Congenital Hydrocephalus Effect Csf Accumulation Cortical Maldevelopment Biology Essay



Congenital hydrocephalus is a severe congenital abnormality which is thought to occur in around 4.65 births per 10,000 in Europe (Garne, 2010). The condition has been recognised for thousands of years, with both Hippocrates (400 BC) and Galen (200 AD) giving early descriptions, however until around 50 years ago, it almost always resulted in death. Through the recent development of shunts to alleviate the symptoms, coupled with an improved awareness of the effects on the brain, we now have a greater understanding of the condition and as a result, are more able to develop appropriate strategies to overcome it (Chumas et. al, 2001; Rachel, 1999). However, more recent experiments have shown that despite treatment, the effects of CSF accumulation may have already had an irreversible effect on cortical development, leaving patients with varying levels of neurological or intellectual deficit (Mashayekhi, 2002; Fernell, 1994).

Congenital hydrocephalus occurs when there is an abnormal accumulation of cerebrospinal fluid (CSF) within the cranial cavity, causing increased intracranial pressure and abnormal head enlargement (Bell, 1978). It occurs most commonly when CSF flow through the ventricular system or subarachnoid space is obstructed, or it can also be a caused by abnormal reabsorption of CSF, resulting in a disequilibrium between the production of CSF, which mainly occurs at the choroid plexus, and its absorption at the arachnoid granulations (Punt, 1996; Chumas et. al 2001). As such, in 2004, Garton and Piatt described hydrocephalus as a disturbance of CSF physiology.

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This review will give an overview of the literature surrounding congenital hydrocephalus. As well as covering the causes, diagnoses and treatment of the condition, it will focus on the effect of CSF accumulation on cortical development. The study of model diseases which are also caused by CSF abnormalities will facilitate a greater understanding of the role of CSF in cortical development, and how this may be compromised in hydrocephalus. Exploration of the physiological mechanisms at play will enable researchers and physicians to consider new and innovative courses of treatment, but more crucially, may enable them to find ways of preventing it altogether.


There are a variety of different terminologies which are used to describe what is most widely known as congenital hydrocephalus. Classifying characteristic types of hydrocephalus is crucial as it enables clinicians to make earlier and more accurate diagnoses of the condition, and therefore select the most appropriate courses of treatment as quickly as possible (Rekate, 2009). In 1995 Mori et. al classified hydrocephalus with a focus on the age onset of the condition, and proposed three large subclasses. They regarded congenital hydrocephalus as one class; including fetal hydrocephalus, early life onset hydrocephalus and hydrocephalus that occurs as a result of MMC. Their second class was idiopathic adult hydrocephalus, and the third class included hydrocephalus occuring secondarily to other pathologies such as postmeningitic or posthaemorraghic hydrocephalus.

Hydrocephalus can also be classified into two categories with regard to CSF flow. If it is caused by an obstruction within the ventricles of the brain, then the condition can be termed "communicating hydrocephalus", and results in an accumulation of CSF within the ventricular system. However if the obstruction of CSF flow occurs outside of the ventricles, then it is classified as "non-communicating" hydrocephalus (Dandy, 1919; Rekate, 2009; Thompson, 2009). Generally, the presentation of clinical features such as abnormal head enlargement means that congenital hydrocephalus is not usually difficult to recognise but sometimes a very early intrauterine or a late post-natal onset can be more difficult to diagnose (Mori et. al, 1995). In addition to, or possibly fuelling the difficulties in hydrocephalus diagnosis and classification is the fact that it is caused by a wide range of aetiologies.


The cerebral aqueduct or aqueduct of Sylvius can sometimes incur a stenosis which is one of the most common causes of congenital hydrocephalus, and is also a common complication in a number of other developmental abnormalities. The cerebral aqueduct, otherwise known as the aqueduct of Sylvius, allows CSF flow between the third and fourth cerebral ventricles. As a blockage here impedes this pathway, patients presenting with hydrocephalus as a result of aqueductal stenosis will show dilations in both the third and lateral ventricles, however the fourth ventricle will be unaffected (Magram, 2003).


