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Dandy-Walker Syndrome: Brain Developmental Disorder associated to Hydrocephalus Renzo Recella, Dwell Joy Armada, Joel Libao, Joseph

Dandy-Walker Syndrome: Brain Developmental Disorder associated to Hydrocephalus

Dandy-Walker Syndrome: Brain Developmental Disorder associated to Hydrocephalus Renzo Recella, Dwell Joy Armada, Joel Libao, Joseph

Renzo Recella, Dwell Joy Armada, Joel Libao, Joseph Ryan Davalos, Mark Lawrence Zoilo

Department of Biology Students, College of Science, Polytechnic University of the Philippines, Sta. Mesa, Manila

Abstract

Human brain development is a complex and orchestrated sequence of stages. Dandy-walker syndrome (DWS) is a condition that affects the development of the part of the brain that coordinates movement, the cerebellum. Cerebellum is located at the back of the underlying the occipital and temporal lobes of the cerebral cortex. It contains 50% of neurons in the brain despite having only 10% of total volume of the brain. Individuals with DWS have hydrocephalus, buildup of fluid in the brain, which causes increased brain size (macrocephaly). Cysts form in the fourth ventricle causing the ventricle to enlarge and the part of the skull called the posterior fossa is abnormally large. These malformations often result in problems with movement, coordination, intellect, and other neurological functions. This study features articles that associates DWS to hydrocephalus – how abnormal brain development cause enlargement and malformations in individual.

Keywords: Dandy-walker syndrome, cerebellum, abnormal brain development, hydrocephalus

Introduction

Centuries of sustained research remains unclear and baffled brain scientist and still have little understanding on how a brain, a three pound organ and the seat of all human activity works (Yuste and Church, 2005). Brain is an organ that serves as the center of nervous system in all vertebrate and most invertebrate animals. In humans, it has more developed cerebral cortex and is one of the largest and complex organs in human body and has been called the most complex object in the known universe (Rajeev, 2012). Human brain complexity has made it difficult to study many brain disorders in model organisms (Lancaster et al., 2013).

The development of the brain occurs with the interaction of synchronized processes, undergoes complex and orchestrated sequence of stages rather than by simply growing through changing in a shape of a small swelling at the front of the nerve cord to a

complex

areas

and

connection

in

the

early

embryonic stage (Lenroot and Giedd, 2006). Brain development begins with the formation of specialized fold of ectodermal tissue called neural tube and by expansion of neuroephitelium to produce radial glial cells that divides in the apical surface within the ventricular zone to also produce neurons and intermediate progenitors (Lenroot and Giedd, 2006; Lancaster et al., 2013). The intermediate progenitors and neurons populate and migrate to adjacent subventricular zone, which is divided to inner subventricular zone, and outer subventricular zone by inner fiber layer, and intermediate zone respectively to fill specific layer within the cortical layer. Brain development in the first 2 years after birth is very essential. Volumes of brain substructure are known to change during development. But with this short period of time, brain growth plays an important role in

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neurodevelopmental disorders (Knickmeyer et al.,

2008).

Cerebellum Development and Dandy-Walker Syndrome associated to Hydrocephalus

Human brain has many parts but will focus more and involved only on the cerebellum and its relation to Dandy- Walker syndrome resulting to hydrocephalus. Cerebellum is located at the back of the underlying the occipital and temporal lobes of the cerebral cortex and contains 50% of neurons in the brain despite having only 10% of total volume of the brain (Kneirim, 1997).

The cerebellum, in newborn human is considered vulnerable because of the rapid growth at that time when a period comparable in the developing animal (Biran et al., 2011). The cerebellum is one of the first to begin differentiation, but still one to achieve maturity late. It also undergo rapid changes including changing its size and to reorganize its cortical layer during late fetal and postnatal development and continues to change for months after birth (Friede, 1972). These developments of cerebellum can be classified and describe in 4 stages. Louie and Glesson (2005) explained the 4 stages of cerebellum development as the characterization of cerebellar territory at the midbrain–hindbrain boundary, the formation of two compartments for cell proliferation, migration of external granule layer cells to processes of Bergman glia and to their final position in the internal granule layer and last is the establishing of cerebral circuitry and further differentiation.

