Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare disorder that primarily affects the development of the brain. Affected individuals are born with an unusually large brain and head size (megalencephaly). The head and brain continue to grow rapidly during the first 2 years of life. MPPH syndrome is also associated with a brain abnormality called bilateral perisylvian polymicrogyria (BPP). The surface of the brain normally has many ridges or folds, called gyri. In people with BPP, an area of the brain called the perisylvian region develops too many gyri, and the folds are irregular and unusually small. Other brain abnormalities, including a buildup of fluid in the brain (hydrocephalus), have also been reported in people with MPPH syndrome.

The problems with brain development cause a variety of neurological signs and symptoms. People with MPPH syndrome have delayed development and intellectual disability that ranges from mild to severe. About half of affected individuals develop recurrent seizures (epilepsy) beginning early in childhood. People with MPPH syndrome also have difficulty coordinating movements of the mouth and tongue (known as oromotor dysfunction), which leads to drooling, difficulty swallowing (dysphagia), and a delay in the production of speech (expressive language).

About half of people with MPPH syndrome have an extra finger or toe on one or more of their hands or feet (polydactyly). The polydactyly is described as postaxial because it occurs on the same side of the hand or foot as the pinky finger or little toe.

The brain abnormalities characteristic of MPPH syndrome are also found in a closely related condition called megalencephaly-capillary malformation syndrome (MCAP). However, MCAP includes abnormalities of small blood vessels in the skin (capillary malformations) and several other features that are not usually part of MPPH syndrome.

MPPH syndrome can be caused by mutations in the AKT3, CCND2, or PIK3R2 gene. The proteins produced from all three genes are involved in a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell growth and division (proliferation), and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain.

Mutations in the AKT3, CCND2, or PIK3R2 gene increase the activity of their respective proteins or prevent the proteins from being broken down when they should. As a result, chemical signaling through the PI3K-AKT-mTOR pathway is enhanced, which increases cell growth and division. In the brain, the increased number of cells leads to rapid and abnormal brain growth starting before birth. The rapid growth disrupts the structure and function of the developing brain. It is less clear how increased PI3K-AKT-mTOR signaling contributes to polydactyly, although the extra digits are probably related to abnormal cell proliferation in the developing hands and feet. CCND2 and PIK3R2 gene mutations are more likely to cause polydactyly than are AKT3 gene mutations.

Normal Function

The AKT3 gene provides instructions for making a protein that is most active in the nervous system. The AKT3 protein is a key regulator of a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell growth and division (proliferation), and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain. Studies suggest that the AKT3 protein plays a critical role in determining brain size.

Health Conditions Related to Genetic Changes

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

Several mutations in the AKT3 gene have been found to cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. This rare condition affects the development of the brain, causing an unusually large brain and head size (megalencephaly) and other abnormalities of the brain's structure.

Each of the known mutations changes a single protein building block (amino acid) in the AKT3 protein. These changes are described as "gain-of-function" because they increase the activity of the protein. This enhanced activity increases chemical signaling through the PI3K-AKT-mTOR pathway, which causes excessive cell growth and division. The increased number of cells leads to rapid and abnormal brain growth starting before birth.

Other disorders

Changes involving the AKT3 gene are also involved in other disorders of brain growth. Megalencephaly without the other features of MPPH syndrome (described above) has been associated with gain-of-function AKT3 gene mutations or extra copies (duplication) of the region of chromosome 1 containing the AKT3 gene. These genetic changes increase the amount or activity of the AKT3 protein, which enhances chemical signaling through the PI3K-AKT-mTOR pathway and causes excessive cell growth and division, particularly in the brain.

Other genetic changes involving the AKT3 gene are associated with an unusually small brain and head size (microcephaly). These changes include a deletion of the AKT3 gene or a loss of the region of chromosome 1 containing the AKT3 gene. The resulting reduction in AKT3 protein activity likely decreases signaling through the PI3K-AKT-mTOR pathway and restricts cell growth and division in the developing brain.

Changes involving the AKT3 gene can also cause a brain malformation called isolated hemimegalencephaly. This brain abnormality is an enlargement of one of the two major halves (hemispheres) of the cerebrum, which is the large part of the brain that controls most voluntary activity, language, sensory perception, learning, and memory. Like the genetic changes that cause MPPH syndrome and megalencephaly (described above), the AKT3 gene changes that result in isolated hemimegalencephaly are gain-of-function, ultimately leading to increased cell growth and division in the developing brain. However, unlike the mutations that cause those other abnormalities of brain growth, the genetic changes related to isolated hemimegalencephaly are somatic, meaning they occur at some point during embryonic development. As brain cells continue to grow and divide, some of these cells will have the genetic change, and others will not (a situation known as mosaicism). The mosaic nature of these genetic changes helps explain why they cause overgrowth in only one of the two cerebral hemispheres.

