TSEN54 Pontocerebellar Hypoplasia

Clinical characteristics: TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known.

1. PCH2. Children usually succumb before age ten years (those with PCH4 and 5 usually succumb as neonates). Children with PCH2 have generalized clonus, uncoordinated sucking and swallowing, impaired cognitive development, lack of voluntary motor development, cortical blindness, and an increased risk for rhabdomyolysis during severe infections. Epilepsy is present in approximately 50%.

2. PCH4. Neonates often have seizures, multiple joint contractures ("arthrogryposis"), generalized clonus, and central respiratory impairment.

3. PCH5 resembles PCH4 and has been described in one family.

Diagnosis/testing: The diagnosis of TSEN54-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of biallelic TSEN54 pathogenic variants.

Management: Treatment of manifestations: PCH2: Treatment of irritability, swallowing incoordination, epilepsy, and central visual impairment is symptomatic. Physiotherapy can be helpful. Adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis. PCH4 and PCH5: No specific therapy is available.

Surveillance: PCH2: Routine monitoring of respiratory function, feeding, musculoskeletal and neurologic manifestations, developmental milestones, and family needs.

Genetic counseling: TSEN54-PCH is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TSEN54 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the TSEN54 pathogenic variants have been identified in an affected family member, molecular genetic testing to determine carrier status of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.