Pontocerebellar hypoplasia

Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. People with these conditions have an unusually small and underdeveloped cerebellum, which is the part of the brain that coordinates movement. A region of the brain called the pons also fails to develop properly. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals from the cerebellum to the rest of the brain.

Researchers have described six forms of pontocerebellar hypoplasia. These forms have somewhat different signs and symptoms and different genetic causes. All forms of this condition are characterized by abnormal brain development, problems with movement, delayed development, and intellectual disability. The signs and symptoms are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.

Pontocerebellar hypoplasia type 1 (PCH1) causes problems with movement characteristic of spinal muscular atrophy, which is a genetic disorder that affects the control of muscle movement. Other signs and symptoms of PCH1 include very weak muscle tone (hypotonia), joint deformities called contractures, a small head size (microcephaly) that becomes more pronounced as the body grows, and breathing problems that are evident at birth. Most children with PCH1 live only into infancy.

Major features of pontocerebellar hypoplasia type 2 (PCH2) include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of speech and communication. Affected children typically develop jitteriness (generalized clonus), muscle spasms, and other movement abnormalities. Many also have impaired vision, seizures, and microcephaly that becomes more pronounced as the body grows. Another form of pontocerebellar hypoplasia, type 4 (PCH4), is very similar to PCH2. However, children with PCH2 often live into childhood, while those with PCH4 have serious breathing problems and usually do not survive past infancy.

Pontocerebellar hypoplasia type 3 (PCH3), type 5 (PCH5), and type 6 (PCH6) are very rare. PCH3 is associated with the degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). PCH5 is very severe, and the few individuals found to have this form of the disorder have died before or soon after birth. PCH6 is the most recently discovered subtype; it is characterized by hypotonia, poor feeding in infancy, delayed development, and seizures.

The prevalence of pontocerebellar hypoplasia is unknown, although most forms of the disorder appear to be very rare.

The various forms of pontocerebellar hypoplasia are caused by mutations in several different genes. VRK1 gene mutations have caused PCH1 in at least one family. Mutations in three related genes, TSEN2, TSEN34, and TSEN54, can result in PCH2. TSEN54 gene mutations are also responsible for PCH4. Mutations in the RARS2 gene can cause PCH6. The genetic causes of PCH3 and PCH5 are unknown.

The genes that have been found to cause pontocerebellar hypoplasia appear to play essential roles in the development and survival of nerve cells (neurons). Many of these genes are known or suspected to be involved in processing RNA molecules, which are chemical cousins of DNA. Fully processed, mature RNA molecules are essential for the normal functions of all cells, including neurons. However, it is unclear how mutations in genes related to RNA processing disrupt the normal development of the cerebellum and pons.

Researchers are working to find additional genetic changes that cause the different forms of pontocerebellar hypoplasia.

Read more about the RARS2, TSEN2, TSEN34, TSEN54, and VRK1 genes.

All of the recognized forms of pontocerebellar hypoplasia are inherited in an autosomal recessive pattern, which means both copies of the associated gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.