View source for Megalencephaly

{{Infobox medical condition (new)
| name            = Megalencephaly
| synonyms        = Macrencephaly
| image           = PMC3492204 1750-1172-7-27-3.png
|alt=| caption    = [[Magnetic resonance imaging|MRI]] images showing megalencephaly in four family members who all have [[Macrocephaly|unusually large skull]]s (the family is affected by an [[autosomal recessive]] syndrome caused by a [[Kinesin|KIF7]] mutation that induces [[multiple epiphyseal dysplasia]])<ref>{{cite journal |vauthors=Ali BR, Silhavy JL, Akawi NA, Gleeson JG, Al-Gazali L |title=A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance |journal=Orphanet Journal of Rare Diseases |volume=7 |issue= |pages=27 |date=2012 |pmid=22587682 |pmc=3492204 |doi=10.1186/1750-1172-7-27 |url=https://openi.nlm.nih.gov/detailedresult?img=PMC3492204_1750-1172-7-27-3&query=megalencephaly&lic=by&req=4&npos=38 |doi-access=free }}</ref> 
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| onset           =Congenital
| duration        =Long-term
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'''Megalencephaly''' (or '''macrencephaly'''; abbreviated '''MEG''') is a growth development disorder in which the [[brain]] is abnormally large. It is characterized by a brain with an average weight that is 2.5 [[standard deviations]] above the mean of the general population.<ref name=Striano>{{cite journal|last=Striano|first=P|author2=Federico|title=Mutations in mTOR pathway linked to megalencephaly syndromes|journal=Nature Reviews Neurology|date=October 2012|series=8|issue=10|pages=542–4|doi=10.1038/nrneurol.2012.178|pmid=22907262|volume=8|s2cid=33405738}}</ref> Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly in the general population.<ref name="Sandler">{{cite journal|last=Sandler|first=A|author2=Knudsen|author3=Brown|author4=Christian|date=August 1997|title=Neurodevelopmental dysfunction among nonreferred children with idiopathic megalencephaly.|journal=Journal of Pediatrics|volume=131|issue=2|pages=320–4|doi=10.1016/S0022-3476(97)70176-8|pmid=9290626}}</ref>

A mutation in the [[PI3K/AKT/mTOR pathway|PI3K-AKT pathway]] is believed to be the primary cause of brain proliferation and ultimately the root cause of megalencephaly. This mutation has produced a classification of brain overdevelopment that consists of two syndromes including [[megalencephaly-capillary malformation]] (MCAP) and megalencephaly-[[polydactyly]]-[[polymicrogyria]]-[[hydrocephalus]] (MPPH).<ref name="Mirzaa">{{cite journal|last=Mirzaa|first=G|author2=Riviere, Dobybns|title=Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP.|journal=American Journal of Medical Genetics Part C |date=May 2013|volume=163|issue=2|pages=122–30|doi=10.1002/ajmg.c.31361|pmid=23592320|s2cid=35211056}}</ref> Megalencephaly is usually diagnosed at birth and is confirmed with an [[MRI]].

There are several [[neuropsychiatric disorders]] linked with megalencephaly; however, studies have shown that [[autism]] is the most prevalent association with the malformation of MEG.<ref name="autism">{{cite journal|last=Ghaziuddin|first=M |author2=Zaccagnini |author3=Tsai |author4=Elardo|title=Is Megalencephaly specific to autism?|journal=Journal of Intellectual Disability Research|date=August 1999|volume=43|issue=4|pages=279–82|doi=10.1046/j.1365-2788.1999.00211.x|pmid=10466865|hdl=2027.42/72452 |url=https://deepblue.lib.umich.edu/bitstream/2027.42/72452/1/j.1365-2788.1999.00211.x.pdf|hdl-access=free}}</ref> 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 that causes megalencephaly.<ref name="interview" />

