Pontocerebellar Hypoplasia, Type 1d

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 1D (PCH1D) is caused by homozygous or compound heterozygous mutation in the EXOSC9 gene (606180) on chromosome 4q27.

Description

Pontocerebellar hypoplasia type 1D is a severe autosomal recessive neurologic disorder characterized by severe hypotonia and a motor neuronopathy apparent at birth or in infancy. Patients have respiratory insufficiency, feeding difficulties, and severely delayed or minimal gross motor development. Other features may include eye movement abnormalities, poor overall growth, contractures. Brain imaging shows progressive cerebellar atrophy with relative sparing of the brainstem (summary by Burns et al., 2018).

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

Clinical Features

Burns et al. (2018) reported 4 unrelated children of various ethnicities under the age of 5 years with severe hypotonia apparent either at birth or in the first months of life. Two of the pregnancies were noted to have reduced fetal movements. The patients had poor head control, weak cry, difficulty swallowing, and delayed motor development with severe generalized weakness, no or little antigravity movements, and inability to walk or sit. The oldest child had increased muscle tone and exaggerated deep tendon reflexes. Other features were somewhat variable, but included recurrent respiratory infections due to respiratory insufficiency, high-arched palate, feeding difficulties, poor or absent eye tracking, nystagmus, broken pursuit, absent language, joint contractures, and poor overall growth. EMG and nerve conduction studies were consistent with an axonal motor neuronopathy with neurogenic changes. Skeletal muscle biopsy showed neurogenic atrophy with fiber type grouping and type I fiber predominance. Brain imaging showed progressive cerebellar atrophy with relative sparing of the brainstem. The oldest child (individual 3) had microcephaly, seizures, severe developmental delay, and cerebral atrophy on brain imaging. Her family history was significant for an older sister who died at 8 years of age with spasticity and seizures. Another child (individual 2) had dysmorphic features, including low-set ears, short neck, hypertelorism, and epicanthal folds, arthrogryposis multiplex congenita, congenital fractures of the long bones, and cerebral atrophy; he died of respiratory failure at age 15 months.

Inheritance

The transmission pattern of PCH1D in the families reported by Burns et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients (individuals 1, 3, and 4) with PCH1D, Burns et al. (2018) identified a homozygous missense mutation in the EXOSC9 gene (L14P; 606180.0001). The mutation in individual 1, who was a 28-month-old girl born of unrelated parents from El Salvador, was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. Individual 3 was a 4.5-year-old girl born of consanguineous Saudi Arabian parents, and individual 4 was a 19-month-old girl born of unrelated parents of African, European, and Filipino ancestry. The mutation segregated with the disorder in all 3 families, and haplotype analysis suggested a common ancestor. Another unrelated patient (individual 2), a boy of African, Canadian, and Jamaican descent who had a more severe phenotype with congenital fractures and death at age 15 months, was compound heterozygous for L14P and a nonsense mutation in the EXOSC9 gene (R161X; 606180.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family. Immunoblotting of patient cells showed decreased levels of the EXOCS9 protein, suggesting instability or reduced assembly and function of the exosome complex. RNA sequencing in fibroblasts and skeletal muscle derived from several patients showed significant changes in RNA metabolism and gene expression, particularly affecting genes involved in cellular and embryonic developmental processes of the neuronal system. Other genes affected included those involved in arthrogryposis and skeletal dysplasia or bone disease. However, EXOSC9 mRNA and mRNAs encoding other subunits of the exosome complex did not show a significant difference in expression. The findings suggested a loss of function of RNA processing by the exosome.

Animal Model

Burns et al. (2018) found that knockdown of the exosc9 gene in zebrafish embryos resulted in brain abnormalities with absence of portions of the cerebellum and hindbrain, as well as abnormal motor neuron development and migration and abnormalities at the neuromuscular junction.