Pontocerebellar Hypoplasia, Type 11

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 11 (PCH11) is caused by homozygous mutation in the TBC1D23 gene (617687) on chromosome 3q12.

Description

PCH11 is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with intellectual disability and poor speech, microcephaly, dysmorphic features, and pontocerebellar hypoplasia on brain imaging. Additional features are more variable (summary by Marin-Valencia et al., 2017).

For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Clinical Features

Ivanova et al. (2017) reported 7 patients, ranging from 3 to 16 years of age, from 3 unrelated consanguineous families with a similar neurodevelopmental disorder apparent from early infancy. The families were from Turkey, Iran, and Pakistan. The patients had microcephaly, severely delayed psychomotor development, poor speech, and poor ocular contact. Patients either could not walk or achieved walking between 3 to 7 years of age. They had spastic hypertonia, cerebellar syndrome, and motor weakness. Dysmorphic features included protruding ears, bulbous nasal tip, and prominent incisors. More variable features, seen in 1 or 2 patients, included imperforate anus, talipes equinovarus, hyperopia, and strabismus; 3 sibs had coloboma. The patients had a happy expression, and most had behavioral abnormalities, including autistic features, stereotypic behavior, and attention deficit-hyperactivity. Brain imaging showed pontocerebellar hypoplasia with thin or even absent corpus callosum. One patient had Dandy-Walker malformation and evidence of the molar tooth sign.

Marin-Valencia et al. (2017) reported 6 patients from 4 unrelated families, 3 of which were consanguineous, with PCH11. The families were from Egypt, Turkey, and Lebanon. The patients had microcephaly (range -3.4 to -7.77 SD), global psychomotor delay since infancy, impaired language, and impaired social interactions. Height and weight were variably decreased, ranging from normal to -5 SD. Neurologic abnormalities included generalized weakness, global hypotonia, cerebellar deficits such as uncoordinated limb movements, truncal and limb ataxia, hyporeflexia, and impaired or absent ambulation. Brainstem symptoms including dysphagia and dysarthria were present in patients from 1 family. Two patients had seizures, and several patients had recurrent respiratory infections. All patients were alive, and none showed clinical signs of neurologic deterioration. Brain MRI showed pontocerebellar hypoplasia in all subjects, along with thin corpus callosum and cortical hypoplasia in some.

Inheritance

The transmission pattern of PCH11 in the families reported by Ivanova et al. (2017) and Marin-Valencia et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 3 unrelated consanguineous families with PCH11, Ivanova et al. (2017) identified 3 different homozygous truncating mutations in the TBC1D23 gene (617687.0001-617687.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations were predicted to result in a loss of function. Fibroblasts derived from 1 of the patients showed absence of the TBC1D23 protein. Dynamic studies of these cells showed abnormal intracellular vesicular trafficking of dense core vesicles, as well as less dynamic lysosomes with altered anterograde and retrograde transport. Knockdown of the gene using shRNA in cultured primary neuronal cells resulted in decreased numbers of cells with principal axon-like processes, with an increase in the number of cells with multiple neurites similar in size with no principal process. Cells with downregulation of TBC1D23 also tended to have more neurites per cell compared to controls. These findings suggested to Ivanova et al. (2017) that loss of TBC1D23 function could have multiple effects on different aspects of brain development.

In 6 patient from 4 unrelated families with PCH11, Marin-Valencia et al. (2017) identified homozygous mutations in the TBC1D23 gene (see, e.g., 617687.0004 and 617687.0005). The mutations, which were found by exome sequencing of 75 families with PCH, segregated with the disorder in the families. All mutations were predicted to result in splicing defects and a loss of function. Cells available from patients with 2 of the mutations confirmed that the splicing defects resulted in truncated proteins. Patient cells showed absence of TBC1W23 protein, consistent with a loss of function.

Animal Model

Ivanova et al. (2017) found that shRNA knockdown of the Tbc1d23 gene in the cortices of mouse embryos using electroporation resulted in abnormal neuronal positioning in pre- and early postnatal stages, without a change in neuronal proliferation. Expression of wildtype Tbc1d23 rescued the defects.

Marin-Valencia et al. (2017) found that morpholino knockdown of the tbc1d23 ortholog in zebrafish embryos resulted in reduced brain and eye size and curved tails. Mutant animals showed reduced signal in the neural axis and showed altered morphology of the forebrain, brainstem, and cerebellum. The phenotype could be partially rescued by injection of wildtype tbc1d23.