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Neural tube defects, including spina bifida, are a particularly commom form of congenital neurological defect and are thought to occur in around 1 in 2000 births in the US (Northrup and Volcik, 2000). Myelomeningocele (MMC), otherwise known as open spina bifida, is a form of spina bifida that is commonly associated with hydrocephalus, with around 85% of patients who have MMC also presenting with hydrocephalus. (Dias and McLone, 1993). The main pathology of MMC is a failure of the neural tube to close during development. The neural tube is formed during the third week of gestation, at which point the neural plate can be seen as a thickening of the dorsal neuroectoderm. The cranial end of this tube will go on to become the brain and the caudal end will develop into the spinal cord. Failure of this tube to close properly causes a protrusion through the vertebral arches, which usually manifests itself in a sac structure at the level of the malformation. The sac commonly contains cerebrospinal fluid, meniges and the spinal cord or roots, therefore exposing them to the external environment (Adzick, 2010; Vintzileos, 1983). A feature common to the majority patients with MMC, as well as being associated with other neural tube defects is the Arnold-Chiari II malformation, developmental abnormality which occurs when there is a dislocation of the cerebellar tonsils through the foramen magnum and into the spinal canal (McLone and Dias, 2003).


Similarly, the Dandy Walker malformation is also a congenital malformation. It has variable features including the formation of a cyst on the posterior fossa, upward displacement of the lateral sinuses, atero-lateral displacement of the cerebellar hemispheres and displacement of the tentorium and lateral sinuses, amongst other related malformations. A study by Klein et. al investigating the prognosis of patients with dandy walker malformations found that a large proportion of those with severe dandy walker malformations also presented with hydrocephalus (Klein et. al, 2003; Altman et. al, 1992; Barchovich et. al, 1989)


In contrast to the aforementioned aetiologies, Rolf et. al in 2001 showed that an L1 deficiency in mice is a genetic causative agent of severe hydrocephalus. L1 is a member of the transmembrane glycoprotein immunoglobulin super family and is a neural adhesion molecule. It has been shown to have roles in synaptic plasticity and nerve cell migration, elongation, fasciculation and survival, and therefore must play a crucial role in brain development (Lindner et. al, 1983; Chen et. al, 1993; Lüthi et. al, 1994). Mutations in this gene in humans have been shown to cause CRASH syndrome or L1 disease, of which one of the symptoms is severe hydrocephalus. Other symptoms include corpus callosum hypoplasia and retardation (Fransen et. al, 1995). Rolf and his colleagues however stated that severe hydrocephalus was in fact, a secondary pathology of ventricular enlargement, as this closes off the aqueduct of Sylvius leading to obstructive hydrocephalus.


Aside from fetal malformations, there are a number of other reported causes of congenital hydrocephalus. If the mother is suffering from Toxoplasmosis or Cytomegalovirus at the time of pregnancy, this can often lead to fetal-onset hydrocephalus in the child. Postnatally, infections such as bacterial meningitis can cause the condition, along with intracranial haemorrhages. Further to these reported causes, fetal onset hydrocephalus is often idiopathic, which causes clinicians further difficulties, both in diagnosing the condition and in the selection of a treatment plan (Punt, 1996; Buxton, 2008).


As with many CNS abnormalities, hydrocephalus is not usually associated with a family history and therefore the first opportunity for diagnosis often lies with the fetal ultrasound scans which are taken during pregnancy. A study by Moritake et. al which looked at the diagnosis of congenital hydrocephalus in Japan showed that in fetal onset hydrocephalus, more diagnoses were made using ultrasound than other methods, with the first signs of hydrocephalus usually presenting at 18-20 weeks. However, in postnatal onset hydrocephalus, CT was the preferential mode of diagnosis (Garne, 2010; Moritake et. al, 2008). A study in 2002 by Futagi et. al highlighted the importance of the ratio between the lateral ventricular width and the hemispheral width in the developing brain of hydrocephalus. This can be visualised using either ultrasonography or MRI, and repeated measures of this ratio allow clinicians to determine the severity and speed of onset of the condition, with sudden increase in this ratio indicates that the condition is developing rapidly.

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Current treatment for congenital hydrocephalus usually involves a surgical procedure in which patients are fitted with a shunt mechanism which redistributes the excess CSF to another cavity in the body. A variety of different cavities can be exploited such as the atrium, thoracic duct or the blood stream, however current procedure usually diverts excess CSF to the peritoneum, which is termed a ventriculoperitoneal shunt. However shunts are also commonly associated with problems such as infection, over shunting or shunt failure (Chumas et. al, 2001; Jackson, 1990). An alternative to shunting is third ventriculostomy, in which endoscopy is used to create an alternative route for CSF into the third ventricle. This can eliminate the potential issues associated with shunts, however the procedure is not always successful, meaning the child then has to be fitted with a shunt (Di Rocco et. al, 2006; Drake, 2006).


