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.
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.
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