Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Pontocerebellar hypoplasia type 9 (PCH9) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in AMPD2 and characterized by prenatal hypoplasia of the cerebellum and pons, postnatal microcephaly, and severe global developmental impairment. Neuroimaging classically shows a “figure 8” midbrain configuration and agenesis or hypoplasia of the corpus callosum (PMID:29463858).
Inheritance of PCH9 is autosomal recessive, with eight novel and 17 previously reported probands in six unrelated families (25 total probands) segregating biallelic AMPD2 variants (PMID:29463858).
Genetic analysis has identified a spectrum of eight pathogenic variants, including six missense changes, one frameshift, and one nonsense mutation; for example, c.520G>T (p.Glu174Ter) has been observed in affected individuals (PMID:29463858).
Loss-of-function is the proposed mechanism of pathogenicity. In vitro assays of the p.Gly491Arg variant demonstrated an 82% decrease in AMPD2 enzymatic activity in patient cells compared with controls (p = 0.029), supporting disrupted purine metabolism as the disease driver (PMID:39086442).
A homozygous AMPD2 frameshift variant has been reported in two individuals presenting with spastic paraplegia type 63 without classic PCH9 features, suggesting isoform-specific effects and partial phenotypic spectrum (PMID:29463858).
Integration of robust genetic segregation and functional data yields a strong gene–disease association. Early recognition of characteristic imaging findings and confirmatory AMPD2 sequencing are critical for accurate diagnosis, prognostication, and genetic counseling.
Key Take-home: Biallelic AMPD2 loss-of-function variants cause PCH9, and molecular confirmation informs clinical management and family planning.
Gene–Disease AssociationStrong25 probands across six unrelated families segregating biallelic variants, consistent recessive transmission and concordant neuroimaging [PMID:29463858] Genetic EvidenceStrongEight novel and 17 previously reported probands with biallelic AMPD2 variants, including one frameshift and one nonsense; segregation in six families [PMID:29463858] Functional EvidenceModerateIn vitro assay of p.Gly491Arg variant showed 82% reduction in enzymatic activity (p = 0.029), supporting loss-of-function [PMID:39086442] |