In 1981, Kohn and his colleagues presented a rat model in which congenital hydrocephalus as a result of CSF flow by aqueductal stenosis is naturally inherited: the H-Tx rat, which has since been the basis for the majority of current hydrocephalus research. Jones et. al have performed extensive studies investigating the role of specific genetic influences in the development of hydrocephalus in H-Tx rats. Initially they characterised the expression of hydrocephalus in their H-Tx strain, describing the H-Tx as an unusual mutant because the frequency of hydrocephalic offspring does not decrease over generations, despite the fact that the breeding pairs are unaffected. In addition, if hydrocephalic offspring are treated with shunts to allow their survival, there is no increase in the prevalence of the condition. This shows that the hydrocephalic rats are not a separate strain as all H-Tx rats have the same propensity for expression, but that the susceptibility genes are not completely penetrable, hence why not all H-Tx rats are hydrocephalic. From their breeding study, they concluded that the most likely scenario would be that all animals are homozygous for the loci controlling hydrocephalus. However at this point, they were unsure as to the mechanisms controlling the percentage of penetration of the susceptibility genes, which was around 40% in their study (Jones et. al, 2000). Although this information may shed some light as to the extraordinary inheritance pattern seen in this particular strain, it does not explain the mechanisms by which these rats develop hydrocephalus, why they do, or what the resulting effects are on cortical development.


CSF is a clear fluid which is produced primarily by the choroid plexuses and ependymal lining of the ventricular system, the total volume of which in humans is thought to be around 140ml (Speake et. al, 2001). The choroid plexuses themselves are epithelial tissues which have a rich blood supply and are responsible for around 65% of CSF production (Wright, 1979; Thompson, 2009). From its secretion into the lateral ventricles of the ventricular system, the normal path of CSF flow is into the third ventricle from whence it drains into the cerebal aqueduct and into the fourth ventricle. Finally, it enters either the subarachnoid space or basal cisterns. CSF reabsorption is facilitated by the arachnoid villi where it is continually reabsorbed and transported into the blood stream (Vintzileos et. al, 1983). Functionally, CSF is widely recognised as having a significant role in the protection of the brain. CSF creates a buoyant environment which allows it to act as a shock absorbent and additionally, it ensures the effective removal of metabolites through CSF drainage. As well as being the primary source of CSF production, the choroid plexus also acts as a barrier between the blood and CSF, regulating the transport of nutrients and peptide hormones across this barrier into the brain. However recent research has postulated that CSF, its constituents, and the choroid plexus have greater roles in neural development, CNS repair and homeostasis than has previously been believed. (Redzic et. al, 2005).

CSF is thought to have two key roles during early embryonic brain development which work in conjunction with each other. Firstly, it is thought that an accumulation of CSF within the ventricles causes a regulated increase in the resistance of the neuroepithelium, therefore stimulating an increase in neuroepithelium proliferation resulting in overall brain expansion. The second role is a regulatory one, which proposes that trophic factors within the CSF are crucial in regulating the behaviour of the neuroepithelial cells regarding proliferation, differentiation and survival (Gato and Desmond, 2009). In 2008, Bachy et. al explored the role of embryonic CSF particles, namely lipoprotein and exosome-like particles, on early developmental processes such as expansion of the embryonic brain and neuroepithelial cell development. After confirming their presence within the embryonic CSF, they labelled the lipoprotein particles with lipophilic dyes and noted accumulations at recognised 'signalling centres' along the neuroepithelium. These signalling centres are known to be important in the regulation of regionalisation and differentiation of the brain during development via the production of growth factors e.g. FGF-8 and morphogens such as SHH. It is thought that through interactions with the neural epithelium at these signalling centre sites, the lipidic particles play a role in the trafficking of these messengers. The presence of exosomal particles was also identified, and it was noted that high levels of exsosomal activity took place at various regional locations along the epithelium of the developing neural tube, suggesting that these exosomal particles may therefore facilitate the transduction of signals which promote neuroepithelial development.

