Holoprosencephaly (HPE)

Holoprosencephaly (HPE)

Treatments

• drugs for seizures
• surgery for cleft lip
• hormone replacement for dysfunctional pituitary gland
• feeding tubes

What is Holoprosencephaly?

• failure of the prosencephalon (the forebrain) to separate into separate hemispheres during embryonic development
• results in a single lobed brain as well as a wide range of facial deformities
• this malformation usually occurs during the first few weeks of the brain development which begins during the 5th week of gestation (embryonic development)
• the degree of separation of the lobes results into three different classifications of HPE: alobar, semilobar, and lobar

Causes of HPE

Effects

lobar HPE MRI

Alobar HPE

normal brain MRI

• most severe
• no sign of division of the forebrain into two cerebral hemispheres
• characteristics:
• cyclopia with possible absence of nose
• bilateral cleft lip
• eyes close together
• relatively normal facial appearance

normal brain MRI

Lobar HPE

alobar holoprosencephaly MRI

chromosomal

environmental

gene mutations

• most of the cerebral hemispheres and lateral ventricles are separated, but the frontal lobes
• characteristics:
• bilateral cleft lip
• depressed nasal ridge
• closely spaced eyes
• relatively normal facial appearance

• experiments have shown that a diabetic mother increases the risk of holoprosencephaly

Semilobar HPE

• HPE can result from a copy of chromosomes like trisomy 13 or trisomy 18

normal brain MRI

semilobar HPE MRI

• some evidence of separation of brain hemispheres
• characteristics:
• bilateral cleft lip
• closely-spaced eyes
• depressed nasal ridge
• relatively normal facial appearance

• causes nonsyndromic HPE ( 25-50% of individuals with holoprosencephaly have this)
• mutations are autosomal dominant
• 11 gene mutations have been found to cause HPE
• the genes involved produce signaling proteins that instruct the cells to form right and left hemispheres
• about 25% of individuals with nonsyndromic HPE have a mutation in either the SHH, ZIC2, SIX3, or TGIF1 gene

• developmental delay and intellectual disability
• motor disability
• seizures
• feeding/digestive difficulties
• hypothalamic and brain stem dysfunction
• malfunction of pituitary gland

SHH Gene produces a signaling protein that causes the eye field to separate into two separate eyes and a signaling protein that is involved in the separation of the forebrain

ZIC2 gene produces a protein that regulate genes that are involved in both the early stages and late stages of the development of the forebrain

TGIF1 gene produces proteins that blocks retoic acid from entering and also blocks TGF- (transforming growth factor beta) which will affect forebrain development if not blocked.

SIX3 gene produces a protein that regulates proteins involved in the development of the forebrain which activate and deactivate genes involved in the development like SHH

Diagnosis

• use MRI scan or CT scan to determine the type of HPE
• can also be diagnosed before birth by prenatal ultrasonography

Sources

Genetics Home Reference. "Nonsyndromic Holoprosencephaly". ghr.hlm.nih.gov.

National Human Genome Research Institute. "Learning about Holoprosencephaly (HPE)". www.genome.gov.

Solomon, Benjamin D, Andrea Gropman and Maximilian Muenke. Holoprosencephaly Overview. Gene Reviews [Internet]. National Center for Biotechnology Information, 28 Oct. 2009. Web. 13 May 2014.