==Classification==

===Macrocephaly===
[[Macrocephaly]] is a term used to refer to a person who has an abnormally large head. The circumference of the head must be above the 97th percentile or at least 2 standard deviations from the mean of normal weight and gender groups, according to the [[World Health Organization]] recommendations.<ref name=Striano /><ref name="Daymont">{{cite journal|last=Daymont|first=C|author2=Zabel M |author3=Feudtner C |author4=Rubin D |title=The test characteristics of head circumference measurements for pathology associated with head enlargement: a retrospective cohort study.|journal=BMC Pediatrics|date=January 2012|volume=12|issue=9|doi=10.1186/1471-2431-12-9|pmid=22269214|pages=9 |pmc=3331824|doi-access=free}}</ref> A person with macrocephaly does not necessarily indicate that megalencephaly is also present. Large skulls usually exhibit no neurodevelopment conditions at all, meaning most individuals with macrocephaly are healthy.{{citation needed|date=December 2020}}

===Hemimegalencephaly===
[[File:OJO-7-43-g005.jpg|thumb|Left-sided [[hemimegalencephaly]] in a person with [[neurofibromatosis]]<ref>{{cite journal |vauthors=Acharya N, Reddy MS, Paulson CT, Prasanna D |title=Cranio-orbital-temporal neurofibromatosis: an uncommon subtype of neurofibromatosis type-1 |journal=Oman Journal of Ophthalmology |volume=7 |issue=1 |pages=43–5 |date=January 2014 |pmid=24799805 |pmc=4008903 |doi=10.4103/0974-620X.127934 |url= |doi-access=free }}</ref>]]
{{Further|Hemimegalencephaly|}}
Hemimegalencephaly is an extremely rare form of macrocephaly and is characterized by uneven development of brain hemispheres (one half of the brain is larger than the other).<ref>{{cite web|last=Johns Hopkins Medicine|first=Neurology and Neurosurgery|title=Hemimegalencephaly|url=http://www.hopkinsmedicine.org/neurology_neurosurgery/specialty_areas/epilepsy/seizures/causes/hemimegalencephaly.html}}</ref> It can present by itself or in association with [[phakomatosis]] or [[hemigigantism]]. Additionally, hemimegalencephaly will frequently cause severe [[epilepsy]], focal neuro-logical deficits, [[macrocrania]], and mild to severe intellectual disability.<ref>{{cite journal|last=Di Rocco|first=C |author2=Battaglia, Pietrini |author3=Piastra, Massimi|title=Hemimegalencephaly: clinical implications and surgical treatment|journal=Child's Nervous System|date=August 2006|volume=22|issue=8|pages=852–866|doi=10.1007/s00381-006-0149-9|pmid=16821075|s2cid=23996880 }}</ref>

=== MCAP ===
Megalencephaly-capillary (MCAP) is one of the two major syndromes of megalencephaly. Typically, MCAP and MPPH can be distinguished by somatic features.<ref name=mirzaa2>{{cite journal|last=Mirzaa|first=Ghayda |author2=Conway |author3=Gripp |author4=Lerman-Sagie |author5=Siegel |author6=deVries |author7=Lev |author8=Kramer |author9=Hopkins |author10=Graham |author11=Dobyns |title=Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis|journal=American Journal of Medical Genetics|date=February 2012|volume=158A|issue=2|pages=269–91|doi=10.1002/ajmg.a.34402|pmid=22228622|doi-access=free }}</ref> 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.<ref name=Nakamura>{{cite journal|last=Nakamura|first=K |author2=Kato |author3=Tohyama |author4=Shiohama |author5=Hayasaka |author6=Nishiyama |author7=Kodera |author8=Nakashima |author9=Tsurusaki |author10=Miyake |author11=Matsumoto |author12=Saitsu |title=AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH|journal=Clinical Genetics|date=June 2013|doi=10.1111/cge.12188|pmid=23745724|volume=85|issue=4 |pages=396–398|s2cid=12057608 }}</ref> Furthermore, MCAP can occasionally be linked with asymmetric brain overgrowth (hemimegalencephaly) as well as segmental overgrowth of the body ([[hemihypertrophy]]).<ref name=Mirzaa />

=== 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 features.<ref name=mirzaa2 /> In differentiation to MCAP, MPPH lacks consistent somatic features other than [[Polydactyly#Types of polydactyly|postaxial polydactyly]].<ref name=Nakamura /> Furthermore, brain and body development is normally symmetric in the majority of patients that appear to have MPPH symptoms.<ref name=Mirzaa />

==Presentation==
[[File:Stoddart 79.jpg|thumb|“[[Imbecile]]” with megalencephaly, head circumference 29 inches]]
===Autism===