Other Names for This Gene

• PKB gamma
• PKB-GAMMA
• PKBG
• PRKBG
• RAC-gamma
• RAC-gamma serine/threonine protein kinase
• RAC-PK-gamma
• STK-2
• v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)

Genomic Location

Normal Function

The CCND2 gene provides instructions for making a protein called cyclin D2. Cyclins are a family of proteins that control how cells proceed through the multi-step cycle of cell division. Cyclin D2 helps to regulate a step in the cycle called the G1-S transition, in which the cell moves from the G1 phase, when cell growth occurs, to the S phase, when the cell's DNA is copied (replicated) in preparation for cell division. Cyclin D2's role in the cell division cycle makes it a key controller of the rate of cell growth and division (proliferation) in the body.

The cyclin D2 protein is regulated by a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell proliferation, and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain.

Health Conditions Related to Genetic Changes

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

At least seven mutations in the CCND2 gene have been found to cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. This rare condition affects the development of the brain, causing an unusually large brain and head size (megalencephaly) and a brain abnormality called bilateral perisylvian polymicrogyria (BPP). Some affected individuals also have an extra finger or toe on one or more of their hands or feet (polydactyly).

Each of the known mutations changes a single protein building block (amino acid) in the cyclin D2 protein. These changes prevent the protein from being broken down (degraded) when it is no longer needed. The resulting buildup of cyclin D2 in cells triggers them to continue dividing when they otherwise would not have, leading to abnormal cell proliferation. In the brain, the increased number of cells leads to rapid and abnormal brain growth starting before birth. It is less clear how a buildup of cyclin D2 contributes to polydactyly, although the extra digits are probably related to abnormal cell proliferation in the developing hands and feet.

Other Names for This Gene

• G1/S-specific cyclin-D2
• KIAK0002
• MPPH3

Genomic Location

Normal Function

The PIK3R2 gene provides instructions for making one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The primary function of the subunit, which is known as P85β, is to regulate the PI3K enzyme's activity.

PI3K is a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions as part of a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell growth and division (proliferation), and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain.

Health Conditions Related to Genetic Changes

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

At least four mutations in the PIK3R2 gene have been found to cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. This rare condition affects the development of the brain, causing an unusually large brain and head size (megalencephaly) and other abnormalities of the brain's structure. Some affected individuals also have an extra finger or toe on one or more of their hands or feet (polydactyly).

Each of the known mutations changes a single protein building block (amino acid) in the P85β subunit of PI3K. The most common mutation replaces the amino acid glycine with the amino acid arginine at position 373 (written as Gly373Arg or G373R). All of the mutations are described as "gain-of-function" because they increase the activity of PI3K. This enhanced activity increases chemical signaling through the PI3K-AKT-mTOR pathway, which leads to excessive cell growth and division. In the brain, the increased number of cells leads to rapid and abnormal brain growth starting before birth. It is less clear how these changes contribute to polydactyly, although the extra digits are probably related to abnormal cell proliferation in the developing hands and feet.

Other disorders

Mutations in the PIK3R2 gene have been found to cause a brain abnormality called bilateral perisylvian polymicrogyria (BPP). The surface of the brain normally has many ridges or folds, called gyri. In people with BPP, an area of the brain called the perisylvian region develops too many gyri, and the folds are unusually small. BPP is one of the major brain abnormalities associated with MPPH syndrome (described above), but mutations in the PIK3R2 gene have also been identified in people with BPP who do not have the other signs and symptoms of MPPH syndrome.

Like the genetic changes that cause MPPH syndrome, the PIK3R2 gene mutations associated with BPP are gain-of-function, ultimately leading to increased cell growth and division in the developing brain. The increased number of cells causes abnormal development of the gyri starting before birth. Gly373Arg, the most common mutation identified in people with MPPH syndrome, can also cause BPP.

In some cases of BPP, a PIK3R2 gene mutation is present from birth in essentially every cell of the body. In other cases, the mutation is somatic, meaning it occurs at some point during embryonic development. As cells continue to grow and divide, some of these cells will have the genetic change, and others will not (a situation known as mosaicism). It is unclear why mutations in the same gene, and sometimes the very same mutation, cause BPP in some people and MPPH in others. It is possible that the number and location of brain cells that have the mutation (in cases of mosaicism) help determine which abnormalities of brain growth will occur.

Other Names for This Gene

• p85
• p85-BETA
• P85B
• phosphatidylinositol 3-kinase 85 kDa regulatory subunit beta
• phosphatidylinositol 3-kinase regulatory subunit beta
• phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 2 (p85 beta)
• phosphoinositide-3-kinase regulatory subunit beta
• phosphoinositide-3-kinase, regulatory subunit 2 (beta)
• PI3-kinase subunit p85-beta
• PI3K regulatory subunit beta
• ptdIns-3-kinase regulatory subunit p85-beta

Genomic Location

This condition is considered autosomal dominant, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Almost all cases of this condition result from new (de novo) gene mutations that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

In a small number of cases, people with MPPH syndrome have inherited the altered gene from an unaffected parent who has a mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism.

Rarely, the condition can also result from somatic mosaicism, in which some of an affected person's cells have a gene mutation and others do not. The genetic changes, which are called somatic mutations, arise randomly in one cell during embryonic development. As cells continue to divide, only cells arising from the first abnormal cell will have the mutation.

MPPH syndrome appears to be a rare disease. About 60 affected individuals have been described in the medical literature.