Although the wide range of aetiologies do to some extent, explain the anatomical features which occur in congenital hydrocephalus, they do not account for the neurological or cortical deficiencies which result in the affected children, even after the primary pathology has been reduced by shunt treatment (McAllister and Chovan, 1998). There have been a number of reports stating that children with congenital hydrocephalus may have reduced intelligence levels, such as that of Futagi et. al in 2002, who stated that they saw a strong correlation between an early onset of the condition and poor intelligence. Furthermore, those patients who were treated for postnatal onset hydrocephalus generally had a stronger intellectual quotient than those who were treated for in utero onset hydrocephalus. In 2002 Mashayekhi et. al explored the physiological role for CSF in cortical development, and carried out studies to investigate the presence and nature of cortical maldevelopment in hydrocephalus, using the H-Tx rat as a model. In terms of morphology, it was found that the cortex of the affected H-Tx rats showed distinct growth hindrance, with a 30-60% reduction in cortical thickness compared to controls or unaffected H-Tx rats. This reduction was first noted after day 18, when the cerebral aqueduct blockage is known to ensue. In addition, the germinal epithelium thickness was significantly reduced in hydrocephalic rats, except for at day 21, where it was shown only to be significantly different from the unaffected H-Tx rats and not from the control wistar group. Importantly, the decreased thickness was most prominent during days 19-20 of gestational development and 1-2 days post birth, days when there would normally be a characteristic surge of germinal matrix stem cell activity, leading to the production of neuronal and glial cell precursors.

Mashayekhi et. al suggested a number of reasons as to why germinal layer thickness is reduced in hydrocephalic rats. One proposed explanation in this case was that a possible abnormal increase in intracranial pressure caused stretching of the brain. However it was shown experimentally that this was not the case. Cranial plates in the H-Tx rat do not fuse until 10 days post gestation, and as there is not reported to be a distinct increase in intracranial pressure until this time, it probably not a factor in germinal epithelium thickness and therefore will not affect germinal matrix cell activity. This is a key point as there has been previously been some misconception in the literature, with the assumption that the brain damage often seen in hydrocephalus is directly related to the increased intracranial pressure that develops if hydrocephalus is left untreated after birth (Frim, 1998).

To further support their hypothesis that an obstruction of CSF flow results in deficient cortical development, in vitro studies were carried out which analysed cortical cells taken from both hydrocephalic and normal rats. Once removed from affected H-Tx rats and cultured normally, the cortical cells were able to proliferate as normal, however when cultured with CSF taken from affected H-Tx ventricles, proliferation ceased. Furthermore, proliferation in the cells extracted from non-hydrocephalic rats was inhibited when cultured with CSF taken from hydrocephalic ventricles. This demonstrates that there is no abnormality in the cortical cells themselves which prevents them from proliferating, rather that an external factor i.e. the CSF which has accumulated within the ventricular system, is having an inhibitory effect on proliferation (Mashayekhi et. al, 2002).

Following on from their previous study into the role of CSF in cortical maldevelopment, the same team (minus Pourghasem) analysed the cell cycle control which underlies these developmental abnormalities. The aforementioned in vitro studies were supported when it was shown that the unaffected cortical cells showed a dose dependant decrease in proliferation when cultured with CSF from affected rats. It was also shown that, in vivo, a large proportion of the germinal matrix cells present in hydrocephalic rats are stuck in the S-phase of the cell cycle, and therefore do not reach G2 or the mitotic stage and as such, are not able to proliferate. However when these cells are extracted and cultured normally, they are then released from the S phase and are able to proliferate normally. Interestingly, the S phase of the cell cycle is most commonly associated with repairing damaged DNA or initiating apoptosis of severely distorted DNA, however apoptosis of the germinal matrix is not a significant feature of hydrocephalus until post gestation when intracranial pressure is known to increase.

This further supports the suggestion that germinal matrix cell proliferation is inhibited by CSF. They postulate that the inhibitory effects of CSF in this case may be due to an altered concentration of CSF constituents, either as a result of the obstruction of CSF flow, or because the choroid plexus changes causing the release of a new factor into CSF which leads to inhibition (Owen-Lynch, 2003).


A possible explanation for the cell cycle arrest seen in hydrocephalic germinal matrix cells is an imbalance in cerebral folate levels. Folates, such as 5-MTHF, are transported across the blood to brain barrier and into the CSF compartment via active transport across the choroid epithelium by the FR1 folate receptor. There are other folate receptors, however FR1 is the primary receptor in the choroid epithelium. 5-MTHF moves across the capillaries supplying the choroid epithelium and binds to FR1 folate receptors on the basolateral surface, where it is then actively transported into the epithelial cell. The expression of these folate receptors is stimulated by the presence of 5-MTHF in the blood. 5-MTHF travels across the cell and diffuses passively into the CSF from the apical side of the epithelium via a reduced folate carrier 1 (Ramaekers et. al, 2002). The role of folate in neural tube defects has already been reported by recent epidemiology studies regarding the fortification of cereal and grain products with folic acid.

