AMPD2 mutation and pontocerebellar hypoplasia type 9

Inspired by a colleague's patient

In 8 patients from 5 families with pontocerebellar hypoplasia type 9, Akizu et al. (2013) identified 5 different homozygous mutations in the AMPD2 gene. Two mutations resulted in premature termination, whereas 3 were missense mutations at highly conserved residues. 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. The patients had microcephaly (up to -9 SD), profoundly delayed psychomotor development, and spasticity. All except 2 had seizures. Brain imaging showed pontocerebellar hypoplasia with a 'figure 8' appearance of the brainstem, as well as cerebral cortical atrophy and corpus callosum hypoplasia. Studies in patient cells showed a dose-dependent negative effect of adenosine on cell survival and decreased protein translation following adenosine treatment. Patient cells had increased levels of ATP and decreased levels of guanine nucleotides, which suggested a blockage of de novo purine biosynthesis in proliferating neural progenitor cells. The findings suggested that AMPD2 plays a role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis through IMP. In turn, decreased levels of guanine result in defective GTP-dependent initiation of protein translation. These defects could be rescued in vitro by administration of ribonucleotide purine precursors. 

http://www.omim.org/entry/102771

Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E,Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, Gleeson JG. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell. 2013 Aug 1;154(3):505-17.

Abstract

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

Marsh AP, Lukic V, Pope K, Bromhead C, Tankard R, Ryan MM, Yiu EM, Sim JC, Delatycki MB, Amor DJ, McGillivray G, Sherr EH, Bahlo M, Leventer RJ, Lockhart PJ. Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss. Neurol Genet. 2015 Jul 16;1(2):e16.

Abstract

OBJECTIVE:

To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy.

METHODS:

Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells.

RESULTS:

Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations.

CONCLUSIONS:

We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.