What’s new in pontocerebellar hypoplasia?An update on genes and subtypes

Baseline

PCH was first described over 100 years ago and was initially thought to be a condition where parts of the brain simply failed to grow properly. Later research showed that many forms of PCH involve early brain degeneration starting before birth. Over time, researchers identified many subtypes based on symptoms, brain imaging, and genetic causes. All known PCH types are inherited in an autosomal recessive manner, meaning both parents must be carriers of the gene mutation.

PCH1

PCH1 combines underdevelopment of the cerebellum and pons with degeneration of motor neurons in the spinal cord, similar to spinal muscular atrophy. This leads to severe muscle weakness, low muscle tone, and breathing problems. Some forms are fatal shortly after birth, while others allow survival into childhood or adolescence. Several genes can cause PCH1, including EXOSC3, EXOSC8, SLC25A46, and rarely VRK1. Disease severity varies widely depending on the gene and mutation.

PCH2

PCH2 is the most common and best-studied form. It is most often caused by a specific mutation in the TSEN54 gene. Babies show feeding and swallowing problems, and later develop severe movement disorders, epilepsy, and almost complete lack of cognitive development. Head size becomes progressively smaller due to brain atrophy. Brain imaging shows a characteristic “dragonfly” appearance of the cerebellum. Life expectancy is reduced, and many children do not survive beyond childhood.

PCH3

PCH3 is marked by progressive small head size, seizures, growth delay, and distinctive facial features. Unlike PCH2, typical involuntary movement disorders are absent. It is caused by mutations in the PCLO gene. Only a few families worldwide have been described.

PCH4&5

PCH4 and PCH5 represent the most severe end of the TSEN54-related disease spectrum. Symptoms often begin before birth and include excessive amniotic fluid, joint contractures, breathing failure, and severe brain underdevelopment. Survival beyond the newborn period is rare. PCH5 is now considered part of PCH4 rather than a separate condition.

PCH6

PCH6 is associated with severe epilepsy starting in infancy, progressive brain atrophy, and often high levels of lactic acid, suggesting mitochondrial dysfunction. It is caused by mutations in RARS2, a gene needed for energy production in brain cells. Development is severely delayed, and seizures are often difficult to control.

PCH7

PCH7 is unusual because it is characterized by brain malformations with disorders of sex development, especially in boys. Children have severe developmental delay, muscle tone abnormalities, seizures, and profound underdevelopment of the pons and cerebellum. It is caused by mutations in the TOE1 gene.

PCH8

PCH8 is ultra-rare and appears to be non-progressive, meaning the condition does not worsen over time. Children have severe developmental delay and movement disorders, but some can walk independently. Brain imaging shows marked underdevelopment of the pons and cerebellum. The cause is a mutation in CHMP1A, a gene involved in cell growth and gene regulation.

PCH9

PCH9 causes progressive small head size, severe developmental disability, visual impairment, swallowing difficulties, and muscle stiffness. Older patients may develop nerve damage. It is caused by mutations in AMPD2, which disrupts the production of important cellular building blocks called purines.

PCH10

PCH10 has been described mainly in families from Turkey. Children have severe developmental delay, seizures, progressive stiffness, and nerve damage. Brain imaging shows brainstem abnormalities but only mild cerebellar involvement. It is caused by mutations in CLP1, which interacts with the TSEN complex and is involved in RNA processing.

PCH11

PCH11 is another non-degenerative form. Children have developmental delay, low muscle tone, and small head size, but some can walk and show limited voluntary movement. It is caused by mutations in TBC1D23.

Management and Treatment

There is no cure for any form of PCH. Treatment focuses on managing symptoms:

• Feeding support (tube or PEG feeding)
• Monitoring and treatment of breathing problems
• Anti-seizure medications
• Physiotherapy and supportive equipment

Some medications may help specific symptoms, but responses vary. Experimental treatments are being explored for certain subtypes, such as PCH9, but none are yet established.

Differential Diagnosis

Many other conditions can resemble PCH on brain imaging, especially disorders that also cause cerebellar and brainstem underdevelopment. Careful interpretation of MRI findings, clinical symptoms, and genetic testing is essential.

Conditions that can mimic PCH include:

• Congenital disorders of glycosylation
• CASK-related disorders
• Tubulin-related brain malformations
• RELN and VLDLR-related conditions
• Muscular dystrophies affecting the brain
• Hoyeraal-Hreidarsson syndrome
• Spinocerebellar ataxias
• ATADA3-related disorders
• Extreme prematurity

Each condition has distinguishing features that can help differentiate them from PCH.

Pathomechanisms of PCH

Many PCH subtypes are caused by defects in RNA processing or protein production, which are essential for brain development. Others involve mitochondrial dysfunction, problems with cell structure, or impaired transport within cells. The cerebellum appears especially vulnerable to said impairments during late pregnancy, a period of rapid growth, which may explain why it is so severely affected.

Incidence of PCH

PCH is extremely rare. The most common form, PCH2A, is estimated to occur in fewer than 1 in 200,000 births. Many subtypes are known from only a handful of families worldwide.