The first stage in the development of cerebellum is the characterization of the cerebellar territory at the midbrain-hindbrain boundary. Formation and maintenance of the midbrain-hindbrain boundary is characterized by the hierarchal program of gene expression initiated by fibroblast growth factor 8 (Fgf8), along with cellular morphogenesis, culminating in the formation of the tectal-isthmo- cerebellar structures and the isthmic organizer located at the midbrain-hindbrain boundary is very

important in the development of the signaling center that is responsible for patterning mesencephalic and metencephalic regions of the vertebrate brain (Dworkin et al., 2012). Cell fate in the cephalic neural primordium is tightly controlled by feedback inhibition of an organizer in the midbrain-hindbrain boundary and this organizer will produce fibroblast growth factor which is important to mimic, organizer activity in the midbrain and anterior hindbrain patterning (Rhinn and Brand, 2001). Patterning of the neural primordium also involves special groups of cells which are called neuroephitelial organizer which also controls the cell fate of the surrounding cells by producing secreted molecules. Once the proper positioning of organizer is done, Fgf8 and Wnt1 proteins from the organizer are being secreted and functions as an organizing influence in the surrounding neural tissues. Rhinn and Brand (2001) ; Louie and Gleeson (2005) discussed restricted expression of secreted factors such as Fgf8, Wnt1, homeobox proteins En1 and En2 and the paired box genes Pax2 and Pax 5 and the role of fibroblast growth factors in early specification midbrain-hindbrain structures and boundary. They states that Fgf8 and Wnt1, these fibroblast promoting factors functions as to mediate organizing activity and maintaining expression of En genes. Fgf8 is defined as anterior limit of hox gene expression and is required for the maintenance of marker gene expression in the midbrain and isthmus and is a crucial molecular component in the midbrain-hind brain boundary and the feedback inhibition mentioned before has evolved to control their activity.

The second stage in cerebellum development is the formation of two compartments for cell proliferation. The development of forebrain, facial structures, spinal cord and the hollow center will become brain and will form the ventricles and around these ventricles forms the proliferative zones which will give rise to young neurons (Lenroot and Giedd, 2006). This two compartments are known as the Purkinje cells and the granule cells precursors. Purkinje cells, one of the largest neuron in the

3

human brain, along with deep cerebellar nuclie formed in the roof of the fourth ventricle. Granule cell layer and the precerebellar nuclie cells are formed in the rhombic lip (Louie and Gleeson, 2005). Purkinje cells migrate outward and form a monolayer in the cortex whereas the granule neuron forms the external granule layer by migrating to the surface of the developing cerebellum. The external granule layer in the developing cerebellum consists of neural progenitors from rostral rhombic lip which is located in the hindbrain circling the opening of the fourth ventricle that give rise to the granule neurons of the cerebellum (Lin et al., 2001). Next and the third stage after the cell proliferation is the inward migration of the external granule layer cells to the Bergman glia processes which plays an important role in the dendritogenesis, synaptogenesis, maturation of cerebellar purkinje cells and migration of granule cells in the early cerebellum development (Louie and Gleeson, 2005). Bergman glia is also important in synaptic pruning, which is the elimination of synapse that occurs during early childhood and puberty.

The final stage of cerebellum development is the establishing of cerebellar circuitry and for the further differentiation. Purkinje cells form the heart of cerebellar circuitry. Purves et al. (2001) discussed the circuit events occur in the cerebellum. Dendrites form a molecular layer from single layer of purkinje layer and extensively branch in the right angle with the parallel fibers. With this formation, purkinje cells receive large numbers of parallel fibers and direct modulatory input and numerous synaptic contacts from a single climbing fiber. The climbing fiber regulates movement of the mossy – parallel fiber of the granule cells in the connection to purkinje cells. They also state that this circuit is repeated over and over through the course of every subdivision of cerebellum and this modulation of signal flow provides basis for real-time and long-term regulation that includes motor learning.

