Novel
            <i>AMPD2</i>
            mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities

Accogli, Andrea; Iacomino, Michele; Pinto, Fausto J.; Orsini, Alessandro; Vari, Maria Stella; Selmi, Raed; Torella, Annalaura; Nigro, Vincenzo; Minetti, Carlo; Severino, Mariasavina; Striano, Pasquale; Capra, Valeria; Zara, Federico

doi:10.1212/nxg.0000000000000179

Cited by 23 publications

(21 citation statements)

References 7 publications

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“…AMPD1 is highly expressed in skeletal muscle and diaphragm, AMPD2 is mainly expressed in brain, liver, and thymus and AMPD3 is most strongly expressed in erythrocytes (Morisaki et al, 1990;Mahnke-Zizelman and Sabina, 1992). Mutations in AMPD2 result in pontocerebellar hypoplasia due to loss of brainstem and cerebellar parenchyma (Akizu et al, 2013;Marsh et al, 2015;Accogli et al, 2017;Kortum et al, 2018;Abreu et al, 2020) but a homozygous AMPD2 frameshift variant has been associated with HSP type 63 (Novarino et al, 2014). AMPD2 plays a role in guanine nucleotide homeostasis by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis; AMPD2 deficiency results in increase of ATP and decrease of GTP levels, which leads to impairment of GTPdependent initiation of protein synthesis (Akizu et al, 2013).…”

Section: Amp Deaminasementioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

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Section: Amp Deaminasementioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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“…Facial dysmorphisms are reported with dental abnormalities in a minority of patients. The presence of axonal neuropathy is reported in older patients and is probably age-dependent [ 55 – 57 ]. Brain MRI showed pontocerebellar hypoplasia, severe hypoplasia of the corpus callosum with, on axial images, a characteristic ‘figure 8’ shape of the mesencephalon, with hypoplastic cerebral peduncles (Fig.…”

Section: Main Textmentioning

confidence: 99%

What’s new in pontocerebellar hypoplasia? An update on genes and subtypes

Dijk

Baas

Barth

et al. 2018

Orphanet J Rare Dis

126

116

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BackgroundPontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH.Main textIn this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype.ConclusionsMany new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.

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“…His brain MRI demonstrated the typical “figure 8” appearance of the upper brainstem reported in other individuals with AMPD2 biallelic variants associated with PCH9. He also demonstrated periventricular white matter changes that have been reported in other individuals, including: one individual with “periventricular leukomalacia” (Akizu et al, ), three patients with “leukoencephalopathy similar to periventricular leukomalacia” (Accogli et al, ), and five of eight patients demonstrating hypomyelination (Kortüm et al, ).…”

Section: Discussionmentioning

confidence: 78%

“…The second was a novel homozygous nonsense variant in the (Akizu et al, 2013), three patients with "leukoencephalopathy similar to periventricular leukomalacia" (Accogli et al, 2017), and five of eight patients demonstrating hypomyelination (Kortüm et al, 2018).…”

Section: Case Reportmentioning

confidence: 99%

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

Abreu

Koboldt

Gastier‐Foster

et al. 2019

American J of Med Genetics Pt A

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Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole‐exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical “Figure 8” appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.

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Novel AMPD2 mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities

Cited by 23 publications

References 7 publications

Metabolic Aspects of Adenosine Functions in the Brain

Metabolic Aspects of Adenosine Functions in the Brain

What’s new in pontocerebellar hypoplasia? An update on genes and subtypes

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

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