It has been shown that in affected hydrocephalic H-Tx rats, the uptake of folate in the germinal matrix cells is reduced. This issue was addressed by Cains et. al (2009), with one suggestion being that an absence or malfunction of a crucial folate transport protein causes a lack of bioavailable folates such as 5-MTHF in the CSF. As seen in some of the aforementioned extraction studies, when affected germinal matrix cells are cultured normally, cell proliferation is regained. This shows that there is no inherent fault in these cells, and that extrinsic factors must be having an inhibitory effect proliferation. A second explanation suggested that an alteration or default in folate metabolism causes a lack of folate metabolites within the CSF. When cortical cells from unaffected H-Tx rats were cultured with CSF from affected H-Tx rats, germinal epithelium proliferation ceased. However, when a range of folate metabolites were added to this culture, the inhibitory effects of the CSF were minimised and normal cell proliferation ensued. These metabolites had varying effects, for example when added to germinal epithelial cells, tetrahydrofolate did in fact decrease cell proliferation, however this decrease was not made any worse by the addition of CSF from an affected H-Tx rat. Where as thymidine had the opposite effect, causing an increase in cell proliferation yet similarly, this was unchanged by the further addition of affected H-Tx CSF. The fact that the addition of folate metabolites can rescue the inhibitory effects of affected H-Tx rat CSF to germinal epithelial cells and allow them to proliferate, supports the idea that the disturbed cell cycle observed in the hydrocephalic brain is likely to be a result of a lack of folate metabolites within the CSF.

As their in vitro studies clearly demonstrated that folate metabolism must play a key role in germinal cell proliferation in the developing brain, Cains et. al then investigated the effects of various different maternal folate supplements on cortical development. The supplements given were folic acid, folinic acid, tetrahydrofolate and two mixtures; mix 1 containing an equal mixture of folinic acid and tetrahydrofolate diluted with saline and mix 2 containing a higher, undiluted mixture of folinic acid and tetrahydrofolate. The maternal supplements reach the fetal CSF via the placenta after they are metabolised by the mother, however the exact mechanisms involved in the process are not currently well understood. Administration of folic acid alone resulted in an increase in the incidence of hydrocephalus. However all of the other supplements were found to decrease the incidence of hydrocephalus, most notably mix 2, which caused the incidence to reduce by more than half from 33% to 14%. In addition to reducing the incidence of hydrocephalus in the offspring, development of the fetal cortex was also improved. Both affected and unaffected H-Tx rats present with a decreased cortical thickness when compared with the SD control rat. When the maternal rat was treated with supplements, the resulting affected H-Tx rats showed an increased cortical thickness compared to that of the control affected H-Tx rats who received a saline supplement, however this was still less than the thickness seen in both the unaffected H-Tx rat and the SD control rat. Unaffected H-Tx rats also saw an increase in the cortical thickness. BrdU staining studies also showed that cell proliferation was increased in response to the maternal supplements, although this was still lower in the affected H-Tx rats than in control SD and unaffected H-Tx. Furthermore, nestin staining showed that the increases seen in cell proliferation also lead to an increase in neuronal progenitor cells. As maternal folate supplementation lead to increases in both unaffected and hydrocephalic H-Tx rats, it supports the thought that folate plays a vital role in preventing congenital hydrocephalus itself and therefore preventing the resulting developmental restrictions (Cains et al., 2009).


Currently, all pregnant women are recommended to take folic acid supplements to maintain the mother's folate levels during pregnancy. This ensures that the fetus also has an adequate folate supply and reduces the risk of neural tube defects occurring during the pregnancy. Folic acid is a synthetic form of folate which is found in food and supplements, and in 1998 the US began to fortify all grain products with folic acid, in the hope of reducing supplement compliance issues, as well as catching unanticipated pregnancies (Bailey, 2000; Herbert and Bigaouette, 1997). Other countries have since done the same and a recent study in Canada showed that a 46% reduction in the prevalence of neural tube defects occurred between 1993 and 2002 following the fortification of grain products (De Wals, 2003; De Wals, 2007). However, folic acid is not known to reduce the incidence of hydrocephalus and as seen above, Cains et al. (2009) reported that folic acid actually caused an increase in the incidence of hydrocephalus in the H-Tx rats. Furthermore, folic acid is also known to mask pernicious anaemia and Vitamin B12 deficiency in humans (Herbert and Bigaouette, 1997).