There is an extremely high association between megalencephaly and [[autism]]. Approximately 20% of autistic children have megalencephaly, making it the most common physical characteristic of autism.<ref name=interview>Interview with [http://www.seattlechildrens.org/medical-staff/Ghayda-Mirzaa/ Dr. Ghayda Mirzaa] (October 1st, 2013)</ref> People who 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 the primary cause/result of megalencephaly.{{citation needed|date=December 2020}}

Since most children with megalencephaly also have autism, the goal of treatment for MEG is focused on managing the signs and symptoms associated with autism.{{citation needed|date=December 2020}}

===Other associations===
Megalencephaly is also seen in the following conditions:<ref>{{Cite web |title=Megalencephaly (Concept Id: C0221355) |url=https://www.ncbi.nlm.nih.gov/medgen/65141 |access-date=2023-11-05 |website=www.ncbi.nlm.nih.gov |language=en}}</ref>

* [[Achondroplasia]]
* [[Apert syndrome|Acrocephalosyndactyly type I]]
* Chromosome 4Q32.1-q32.2 triplication syndrome
* Craniometadiaphyseal dysplasia wormian bone type
* [[Curry–Jones syndrome|Curry-Jones syndrome]]
* [[Early-onset parkinsonism-intellectual disability syndrome]]
* [[Intellectual disability]], [[Dominance (genetics)|autosomal recessive]] 34
* Macrocephaly, [[Dysmorphic feature|dysmorphic facies]], and [[psychomotor retardation]]
* Macrocephaly-intellectual disability-[[neurodevelopmental disorder]]-small thorax syndrome
* Macrocephaly/megalencephaly syndrome, autosomal recessive
* [[Megalencephalic leukoencephalopathy with subcortical cysts]]
* Megalencephaly with [[Myelin|dysmyelination]]
* Megalencephaly, [[Dominance (genetics)|autosomal dominant]]
* Megalencephaly-[[Vascular malformation|capillary malformation]]-[[polymicrogyria]] syndrome
* Megalencephaly-polymicrogyria-[[polydactyly]]-[[hydrocephalus]] syndrome 1 and 3
* [[Polyhydramnios]], megalencephaly, and symptomatic [[epilepsy]]
* Pseudoaminopterin syndrome
* [[Severe achondroplasia with developmental delay and acanthosis nigricans|Severe achondroplasia-developmental delay-acanthosis nigricans syndrome]]

==Causes==

Although very little is still known as to the direct cause of megalencephaly, recent studies have begun to provide early indications of possible sources for its formation. Recent research has shown that there is a strong link between genetic pathways that cause brain develop and mutations in that pathway that result in brain overgrowth.{{citation needed|date=December 2020}}

===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 in the activation of the PI3K-AKT pathway.<ref>{{cite journal|last=Fam|first=H|title=Caught in the AKT: identification of a de novo pathway in MCAP and MPPH and its therapeutic implications|journal=Clinical Genetics|date=December 2012|volume=82|issue=6|pages=521–2|doi=10.1111/cge.12003|pmid=22989095|s2cid=27129200}}</ref> 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.<ref>{{cite journal|last=Engelman|first=J|title=Targeting PI3K signalling in cancer: opportunities, challenges and limitations|journal=Nature Reviews Cancer|date=August 2009|volume=9|issue=8|pages=550–62|doi=10.1038/nrc2664|pmid=19629070|s2cid=7632764}}</ref> AKT is a crucial signaling molecule part of the PI3K pathway and is also involved in many cellular functions. These functions 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.<ref name=Mirzaa /> There are also several cancers that have been shown to be linked with mutations in the AKT pathway, including melanoma and lung cancer.<ref name=Mirzaa /><ref name="Mirzaa3">{{cite journal|last=Riviere|first=J |author2=Mirzaa |author3=O'Roak |author4=Beddaui |author5=Alcantara |author6=Conway |title=De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.|journal=Nat Genet|date=June 2012|volume=44|issue=8|pages=934–40|doi=10.1038/ng.2331|pmid=22729224|pmc=3408813}}</ref><ref>{{cite journal|last=Stahl|first=J |author2=Sharma |author3=Cheung |author4=Zimmerman |author5=Cheng |author6=Bosenberg |author7=Kester |author8=Sandirasegarane |author9=Robertson |title=Deregulated Akt3 activity promotes development of malignant melanoma|journal=Cancer Research|date=October 2004|volume=64|issue=19|pages=7002–10|doi=10.1158/0008-5472.CAN-04-1399 |pmid=15466193|doi-access= }}</ref>

