Pontocerebellar hypoplasia type 1

Abstract

Objectives: Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.Methods: We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.Results: Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A.C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed in mutation-positive infants but were typical among the mutation-negative subjects.Conclusion: EXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype.

Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

“…Specifically, PCH1b patients homozygous for EXOSC3 (G31A) have a severe disease, while patients homozygous for EXOSC3 (D132A) have a less severe disease ( Figure 1C) Biancheri et al 2013;Rudnik-Schoneborn et al 2013;Schwabova et al 2013;Eggens et al 2014). EXOSC3 (D132A) has also been found in compound heterozygosity with likely null alleles in PCH1b patients with severe disease Rudnik-Schoneborn et al 2013;Eggens et al 2014). On the other hand, EXOSC3 (G31A) has not been found in combination with obvious null alleles, but it has been found in compound heterozygosity with EXOSC3 (W238R) Rudnik-Schoneborn et al 2013).…”

“…EXOSC3 (D132A) has also been found in compound heterozygosity with likely null alleles in PCH1b patients with severe disease Rudnik-Schoneborn et al 2013;Eggens et al 2014). On the other hand, EXOSC3 (G31A) has not been found in combination with obvious null alleles, but it has been found in compound heterozygosity with EXOSC3 (W238R) Rudnik-Schoneborn et al 2013). Although loss of EXOSC3 has been modeled in zebrafish by knockdown with antisense morpholinos , the functional consequences of specific amino acid substitutions in EXOSC3 have not previously been analyzed in detail.…”

“…Instead, PCH1b patients exhibit significant atrophy of the pons and cerebellum, Purkinje cell abnormalities, and degeneration of spinal motor neurons . PCH1b patients also show microcephaly, muscle atrophy, and growth and developmental retardation (Rudnik-Schoneborn et al 2013). Most PCH1b patients do not live past childhood.…”

Human Mendelian diseases related to abnormalities of the RNA exosome or its cofactors

“…Some patients develop growth retardation (9). EXOSC3 mutations are found in 37% of PCH1 patients (11). Patients harbouring mutation in EXOSC3 differ from other PCH1 patients by a longer lifespan, abnormal oculomotor function, and with time could appear a respiratory deficiency.…”

“…Patients harbouring mutation in EXOSC3 differ from other PCH1 patients by a longer lifespan, abnormal oculomotor function, and with time could appear a respiratory deficiency. Nearly 50 patients with a mutation in EXOSC3 have been described since 2012 (9,(11)(12)(13). Most of the patients present two missense mutations or, more rarely, a compound heterozygosity Dis3L2 is an exoribonuclease degrading cytoplasmic mRNA specially uridylated in an exosome-independent pathway (17,18).…”