Cerebral folate deficiency syndrome (CFD) was characterised and later defined by Ramaekers et. al as a neurometabolic condition resulting in low levels of 5-MTHF in the CSF and central nervous system, despite normal levels being present within the red blood cells and plasma (Ramaekers et. al, 2002; 2004). The resulting effect of low CSF 5-MTHF levels is in a decrease in folate dependant post natal development of the central nervous system e.g. cortical thickness and germinal cell proliferation. The symptoms of CFD usually present themselves in what are perceived to be otherwise healthy babies from around 4 months after birth and the following prognosis is not good. Early symptoms include involuntary ballistic movements and ataxia, and a mental retardation can be noted by around 2 years of age. Further symptoms include sensorineural hearing loss and there is also a strong connection to autism, with around one third of individuals with CFD syndrome also being within the autism spectrum. Secondarily to low levels of 5-MTHF in the CSF, CFD patients also experienced reduced levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) in association with normal levels of the dopamine metabolite homovallinic acid (HVA). This alteration in the 5HIAA:HVA ratio could be a factor influencing psychomotor retardation and ataxia (Ramaekers et. al, 2002).

The physiology behind CFD is suggested to be a result of auto-antibodies which bind to the folate receptor, therefore preventing 5-MTHF from being transported across the blood to CSF barrier, thus resulting in a decreased concentration within the CSF. This hypothesis was posed and tested experimentally by Ramaekers et. al in 2005. CSF was acquired from lumbar punctures of 28 patients and a high-performance liquid chromatography was performed. Using electrochemical detection they were able to determine whether the patients did in fact have reduced 5-MTHF levels in their CSF sample. If 5-MTHF levels were low and the patient also presented with two of the other associated symptoms, then a formal CFD syndrome diagnosis was made. Following this, patients were given a folinic acid supplement and were examined at specific time points, with a second lumbar puncture examination taking place 6 months after the original sample was taken. From these samples, serum assays were performed to identify the presence or absence of auto-antibodies against membrane bound folate receptors and compared to 28 control samples. It was found that 25 out of the 28 subjects showed auto-antibodies which blocked folate receptors whereas none of the age matched control subjects showed auto-antibodies to the folate receptor. This suggests that CFD syndrome results from impaired transport of cerebral folate metabolites such as 5-MTHF into the CSF across the blood to CSF barrier as a result of blockage by auto-antibodies for the folate transporters. Additionally, it was shown that the auto-antibodies have a high affinity for the folate receptors on the epithelial cells in the choroid plexus, which further prevents receptor-folate binding. There is not currently an effective method for the diagnosis of CFD, particularly not until its onset at around 4-6 months. However, because folinic acid can enter the cerebrospinal fluid via a reduced folate carrier rather than attempting to cross via the blocked autoantibody folate receptor which would require displacement of the autoantibody, the levels of folate can be normalised. Therefore treatment with pharmacologic doses of folinic could be used to effectively appease the onset of CFD (Ramaekers et. al, 2005).

There are no symptoms which are systemic to all cases of this syndrome and family histories do not currently show any hereditary pattern in CFD syndrome, which means that it can be difficult to diagnose and diagnoses can be as late as age 17 (Djukic, 2007). Additionally, the only biochemical marker that could potentially be used to make an early diagnosis of CFD would be to detect low levels of 5-MTHF, the measuring of which would require a CSF sample via lumbar puncture, which would be unsuitable for very young babies. In terms of treatment, patients were treated with folinic acid and it was found that those who were treated before the age of 6 years showed a distinct improvement in their symptoms, however those treated after this age showed a lesser and slower response, however in both cases, folinic acid treatment prevented worsening of the condition (Ramaekers et. al, 2005).