The cerebellum is a supreme model to study in the neurogenesis and circuit assembly because of its

morphologically unique brain structure that is made up of detailed set of folia separated by fissures (Sundarov and Joyner ,2007). Recent evidence states that cerebellum participates in higher order functions such as cognition, emotion and language processing, proprioceptive motor and autonomic functions. But with this long developmental process, the cerebellum creates opening and is highly susceptible to disruption during embryogenesis resulting to disorders and diseases (Wang and Zoghbi, 2001). One of the disorders is the Dandy-Walker Syndrome (DWS), which can be either inherited or developmentally caused. Dandy-Walker Syndrome is a rare disorder characterized by the congenital malformation of the neural tube and localized defect in the differentiation of the hindbrain resulting to the absence or having small size of the cerebellar vermis, cyst formation in the fourth ventricle and abnormally large size posterior fossa (Kollias, 2014). Dandy-Walker Syndrome is commonly associated with hydrocephalus because the affected individuals have a buildup of fluid, specifically the cerebrospinal fluid in the brain (hydrocephalus) which causes an increased in the head size (macrocephaly). This abnormal accumulation of cerebrospinal fluid results in the widening of the ventricles in the brain. Hydrocephalus occurs up to 80% in the individuals with Dandy-Walker Syndrome but there are many cases and accounts where there is no enlargement of posterior fossa which led to having the Dandy-Walker variant, a lesser type of Dandy-Walker syndrome compare to the classic Dandy-Walker malformation, although the use of this term is been discouraged (Bernardino et al., 2015).

History, Definition and Classification of Dandy- Walker Syndrome

Dandy-Walker syndrome was first introduced in 1887 by Sutton and further characterized by Dandy and Black fan in 1914 followed by Tagart and Walker in 1942. (Kumar et al., 2010). Benda finally labeled this disease as dandy walker in 1954. Dandy- Walker syndrome is defined by hypoplasia and

4

upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWS is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985). It is a rare intracranial congenital abnormality that affects the cerebellum and some of its components; particularly cerebellar vermis, fourth ventricle and is characterized by an enlarged posterior fossa. (Kumar et al., 2010).

Dandy-Walker complex has several variants, Dandy-Walker malformation (DWM) encompasses cystic dilatation of the fourth ventricle, complete or partial agenesis of cerebella vermis and enlarged posterior fossa (Willacy, 2011) while Dandy-Walker variant (DWV) comprises cystic posterior mass with variable hypoplasia of the cerebella vermis and no enlargement of the posterior fossa. However, the third variant mega-cisterna magna comprises enlarged cistern magna with normal cerebellar vermis and fourth ventricle. The clinical manifestations include psychomotor and growth retardation, hypotonia, strabismus, myopia, a short neck, microcephaly, brachycephaly, hypertelorism, antimongoloid slant of palpebral fissures, globulus large nose, large mouth with down turned corners, poorly lobulated ears, high arch palate, cleft palate, small hands and feet, clinodactyly, and the brachymesophalangy of the little fingers. Although it is said that clinical examination cannot replace any imaging modalities, DWM is such a condition that require imaging modalities to diagnose the disorder. Even though there are many signs, none of these are characteristic to diagnose individuals as DWM and diagnosis is solely based on imaging techniques. The present manuscript reports a case encountered in our clinic which was revealed as Dandy-Walker malformation by MRI. (Kumar et al., 2010). Up to now, further explanations and studies are being made

to support the ideas and explanation of the first people who studied about Dandy-Walker syndrome.