===Pur-alpha===
Pur-alpha (purα) is a sequence-specific single-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.<ref>{{cite journal|last=Hokkanen|first=S |author2=Feldmann |author3=Ding |author4=Jung |author5=Bojarski |author6=Renner-Muller |author7=Schuller |author8=Kretzschmar |author9=Wolf |author10=Herms |title=Lack of Pur-alpha alters postnatal brain development and causes megalencephaly|journal=Human Molecular Genetics|date=February 2012|volume=21|issue=3|pages=473–84|doi=10.1093/hmg/ddr476|pmid=22010047|doi-access= }}</ref> Although the exact function is still controversial, it is believed that pur-alpha is responsible for neuronal proliferation during [[neurogenesis]] as well as the maturation of [[dendrites]].<ref>{{cite journal|last=Khalili|first=K |author2=Del Valle |author3=Muralidharan |author4=Gault |author5=Darbinian |author6=Otte |author7=Meier |author8=Johnson |author9=Daniel |author10=Kinoshita |author11=Amini |author12=Gordon |title=Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse|journal=Molecular Cell Biology|date=October 2003|volume=23|issue=19|pages=6857–75|doi=10.1128/MCB.23.19.6857-6875.2003|pmid=12972605 |pmc=193944}}</ref> Thus, pur-alpha is also considered a potential root cause of megalencephaly and brain overgrowth.{{citation needed|date=December 2020}}

==Pathophysiology==

One impact of megalencephaly is the complete lack of [[Motor control|motor]] development. One medical study assessed three patients presenting megalencephaly who showed severely impaired motor and speech development as well as distinct facial abnormalities including [[skull bossing]], a low nasal bridge and large eyes.<ref name=Hengst>{{cite journal|last=Hengst|first=M |author2=Tucke, Zerres |author3=Blaum, Hausler|title=Megalencephaly, mega corpus callosum, and complete lack of motor development. But many with megalancephaly have normal intelligence.: Delineation of a rare syndrome|journal=American Journal of Medical Genetics Part A|date=September 2010|volume=152A|issue=9|pages=2360–4|doi=10.1002/ajmg.a.33577|pmid=20803648|s2cid=205313167 }}</ref>

==Diagnoses==
Diagnosis of megalencephaly has changed over the years, however, with the development of more advanced equipment, physicians have been able to confirm the disorder with better accuracy. Usually, a physical exam is first performed when characteristics of megalencephaly have appeared. This typically occurs at birth or during early child development. A physician will then take head measurements in order to determine the circumference. This is known as the [[head circumference]].<ref name=Daymont /> Then a family background will be recorded in order to determine if there has been a history of megalencephaly in the family.<ref name=NINDS />

A neurological exam will then be performed using the technology of an MRI machine in order 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.<ref name=Striano /><ref name=NINDS />

There is also a strong correlation of [[epilepsy]] and megalencephaly and this can aid doctors in their diagnosis.<ref name=Hengst />

If a diagnosis of megalencephaly is confirmed, the child is referred to a specialist who focuses on managing the symptoms and improving lifestyle. Since megalencephaly is usually presented with autism, the goal of treatment is to improve deficiencies associated with autistic causes. Additionally, since each patient has unique symptoms, there is no one specific treatment method and therefore is heavily reliant on symptoms associated with an individual.{{citation needed|date=December 2020}}

==Prevention==
Since there are very few treatment methods focused on managing megalencephaly, future research is targeted at inhibiting mutation of the pathway. However, this next step could be met with several complications as understanding the underlying mechanism of the mutation is a difficult task. The genetic coding that initiates a single mutation is sporadic and patterns are hard to detect in many cases.<ref name=interview />
Even though very little research has been done to create inhibitors of the PI3K-AKT pathway, several pharmaceutical companies have begun to focus their interests in designing a prevention method for this purpose.<ref name=interview />

