Developmental Abnormalities

Cerebellar hypoplasia

The cerebellum does not reach its normal developmental potential with primary degeneration of the granular layer. Global cerebellar hypoplasia may result from a variety of exogenous or endogenous factors. It is found as a result of intrauterine exposure to drugs (eg. Phenytoin) or irradiation, and as an autosomal recessive trait in a variety of chromosomal disorders, such as trisomies 13, 18 and 21. The MATH1 gene may be a candidate for this disorder. 

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Real-life example in Charley the cat, see video.

Dandy Walker Malformation

DWM is a cerebellar malformation characterized by by the following triad: 1) cystic dilatation of the fourth ventricle and an enlarged posterior fossa with upward displacement of the lateral sinuses, confluens sinuum and tentorium cerebelli. 2) varying degrees of vermian aplasia or hypoplasia, and 3) hydrocephalus.

Although DWM resembles JSRD, it does not present the typical "molar tooth" sign on the MRI. Neither does it present itself in a Mendelian-linked fashion. The first genes identified as the cause of DWM included Zinc finger in cerebellum family of transcription factors such as ZIC1 and ZIC4. 

In half of the cases, mental dysfunctions and seizures have been reported to be part of the symptoms associated with DWM. Other CNS malformations include neuronal heterotopias, polymicrogyria, schizencephaly, occipital encephaloceles, and lumbosacral meningoceles. The etiology of DWM is still unknown. 

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Image 2: Dorsal View

Image courtesy of https://farm4.static.flickr.com/3185/2478463802_959c6180ce.jpg. This image is in the public domain and thus free of any copyright restrictions.

Joubert Syndrome and Related Disorders (JSRDs)

JSRD is a recessively inherited condition clinically defined by congenital ataxia, hypotonia, episodic breathing dysregulation, abnormal eye movements and mental retardation. It is caused by a specific malformation of the brainstem, cerebellum, and the cerebellar peduncles, including vermis hypoplasia.

The underlying genetic cause is still unknown and currently the 5-year survival rate is about 50%. There is no treatment available so the only symptomatic relief can be given.   

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Lissencephaly

Lissencephaly literally stands for “smooth brain” and is a rare genetic brain malformation caused during the 12th to 24th week of gestation. It is characterized by agyria in the cerebral cortex and microcephaly resulting from a defect in neuronal migration. Symptoms include psychomotor retardation, failure to thrive, seizures, and muscle spasticity accompanied by severe mental disorders.

Causes of lissencephaly can be either viral infections of the uterus or fetus during the first trimester or genetic mutations of the reelin gene or other genes on the X chromosomes and chromosome 17. These severe malformations in the brain will most likely not respond to treatments, so instead, only supportive care and symptomatic relief such as shunting or gastrostomy can be provided.

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Pontocerebellar Hypoplasia

These are a group of mostly autosomal recessive disorders characterized by a smaller volume of the pons which may not exceed the width of the medulla oblongata and varying degrees of cerebellar hypoplasias up to complete absence, which is very rare. Most types of pontocerebellar hypoplasias arise in the fetal period, suggesting a rhombic lip defect and the MATH1 gene as a candidate for this disorder.

Pontocerebellar hypoplasias can be classified into congenital olivopontocerebellar atrophy, the type I and type II pontocerebellar hypoplasias with spinal atrophy and extrapyramidal dysfunction, respectively, and the congenital disorders of glycosylation, type I and III.

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Rhomboencephalosynapsis

A rare cerebellar malformation characterized by vermian agenesis or hypogenesis, and dorsal fusion of the cerebellar hemispheres and dentate nuclei, which may be explained by a defect in dorsal patterning at the midbrain-hindbrain border. Clinical findings range from mild truncal ataxia and normal cognitive abilities to severe cerebral palsy and mental retardation. Most cases are irregular and patients have a low life expectancy.

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