megalencephaly

大脳症

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/18 12:37:45」(JST)

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Megalencephaly
Classification and external resources
ICD-10	Q04.5
ICD-9	742.4
OMIM	155350
DiseasesDB	22519

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 from the mean of the general population. 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 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). Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly in the general population. There are several neuropsychiatric disorders linked with megalencephaly, however, studies have shown that autism is the most prevalent association with the malformation of MEG. 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.

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.

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 95th percentile or at least 2.5 standard deviations from the mean of normal weight and gender groups in the United States. 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.

Hemimegalencephaly

Hemimegalencephaly is an extremely rare form of macrocephaly and is characterized by uneven development of brain hemispheres (one-half of brain is larger than other). The syndrome can be presented 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 mental retardation.

MCAP

Megalencephaly-capillary (MCAP) is one of the two major syndromes of megalencephaly. Typically, MCAP and MPPH can be distinguished by somatic features. 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. Furthermore, MCAP can occasionally be linked with asymmetric brain overgrowth (hemimegalencephaly) as well as segmental overgrowth of the body (hemihypertrophy).

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. In differentiation to MCAP, MPPH lacks consistent somatic features other than postaxial polydactly. Furthermore, brain and body development is normally symmetric in the majority of patients that appear to have MPPH symptoms.

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.

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. 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. 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. There are also several cancers that have been shown to be linked with mutations in the AKT pathway, including melanoma and lung cancer.

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. 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. 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 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.

Management

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. Then a family background will be recorded in order to determine if there has been a history of megalencephaly in the family.

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.

There is also a strong correlation of epilepsy and megalencephaly and this can aid doctors in their diagnosis.

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.

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. Studies have shown that reducing epilepsy can increase cell apoptosis and reduce the proliferation of neurons that ultimately leads to brain overgrowth.

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. Even thought 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.

Prognosis

The prognosis of megalencephaly depends heavily on the underlying cause and assosciated neurological disorders. 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, the result is a poor prognosis. In most cases, those diagnosed with this type of megalencephaly usually do not survive through adulthood.

Future research

Future research is targeted at further understanding mutations and how they lead to MCAP and MPPH sydnromes. 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.

Epidemiology

Approximately one out of every 50 (2%) children in the general population are said to have megalencephaly. Additionally, it is said that megalencephaly affects 3-4 times more men 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 making it the most common physical characteristic of autism. 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 the primary cause/result of megalencephaly. This is because megalencephaly has also been described in other neurodevelopmental disorders such as schizophrenia or Alzheimers.

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.

References

UpToDate Contents

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• 1. 幼児および小児における巨頭症：病因および評価 macrocephaly in infants and children etiology and evaluation
• 2. アレキサンダー病 alexander disease
• 3. 自閉症スペクトラム障害：臨床的特徴 autism spectrum disorder clinical features
• 4. カウデン症候群などのPTEN過誤腫症候群 pten hamartoma tumor syndrome including cowden syndrome
• 5. 頭蓋骨縫合早期癒合症候群 craniosynostosis syndromes

English Journal

• Regulation of cerebral cortex size and folding by expansion of basal progenitors.

• Nonaka-Kinoshita M, Reillo I, Artegiani B, Angeles Martínez-Martínez M, Nelson M, Borrell V, Calegari F.SourceCRTD-DFG Research Centre for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
• The EMBO journal.EMBO J.2013 Jul 3;32(13):1817-28. doi: 10.1038/emboj.2013.96. Epub 2013 Apr 26.
• Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex d
• PMID 23624932

• [Megalencephaly with dystonia revealing Canavan disease].

• Maaloul I, Fourati H, Wali M, Chabchoub I, Kamoun T, Mnif Z, Kaabachi N, Hachicha M.SourceService de pédiatrie générale, hôpital Hédi-Chaker, avenue Majida-Boulila, 3029 Sfax, Tunisie. Electronic address: maaloul.ines@hotmail.fr.
• Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie.Arch Pediatr.2013 Jul;20(7):783-6. doi: 10.1016/j.arcped.2013.04.023. Epub 2013 May 30.
• Canavan disease, or N-acetyl aspartic aciduria, is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The disease results from the accumulation of N-acetyl aspartic acid in the brain, due to aspartoacylase deficiency. We report the case of a 6-month-old girl who
• PMID 23727372

Japanese Journal

• 線状骨症-頭蓋骨硬化症-大脳症の歯科学的所見

• 望月 清志,辻野 啓一郎,薬師寺 仁,土屋 喜子,末石 研二,山口 秀晴
• 小児歯科学雑誌 40(3), 571-575, 2002-06-25
• NAID 10012156386

• Lidocaine-dependent Early Infantile Status Epilepticus with Highly Suppressed EEG

• SAWAISHI Yukio,YANO Tamami,ENOKI Masamichi,TAKADA Goro
• Epilepsia : journal of the International League against Epilepsy 43(2), 201-204, 2002-02-01
• NAID 10010874162

Related Links

• Megalencephaly - Wikipedia, the free encyclopedia

Megalencephaly (or macrencephaly) is a condition in which the brain is abnormally large. It usually functions abnormally, as well. Head enlargement may be evident at birth or the head may become abnormally large in the early years of life.

• Megalencephaly Information Page: National Institute of Neurological ...

9 Mar 2009 ... Megalencephaly (Macrencephaly) information sheet compiled by the National Institute of Neurological Disorders and Stroke (NINDS).

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