==Treatment==
There is currently no specific treatment for megalencephaly, however periodic head measurements may be assessed to determine the rate of brain growth.
Those individuals who develop neurological disorders may be prescribed anti-epileptic drugs for seizures.<ref name=Striano /> Studies have shown that reducing epilepsy can increase cell apoptosis and reduce the proliferation of neurons that ultimately leads to brain overgrowth.<ref>{{cite journal|last=Almgren|first=M|author2=Schalling, Lavebratt|title=Idiopathic megalencephaly-possible cause and treatment opportunities: from patient to lab|journal=European Journal of Pediatrics|date=November 2008|volume=12|issue=6|pages=438–45|doi=10.1016/j.ejpn.2007.11.008|pmid=18242108}}</ref>

==Prognosis==
The prognosis of megalencephaly depends heavily on the underlying cause and associated neurological disorders.<ref name="NINDS">{{cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Megalencephaly-Information-Page|title=Megalencephaly Information Page|last=National Institute of Neurological Disorders and Stroke|date=|website=|publisher=National Institute of Health|archive-url=https://web.archive.org/web/20170104205452/http://www.ninds.nih.gov/Disorders/All-Disorders/Megalencephaly-Information-Page|url-status=dead|archive-date=January 4, 2017|access-date=January 2, 2019}}</ref> 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 intellectual disability, the result is 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 |author2=Sato, Yagishita |author3=Ota, Saito |author4=Sugai, Sasaki |author5=Natsume, Tsushima |author6=Amanuma, Endo|title=Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia|journal=Neuroradiology|date=December 2009|series=51|issue=12|pages=821–30|doi=10.1007/s00234-009-0579-7|pmid=19672585|volume=51|s2cid=28924230 }}</ref>

==Epidemiology==

Approximately one out of every 50 (2%) children in the general population are said to have megalencephaly.<ref name=Sandler /> Additionally, it is said that megalencephaly affects 3–4 times more males 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.{{citation needed|date=December 2020}}

==History==

It is believed that megalencephaly was discovered in 1972. Prior to diagnoses that used MRI scanning as a way to confirm brain overgrowth, cases of megalencephaly were diagnosed by autopsy in which the physical brain was measured and weighed.<ref name=interview />

==Research==
Future research is targeted at further understanding mutations and how they lead to MCAP and MPPH syndromes. 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 to determine the exact genetic mutation causing the sequences. Additionally, scientists and pharmaceutical companies have begun to show interest in mutation inhibition and designing preventative methods to eliminate the underlying cause of megalencephaly altogether.<ref name=interview />

== Other relations ==
Intracranial volume also affects this pathology, since it is related with the size of the brain.<ref>{{Cite journal|last1=Adams|first1=Hieab H H|last2=Hibar|first2=Derrek P|last3=Chouraki|first3=Vincent|last4=Stein|first4=Jason L|last5=Nyquist|first5=Paul A|last6=Rentería|first6=Miguel E|last7=Trompet|first7=Stella|last8=Arias-Vasquez|first8=Alejandro|last9=Seshadri|first9=Sudha|year=2016|title=Novel genetic loci underlying human intracranial volume identified through genome-wide association|journal=Nature Neuroscience|volume=19|issue=12|pages=1569–1582|doi=10.1038/nn.4398|pmid=27694991|pmc=5227112}}</ref>

==References==
{{Reflist}}

== External links ==
* [https://www.ninds.nih.gov/health-information/disorders/birth-disorders-brain-and-spinal-cord#megalencephaly Megalencephaly information page] (provided by [[National Institute of Neurological Disorders and Stroke]])

{{Medical resources
| ICD11           = {{ICD11|LA05.1}}
|  ICD10          = {{ICD10|Q|04|5|q|00}}
|  ICD9           = {{ICD9|742.4}}
|  ICDO           =
|  OMIM           = 155350
|  OMIM_mult      =
|  MedlinePlus    =
|  eMedicineSubj  =
|  eMedicineTopic =
|  DiseasesDB     = 22519
|  MeSH=D058627
|  Orphanet=2477
}}
{{Congenital malformations and deformations of nervous system}}
{{Phakomatoses}}

[[Category:Congenital disorders of nervous system]]
[[Category:Neurocutaneous conditions]]