Pontocerebellar Hypoplasia, Type 1c

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 1C (PCH1C) is caused by homozygous mutation in the EXOSC8 gene (606019) on chromosome 13q13.

Description

Pontocerebellar hypoplasia type 1C is a severe autosomal recessive neurodegenerative disorder characterized by severe muscle weakness and failure to thrive apparent in the first months of life. Affected infants showed delayed psychomotor development, often with visual and hearing impairment, and may die of respiratory failure. Brain imaging typically shows cerebellar hypoplasia, hypoplasia of the corpus callosum, and immature myelination (summary by Boczonadi et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Clinical Features

Boczonadi et al. (2014) reported a large consanguineous Hungarian Roma family in which 18 children presented between 2 and 4 months of age with failure to thrive, severe muscle weakness, spastic tetraparesis, and psychomotor retardation. Vision and hearing were impaired in all patients, and deterioration of their condition was usually triggered by intercurrent infection. All affected children died of respiratory failure before 20 months of age. Two sibs from another Hungarian Roma family were similarly affected: 1 died at age 13 months, whereas the other was alive but severely disabled at age 9 months. In a third family, of Pakistani descent, 2 sibs had a similar disorder but did not have visual or hearing impairment. One died at age 28 months, whereas the other was alive at age 5 years. Brain imaging performed in 8 patients showed variable abnormalities, most commonly cerebellar vermis hypoplasia, thin corpus callosum, and cortical atrophy with evidence of immature myelination. Postmortem examination of 8 patients showed a profound lack of myelin in the cerebral and cerebellar white matter and in the spinal cord, predominantly affecting the descending lateral fiber tracts. Myelin was normal in the peripheral nerves.

Inheritance

The transmission pattern of PCH1C in the families reported by Boczonadi et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members from 3 families, 2 of Hungarian Roma descent and 1 of Pakistani descent, with pontocerebellar hypoplasia type 1C, Boczonadi et al. (2014) identified 2 different homozygous missense mutations in the EXOSC8 gene (S272T, 606019.0001 and A2V, 606019.0002). The mutations were found by a combination of homozygosity mapping and exome sequencing. Patient myoblasts and EXOSC8-silenced human oligodendrocytes showed specific increases in mRNAs encoding the myelin proteins MBP (159430) and MOBP (600948), as well as an increase in SMN1 (600354) expression. Patient cells also showed reduced EXOSC3 (606489) levels. Boczonadi et al. (2014) concluded that an imbalanced supply of myelin proteins caused myelin disruption, resulting in the severe neurodegenerative phenotype.

Animal Model

Boczonadi et al. (2014) found that morpholino knockdown of exosc8 in zebrafish embryos resulted in abnormalities in swimming and motor escape responses and abnormal development of motor neurons in the hindbrain, as well as impaired myelination in the spinal cord. Mbp mRNA was initially increased, but later decreased, most likely due to loss of neuronal structures and the surrounding oligodendroglia. Simultaneous knockdown of zebrafish mbp and exosc8 resulted in slightly increased survival, suggesting that dysregulation of mbp expression contributes to the impaired myelination observed in exosc8-null embryos.