Pontocerebellar Hypoplasia, Type 9

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 9 (PCH9) is caused by homozygous mutation in the AMPD2 gene (102771) on chromosome 1p13.

Description

Pontocerebellar hypoplasia type 9 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination (summary by Akizu et al., 2013).

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

Clinical Features

Akizu et al. (2013) reported 8 patients from 5 families with pontocerebellar hypoplasia. Most of the patients were diagnosed at birth or in the first year of life. The patients had microcephaly (up to -9 SD), profoundly delayed psychomotor development, and spasticity. All except 2 had seizures. More variable features included dysphagia, dystonia, clonus, optic atrophy, blindness, and poor visual fixation. Brain imaging showed hypoplasia or atrophy of the cerebellum with a fluid-filled posterior fossa and flattening of the ventral part of the pons. On axial imaging, the brainstem took on a 'figure 8' appearance. There was also generalized atrophy of the cerebral cortex and severe corpus callosum hypoplasia.

Marsh et al. (2015) reported 5 sibs, born of consanguineous parents of Middle Eastern descent, with severe PCH9 associated with axonal peripheral neuropathy in 2 of the patients who survived infancy. All patients had profound global developmental delay, postnatal microcephaly, and pontocerebellar hypoplasia with absence of the corpus callosum on brain imaging. Additional features included axial hypotonia with spasticity, hyperreflexia, extensor plantar responses, cortical visual impairment, impaired swallowing, and early-onset seizures. The patients also had dysmorphic features, including bitemporal narrowing, midface hypoplasia, hypotonic facies, downslanting palpebral fissures, broad nasal bridge, short upper lip, macroglossia, and abnormally shaped ears. Three patients died of infection during the first 2 years of life. The remaining 2 patients, who were 17 and 20 years of age, developed areflexia of the lower limbs associated with an axonal neuropathy. The report expanded the phenotypic spectrum of neurologic abnormalities associated with PCH9 to include symptoms involving the peripheral nervous system.

Inheritance

The transmission pattern of PCH9 in the families reported by Akizu et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 5 families with pontocerebellar hypoplasia type 9, Akizu et al. (2013) identified 5 different homozygous mutations in the AMPD2 gene (102771.0002-102771.0006). The mutations were found by whole-exome sequencing of 30 probands with PCH. The AMPD2 protein was nearly completely absent in patient cells, and the mutations failed to rescue growth defects in knockdown studies of the yeast homolog Amd1. The findings were consistent with null alleles, although 2 missense mutations showed some residual AMP deaminase activity in conditions of overexpression. Detailed studies in patient cells and yeast cells suggested that AMPD2 deficiency results in decreased GTP-dependent initiation of protein translation and decreased survival of neuronal precursor cells. These defects could be rescued in vitro by administration of ribonucleotide purine precursors.

In 4 sibs, born of consanguineous parents of Middle Eastern descent, with PCH9, Marsh et al. (2015) identified a homozygous truncating mutation in the AMPD2 gene (Y752X; 102771.0007). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the AMPD2 protein. Functional studies of the variant were not performed. Two of the patients developed axonal neuropathy in the second decade.

Animal Model

Akizu et al. (2013) found that Ampd2-null mice had normal brain histology. Mice with double knockout of Ampd2 and Ampd3 (102772) had a slightly reduced brain and body weight compared to wildtype, but there was little evidence of neuronal loss early in life. However, they had a severely shortened life span limited to 2 or 3 weeks. After P14, they developed a neurodegenerative phenotype and abnormal gait. Brain studies showed degeneration of the CA3 pyramidal neurons in the hippocampus as well as sparse pyknotic cells in the cortex and cerebellum. These changes were associated with a 25% increase in ATP nucleotide levels and a 33% decrease in GTP levels compared to wildtype.