currently no specific treatment for megalencephaly, however periodic head measurements may be assessed to determine the rate of brain growth. Those that develop neurological disorders may be prescribed anti-epileptic drugs for seizures.[1] Studies have shown that reducing epilepsy can increase cell apoptosis and reduce the proliferation of neurons that leads to brain overgrowth.[19]
Prevention
Since there are very few treatment methods focused on managing megalencephaly, future research is targeted at inhibiting mutation of pathway. This process could cause problems as understanding the underlying mechanism of the mutations is a poorly understood topic. The genetic coding that initiates a single mutation is sporadic and patterns are hard to detect in many cases.[5] Even thought very little research has been done on create inhibitors of the PI3K-AKT pathway, several pharmaceutical companies have begun to focus their interests in designing a prevention method for this purpose.[5]
Prognosis
The prognosis of megalencephaly depends heavily on the underlying cause and assosciated neurological disorders.[18] Because the majority of megalencephaly cases are linked with autism, the prognosis is equivalent to the corresponding condition. Since, hemimegalencephaly is associated with severe seizures, hemiparesis and mental retardation and therefore has a poor prognosis. In most cases, those diagnosed with this type of megalencephaly usually do not survive through adulthood.[20]
Future Research
Future research is targeted at further understanding mutations and how they lead to MCAP and MPPH. The majority of studies of megalencephaly have included mice who present brain abnormalities and overgrowth. The next step is to move to clinical trials involving humans in order determine the exact genetic mutation causing sequences. Additionally, scientists and pharmaceutical companies have began to show interest in mutation inhibition and designing preventative methods eliminate the underlying cause of megalencephaly altogether.[5]
Epidemiology
Approximately one out of every 50 (2%) children in the general population are said to have megalencephaly.[3] Additionally, it is said that megalencephaly affects 3-4 times more than females. Those individuals that are classified with macrocephaly, or general head overgrowth, are said to have megalencephaly at a rate of 10-30% of the time.
Autism
There is an extremely high association between megalencephaly and autism Approximately 20% of autistic children have megalencephaly, with megalencephaly being the most common physical characteristic of autism.[5] Patients that present both megalencephaly and autistic characteristics usually also show signs of hyperactivity as a major symptom. However, there is no definitive evidence that autism is a primary cause/result of megalencephaly. This is because megalencephaly has also been describe in other neurodevelopmental disorders such as schizophrenia or Alzheimers.[4]
Since most children with megalencephaly also have autism, the majority of treatment is focused on managing the signs and issues caused by autism.
References
- ^ a b c d Cardeiro, Dawn. "Megalencephaly". Yahoo Health. Retrieved 11/3/2013.
{{cite web}}: Check date values in:|accessdate=(help) - ^ a b c d e Mirzaa, G (1). "Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP". American Journal Of Medical Genetics, Part C: Seminars In Medical Genetics. 163 (2): 122–30. doi:10.1002/ajmg.c.31361. PMID 23592320.
{{cite journal}}:|access-date=requires|url=(help); Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Sandler, A (1997). "Neurodevelopmental dysfunction among nonreferred children with idiopathic megalencephaly". Journal of Pediatrics. 131 (2): 320–4. doi:10.1016/S0022-3476(97)70176-8. PMID 9290626.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Ghaziuddin, M (1999). "Is Megalencephaly specific to autism?". Journal of Intellectual Disability Research. 43 (4): 279–82. doi:10.1046/j.1365-2788.1999.00211.x. PMID 10466865.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e f Interview with Dr. Ghayda Mirzaa (October 1st, 2013)
- ^ a b Daymont, C (23). "The test characteristics of head circumference measurements for pathology associated with head enlargement: a retrospective cohort study". BMC Pediatrics. 12 (9). doi:10.1186/1471-2431-12-9. PMID 22269214.
{{cite journal}}:|access-date=requires|url=(help); Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)CS1 maint: unflagged free DOI (link) - ^ Johns Hopkins Medicine, Neurology and Neurosurgery. "Hemimegalencephaly".
- ^ Di Rocco, C (2006). "Hemimegalencephaly: clinical implications and surgical treatment". Child's Nevous System. 22 (8): 852–866. doi:10.1007/s00381-006-0149-9. PMID 16821075.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Mirzaa, Ghayda (2012). "Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis". American Journal of Medical Genetics. 158A (2): 269–91. doi:10.1002/ajmg.a.34402. PMID 22228622.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Nakamura, K (10). "AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH". Clinical Genetics. doi:10.1111/cge.12188. PMID 23745724.
{{cite journal}}:|access-date=requires|url=(help); Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Fam, H (2012). "Caught in the AKT: identification of a de novo pathway in MCAP and MPPH and its therapeutic implications". Clinical Genetics. 82 (6): 521–2. doi:10.1111/cge.12003. PMID 22989095.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Engelman, J (2009). "Targeting PI3K signalling in cancer: opportunities, challenges and limitations". Nature Reviews Cancer. 9 (8): 550–62. doi:10.1038/nrc2664. PMID 19629070.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Riviere, J (24). "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes". Nat Genet. 44 (8): 934–40. doi:10.1038/ng.2331. PMID 22729224.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Stahl, J (1). "Deregulated Akt3 activity promotes development of malignant melanoma". Cancer Research. 64 (19): 7002–10. doi:10.1158/0008-5472. PMID 15466193.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Hokkanen, S (1). "Lack of Pur-alpha alters postnatal brain development and causes megalencephaly". Human Molecular Genetics. 21 (3): 473–84. doi:10.1093/hmg/ddr476. PMID 22010047.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Khalili, K (2003). "Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse". Molecular Cell Biology. 23 (19): 6857–75. doi:10.1128/MCB.23.19.6857-6875.2003. PMID 12972605.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Hengst, M (2010). "Megalencephaly, mega corpus callosum, and complete lack of motor development: Delineation of a rare syndrome". American Hournal of Medical Genetics Part A. 152A (9): 2360–4. doi:10.1002/ajmg.a.33577. PMID 20803648.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c National Institute of Neurological Disorders and Stroke. "NINDS Megalencephaly Information". National Institute of Health. Retrieved 11/03/2013.
{{cite web}}: Check date values in:|accessdate=(help) - ^ Almgren, M (2008). "Idiopathic megalencephaly-possible cause and treatment opportunities: from patient to lab". European Journal of Pediatrics. 12 (6): 438–45. doi:10.1016/j.ejpn.2007.11.008. PMID 18242108.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Nakahashi, M (2009). "Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia". Neuroradiology. 51 (12): 821–30. doi:10.1007/s00234-009-0579-7. PMID 19672585.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help)