Rett syndrome is a progressive neurological disease that most commonly results from a mutation in the MECP2 gene and almost exclusively affects females. The affected child appears to be normal at birth, but symptoms such as declining head circumference, apraxia, ataxia, hand movements, loss of speech, and cognitive disorders and autistic signs, start to develop from around 6 months of age (Hagberg, 2005; Lotan and Ben-Zeev, 2006; Ramaekers et. al, 2003). Interestingly, these neurological characteristics pose a strong similarity with those seen in cerebral folate deficiencies. This indicates that folate may also play some role Rett syndrome, and indeed patients do show reduced levels of 5-MTHF in the CSF, despite having normal serum levels. In 2003 Ramaekers et. al proposed a number of potential hypotheses for this phenotypic characteristic. The MECP2 gene encodes for the methyl-CpG-binding protein which represses the transcription of methylated DNA. This is important because one theory was that mutations in this gene prevent the silencing of transcription, resulting in unlimited gene expression, and the transcription of genes that would otherwise be silent to produce defunct folate binding proteins. However this theory is not likely to be correct because 5-MTHF levels elsewhere in the body are found to be normal in Rett syndrome patients. Other suggestions include abnormal post-translational folding of the binding protein which would have a detrimental effect on the specificity of the folate binding site, or that deficient folate transport across the choroid epithelium occurs as a result of poor endo- and potocytosis of the folate binding protein on to the cell membrane. However these scenarios, are too, unlikely and there is currently no explanation for why levels of 5-MTHF in CSF are low in Rett syndrome.

Similarly to CFD, supplementation with folinic acid can lead to a distinct improvement in the presentation clinical features and in this study, 4 patients were given folinic acid supplements for a number of years. One particular patient who had previously been bedridden was able to assume a kneeling position and another was able to bear her own weight and sit up. There were also reported improvements in social skills and the frequency and severity of seizures. Furthermore, the low levels of 5MTHF in the subjects were rescued with folinic acid supplementation in all patients (Ramaekers et. al, 2003).


CSF is clearly a crucial component in facilitating normal cortical development and all the conditions considered in this review demonstrate the detrimental effects of CSF abnormalities on cortical development. As well as creating neuro-epithelial resistance and producing trophic factors, CSF also provides the brain with sufficient folate metabolites which are important in the maintenance of the cell cycle in the developing cortex. Both Rett syndrome and CFD are key models in demonstrating the importance of folate in CSF and the fact that Rett syndrome, CFD and Hydrocephalus share some common symptoms suggests that although the primary aetiologies are different, the resulting low levels of folate metabolites within the CSF have the same effects on cortical development. To further support this conclusion, all three conditions responded well to folate supplementation, with folinic acid being a particularly successful treatment for both Rett syndrome and CFD, as well maternal supplements significantly decreasing incidence of hydrocephalus in H-Tx rats. In addition to decreasing the incidence of the condition, sufficient and appropriate folate supplementation will also protect against deficient cortical development in those patients who still do develop the condition.

The evidence demonstrates that CSF plays a crucial role in the maintenance of normal cortical development, and when normal CSF physiology is compromised, the resulting effects are detrimental. It is clear that there is a great need to reduce the prevalence of neuro-developmental conditions such as hydrocephalus, neural tube defects, CFD and Rett syndrome to name a few. As well as reducing the resulting pain and social consequences that these diseases inflict on the sufferers, it is also important to consider both the social and economic costs of the relentless commitment and patience which is provided by parents, carers and clinicians.


This review has therefore prompted the concept of a cereal bar which will act as a vehicle for folate supplements for expectant mothers, with the hope of minimising the cortical maldevelopment associated with congenital hydrocephalus, as well as reducing the prevalence and severity of other neuro-developmental conditions. The unique selling point of this product is that it will contain folinic acid and Metafolin, a stable form of 5MTHF, in order to avoid the negative effects associated with folic acid. In addition, it will also contain Vitamin B12 ensure there is no masking of Vitamin B12 deficiency or pernicious anaemia by folate. Aside from folate, it will also contain Vitamin D and inositol. Vitamin D is known to prevent bone and muscle weakness, and may also prevent cancers such as colon, breast and prostate cancer (Hollick, 2001), and a recent cohort study showed that 36% of the young adults studied had Vitamin D deficiencies, with this value being significantly higher in older adults (Tangpricha et. al, 2002). Finally, it will include inositiol as this has also been shown to act against the 30% of neural tube defects which do not result from folate deficiencies (Green and Copp, 1997). As well as fulfilling an essential dietary component for pregnant women, this product will also appeal to the wider public as a tasty, convenient and healthy snack with an array of nutritional benefits.