AMPD2-Related Disorders via the AMPD2 Gene

The AMPD2 gene has been associated with at least two disorders: pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia 63 (SPG63).

PCH9 is a highly penetrant neurodevelopmental and neurodegenerative disorder characterized by profound psychomotor development delay, progressive microcephaly, spasticity, and brain abnormalities. Some patients also show dysmorphic features, seizures and axonal peripheral neuropathy. More variable features include dystonia, axial hypotonia, hyperreflexia and optic atrophy. Most patients have onset of disease at birth or in early infancy. PCH9 patients with severe global developmental delay often die in early childhood (Akizu et al. 2013. PubMed ID: 23911318; Alazami et al. 2015. PubMed ID: 25558065; Marsh et al. 2015. PubMed ID: 27066553; Marsh et al. 2017. PubMed ID: 28168832).

Novarino et al. (2014) reported SPG63 in a highly consanguineous family. Two cousins in this family presented at 14 months of age with delayed walking. Both patients developed hypotonia and decreased deep tendon reflexes after several years (Novarino et al. 2014. PubMed ID: 24482476).

PCH9 is inherited in an autosomal recessive (AR) manner (Akizu et al. 2013. PubMed ID: 23911318). SPG63 has been reported in only a few cases and the inheritance pattern in the families reported is consistent with AR transmission (Novarino et al. 2014. PubMed ID: 24482476; Vanderver et al. 2016. PubMed ID: 27159321). AMPD2 encodes adenosine monophosphate deaminase-2, which is an enzyme that functions as a homotetramer and plays important roles in energy metabolism by converting AMP to IMP (Akizu et al. 2013. PubMed ID: 23911318). To date, different types of pathogenic variants (missense, nonsense, and frameshift deletions) have been found in the AMPD2 gene (Human Gene Mutation Database). Pathogenic variants in the catalytic AMP deaminase domain cause loss-of-function, which is believed to be the mechanism of PCH9. Studies have shown that the AMPD2 protein is completely or nearly completely absent in patient cells (Akizu et al. 2013. PubMed ID: 23911318).

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the AMPD2 gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the AMPD2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).