Brain development in Dandy-Walker patients

Signs and Symptoms of Dandy-Walker Syndrome

Possible Medication

After knowing the symptoms or signs of having this abnormality, this part will elaborate the medical processes which are used for diagnosis. This part also shows related treatments for associated problems. Dandy-Walker malformation is best diagnosed with the help of ultrasonography (US) and magnetic resonance imaging (MRI). US may be the initial examination performed because it can be done portably and without sedation, as well as allowing multiplanar imaging. US, however, is limited because it is heavily operator-dependent. Abnormalities such as the gyral, dural, tentorial, and skull anomalies that accompany Dandy-Walker malformations are not clearly depicted by US. The introduction of modern imaging techniques, specifically MRI, has radically changed the evaluation of symptoms related to the posterior fossa. MRI is usually performed for detailed evaluation of Dandy-Walker malformation lesions and complications after the diagnosis is suspected using computed tomography (CT) and US. MRI can best define the relationship between the cyst and the fourth ventricle, and it can detect vermian rotation and the signs of vermian dysgenesis. MRI is relatively expensive. High-quality MRI scans require patient cooperation or sedation. MRI allows surgeons to accurately view the cerebellum and associated structures, determine which form the malformation has taken, and gauge the progress of the malformation. MRI also demonstrates which space should be shunted first. Recently, MRI has been frequently used for diagnosing fetal craniospinal anomalies. Since it can distinguish between hydrocephalus associated with Dandy- Walker and hydrocephalus associated with other etiologies, CT scanning is also useful in Dandy-

5

Walker malformation; however, it exposes the infant to ionizing radiation. Clearly distinguishing the subtypes of Dandy-Walker complex on axial CT images is difficult. In addition, evaluating subtle supratentorial pathologies and associated abnormalities on CT scans may not be easy because its routine use is constrained by the axial plane. The classic abnormal findings of Dandy-Walker malformation described on cranial CT and MRI can also be demonstrated on cranial sonography. US is routinely used during the antenatal period as a screening method, and it is particularly used for postnatal follow-up studies of hydrocephalus. US evaluation of posterior fossa cystic abnormalities in

the newborn is best accomplished via a posterolateral fontanelle approach or through the cisterna magna posteriorly. Plain radiography has been primarily used in the evaluation of shunt malfunction as well as for diagnosing associated anomalies (Incesu, MD., 2013). Medication for DWS is not a one way treatment it includes several medications. Studies have not yet discovered that there is an individual process that could stop all the abnormalities and associated problems. Treatment for individuals with this abnormality, Dandy Walker Syndrome, generally consists of treating the associated problems (Bethesda, MD., 2014).

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2,

484-491

Louie, C., and Gleeson, J,. 2005. Genetic basis of Joubert syndrome and related disorders of cerebellar development. Human Molecular Genetics. 2005. Vol. 14. Review Issue 2. 2005. pp 235–R242

Dworkin, S, Georgy,
Dworkin, S,
Georgy,

D., Srivastava, W.,Pase, E.,

Meng, H.,

Heath, J.,

Lieschke,
Lieschke,

G., and Jane, S,. 2012. Midbrain-hindbrain

boundary

patterning

and

morphogenesis

2012. 139(3). pp 525-36.

are

regulated

by

diverse

grainy

head-like

2-dependent

pathways.

Rajeev, L,. 2012. Lobes of The Brain and Their Functions retrieved from http://www.buzzle.com/articles/lobes-of-the-brain-and- their-function.html

Biran, V., Verney, C., and Ferriero, D,. 2011. Perinatal Cerebellar Injury in Human and Animal Models.

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and Brand M. 2001. The midbrain--hindbrain boundary organizer. Curr Opin Neurobiol.

2001. 11(1). pp 34-42

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Int.
Int.

and Watanabe M. 2002. Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci

2002. 77(2). pp 94-108

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Augustine, G.,

Fitzpatrick, D.,

Katz,C.,

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LaMantia, A.,

McNamara,

J.,

and

Williams,

S,.

2001.

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S.S. Kollias. 2014. Dandy–Walker Syndrome. Encyclopedia of the Neurological Sciences. 2nd Ed 2014. Pp

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935–941

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