Nonsyndromic pontocerebellar hypoplasias (PCH) are a rare heterogeneous group of diseases characterized by hypoplasia and atrophy and/or early neurodegeneration of the cerebellum and pons. Eight subtypes named type 1-8 have been described (see these terms), generally inherited in an autosomal recessive pattern.
The prevalence of PCH is unknown. Most subtypes appear to be very rare.
PCH patients of all subtypes present with progressive microencephaly, delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and seizures.
The majority of PCH cases encompass mutations in tRNA splicing endonuclease (TSEN). Mutations responsible for PCH2, PCH4, PCH5 include mutations in TSEN2 (PCH2), TSEN34 (PCH2) et TSEN54 (PCH2 4, 5). PCH6 is due to mutations in mitochondrial arginyl-tRNA synthetase (RARS2) gene. Approximately half the cases of PCH1 are due to mutations in the gene EXOSC3. The etiology of PCH3 and PCH7 is largely unknown, however mutations in tRNA splicing endonuclease, the mitochondrial arginyl-tRNA synthetase and the vaccinia related kinase 1 underlie a minority of PCH1 cases, and a linkage on chromosome 7 has been reported in 2 PCH3 families. The new very rare form of PCH, PCH8 is caused by a loss-of-function mutation in the CHMP1A gene.
Diagnosis is made on clinical symptoms and neuroradiological findings (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 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 (see these terms) and acquired cerebellar hypoplasia in extreme premature births (<32 weeks) which may disrupt normal brain development.
If the disease causing mutation is known in carrier parents, routine methods for prenatal testing or preimplantation genetic diagnosis are available.
Transmission is autosomal recessive and genetic counseling for the affected family is recommended.
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 is poor. Many children live only into infancy or childhood, although some affected individuals have lived into adulthood.
Last update: July 2013