Non-syndromic pontocerebellar hypoplasia (ORPHA:98523)
A rare group of neurodegenerative disorders with a prenatal onset characterized by hypoplasia and/or atrophy of the cerebellum and pons. Involvement of supratentorial structures is variable. Multiple forms have been described based on severity, age of onset and clinical presentation.
Epidemiology
Prevalence of pontocerebellar hypoplasias (PCH) is unknown. Most subtypes appear to be very rare.
Clinical description
PCH is a clinically heterogeneous group of disorders, characterized by hypoplasia and/or atrophy of cerebellum and pons. Atrophy of supratentorial structures is variably present. There is great clinical variation both between and within the different forms. Delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and epilepsy are common clinical findings.
Etiology
The majority of PCH cases encompass mutations in tRNA splicing endonuclease. Mutations responsible for PCH2, PCH4, PCH5 include mutations in TSEN2 (PCH2), TSEN34 (PCH2; 19q13.42), TSEN15 (1q25.3), and TSEN54 (PCH2 4, 5; 17q25.1). PCH6 is due to mutations in mitochondrial arginyl-tRNA synthetase (RARS2; 6q15) gene. Approximately half the cases of PCH1 are due to mutations in the gene EXOSC3 (9p13.2). In addition, mutations in VRK1 (14q32.2), EXOSC8 (13q13.3) and EXOSC9 (4q27) are associated with PCH1. PCH3 is caused by mutations in the PCLO gene (7q21.11). Mutations in TOE1 (1p34.1) underlie PCH7, PCH8 is caused by a loss-of-function mutation in the CHMP1A gene (16q24.3). PCH9 is caused by mutation in the AMPD2 gene (1p13.3), and PCH10 by mutations in the CLP1 gene (11q12.1). The two most recently described genes associated with PCH are TBC1D23 (3q12.1-q12.2), associated with PCH11, and COASY (17q21.2), linked to PCH12.
Diagnostic methods
Diagnosis is made on clinical symptoms and neuroradiological findings (magnetic resonance imaging; MRI). It can be confirmed by molecular genetic analyses. MRI demonstrates a pontocerebellar hypoplasia, with often more severely affected cerebellar hemispheres than vermis, atrophy of ventral pons and to a lesser extent the cerebral cortex. Other neuroanatomical features include a severe progressive microcephaly and ventriculomegaly.
Differential diagnosis
Differential diagnosis includes progressive cerebello-cerebral atrophy (PCCA), infantile cerebral and cerebellar atrophy (ICCA), congenital disorders of glycosylation type 1A and D, phosphoserine aminotransferase deficiency, certain congenital mitochondrial disorders, progressive encephalopathy with edema hypsarrhythmia and optic atrophy (PEHO) syndrome, dystroglycanopathies like Walker-Warburg syndrome, MEB-disease, Fukuyama congenital muscular dystrophy, lissencephaly, X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum, congenital fibrosis of the extraocular muscles type 3 (CFEOM3) with extraocular involvement, acquired cerebellar hypoplasia in extreme premature births (<32 weeks) which may disrupt normal brain development, and mutations in the CASK¬ gene, that cause Microcephaly and Pontocerebellar Hypoplasia (MICPCH).
Antenatal diagnosis
If the disease causing mutation is known in carrier parents, routine methods for prenatal testing or preimplantation genetic diagnosis are available.
Genetic counseling
Transmission is autosomal recessive and genetic counseling for the affected family is recommended. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic, as there is no cure for PCH, and involves medication for treatment of dystonia, dyskinesia and seizures, percutaneous endoscopic gastrostomy tube feeding and sometimes respiratory support may be necessary. Cot death, sleep apnea, rhabdomyolysis and malignant hyperthermia may be life threatening complications for PCH2 patients.
Prognosis
Prognosis is poor. Many children live only into infancy or childhood, although some affected individuals have lived into adulthood.

                            Last update: 
                            January 2021


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