Pontocerebellar hypoplasia type 2 (ORPHA:2524)
A rare, genetic form of pontocerebellar hypoplasia characterized by pontocerebellar hypoplasia and progressive neocortical atrophy that manifests clinically with uncoordinated sucking and swallowing, and generalized clonus in the neonate. In early childhood, spasticity, chorea/dyskinesia, seizures and progressive microcephaly develop. Voluntary motor development is lacking.
Epidemiology
Pontocerebellar hypoplasia type 2 (PCH2) is reported in at least 81 families to date. It is the most common form of pontocerebellar hypoplasia.
Clinical description
After an uneventful pregnancy and birth without dysmorphic features, affected neonates present usually, but not always, with dysphagia due to bucco-pharyngeal incoordination, respiratory and feeding difficulties and generalized clonus. Extrapyramidal dyskinesia with mixed spasticity such as chorea, athetosis and dystonia develop later. From infancy onward, affected children develop progressive microcephaly, central visual impairment, seizures and a severe impairment of cognitive and motor development, marked by an impaired motor development with failing head control, lack of voluntary hand control and the absence of speech and communication. PCH2 is often fatal in early childhood.
Etiology
PCH2 is generally caused by homozygous mutations in the TSEN54 gene (17q25.1), most frequently a founder mutation, prevalent in families of European extraction: p.A307S/A307S or missense mutations. Rarely mutations in the TSEN2 (3p25.2), TSEN34 (19q13.42), TSEN15 (1q25.3), SEPSECS (4p15.2) or VPS53 (17p13.3) genes are reported.
Diagnostic methods
Diagnosis is made is based on a combination of neuroradiologic and clinical findings : MRI demonstrates variable neocortical atrophy, progressive in time, flattening of the caudate nuclear heads, and pontocerebellar hypoplasia with a typical dragonfly-like cerebellar pattern on coronal sections caused by the flat hemispheres heavily reduced in size together with a comparatively spared vermis. Genetic testing is recommended to confirm the diagnosis.
Differential diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital Disorder of Glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH. Extreme prematurity (gestational age <32 weeks) can cause cerebellar hypoplasia of variable degrees.
Antenatal diagnosis
In case of risk for recurrence of PCH2, genetic prenatal diagnosis, by amniocentesis or chorionic villus sampling and cytogenetic analysis, may be offered. Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.
Genetic counseling
PCH2 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH2. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH and involves medication for treatment of dystonia, dyskinesia and seizures and percutaneous endoscopic gastrostomy tube feeding.
Prognosis
Prognosis is variable; the majority of patients will not reach puberty. Life threatening complications include sleep apnea, rhabdomyolysis and malignant hyperthermia. Cot death is possible.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK