Pontocerebellar hypoplasia type 1

Pontocerebellar hypoplasia type 1 (PCH1) may first present in the prenatal period when mothers feel reduced movement of the baby (reduced fetal movement). The presence of too much fluid surrounding the baby in the womb (polyhydramnios) may also be noted. In most cases, signs and symptoms of PCH1 can be observed in the newborn period, as babies may not be able to breathe properly (respiratory insufficiency) and may have muscle weakness (hypotonia). Babies may also be born with the inability to move joints (joint contractures).^[2]

Later in the newborn period, other symptoms may become apparent including visual impairment, uncontrolled movements of the eye (nystagmus), and uncontrolled movements of the muscles (ataxia). Babies with PCH1 may struggle to feed at the breast or with a bottle because their swallowing muscles are weakened. After a few months, the baby may have a smaller than typical head size (microcephaly).^[4] Affected babies also typically do not meet milestones such as being able to sit up, and they may have intellectual disability.^[1]

In some cases, babies affected by PCH1 may not show signs or symptoms of the disease until they are a few months old. In these cases, the baby may have a better long-term outlook than other affected individuals.^[2] Individuals who survive past infancy may develop seizures as they get older.^[4]

About half of all cases of pontocerebellar hypoplasia type 1 (PCH1) are caused by mutations (changes) in the EXOSC3 gene. Other genes that have been associated with PCH1 include TSEN54, RARS2, and VRK1.^[1] These genes are normally responsible for helping the body process RNA, which is a form of genetic information similar to DNA. When RNA cannot be processed properly, the body does not receive instructions about how it should work and develop. It is thought that the brain and muscles are particularly susceptible to changes in RNA processing. Therefore, when there are changes in any of the genes mentioned above, the body does not process RNA properly, causing the brain and muscles to not work properly.^[1]

Pontocerebellar hypoplasia type 1 (PCH1) is inherited in an autosomal recessive manner.^[1] This means that both copies of the EXOSC3, TSEN54, RARS2, or VRK1 genes must be changed in order to have symptoms of the disease. We inherit one copy of each gene from our mother and the other from our father.

People with a mutation in only one copy of a gene causing PCH1 are known as carriers. Carriers typically do not show signs and symptoms of the disease. When two carriers of PCH1 have children together, for each child there is a:

• 25% chance that the child will have PCH1
• 50% chance that the child will be a carrier of PCH1 like the parents
• 25% chance that the child will have two working copies of the gene, so the child will not have PCH1 and will not be a carrier.

Pontocerebellar hypoplasia type 1 (PCH1) is typically diagnosed when healthcare professionals see signs and symptoms consistent with the disease. Tests that may be ordered include an MRI or CT scan of the brain to visualize the cerebellum and the pons. Other tests such as metabolic tests may also be completed to rule out other causes of the symptoms.^[2] If PCH1 is the suspected cause of the symptoms, genetic testing may be done to confirm the diagnosis.^[5]

Treatment for pontocerebellar hypoplasia type 1 (PCH1) is aimed at treating the signs and symptoms present in each individual. Management options may include physical therapy or braces on the limbs to help with joint contractures, ventilation machines for breathing assistance, anti-seizure medication, and a feeding tube if the child is not able to eat without one.^[4] These treatment options are aimed at relieving some of the symptoms of PCH1, but there is no cure for the disease.^[2][5]

Unfortunately, most children with pontocerebellar hypoplasia type 1 (PCH1) pass away within the first year of life. In some cases, affected individuals have survived later into childhood or into early adulthood. These individuals are most often those who did not show signs and symptoms right at birth, but instead developed symptoms during the first few months of life.^[2] Certain particular mutations within the EXOSC3 gene may be associated with a better prognosis, including a longer estimated survival time.^[5][6]