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Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

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.

SUBMITTER: Marsh AP

PROVIDER: S-EPMC4807911 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

Marsh Ashley P L AP Lukic Vesna V Pope Kate K Bromhead Catherine C Tankard Rick R Ryan Monique M MM Yiu Eppie M EM Sim Joe C H JC Delatycki Martin B MB Amor David J DJ McGillivray George G Sherr Elliott H EH Bahlo Melanie M Leventer Richard J RJ Lockhart Paul J PJ

Neurology. Genetics 20150716 2

<h4>Objective</h4>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.<h4>Methods</h4>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 perf ...[more]

PMID: 27066553

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Project description:IntroductionPontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation.Patients and methodsPatients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview.ResultsThirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome.ConclusionPhenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.

Project description:BackgroundPontocerebellar hypoplasia type 2 (PCH2) is caused by a defect in the TSEN54-gene and leads to severe and early disruption of brain development, especially of cerebellum and pons. The aim of this work was to quantify the infra- and supratentorial brain growth during postnatal brain development in children with PCH2.MethodsMRI data of 24 children with PCH2 (age 0.02-17 years., 13 females) were analysed volumetrically and compared to images of 24 typically developing age- and gender-matched children. All children with PCH2 had the homozygous p.A307S mutation in the TSEN54-gene. In 5 patients follow-up MRI investigations were available. Images of the children with PCH2 were available either on film (n = 12) or in digital format (n = 21). Images on film were digitalized. Brain structures were manually masked and further adjusted semi-automatically using intensity thresholding to exclude CSF. Volumes of cerebellum, brain stem, and pons were measured, as well as supratentorial brain and frontal lobe volume. For validation of the method part of the digital images were processed as images on film. In addition, intra- and inter-rater variabilities were tested.ResultsChildren with PCH2 showed reduced volumes of all measured brain structures compared to healthy controls. Severely hypoplastic cerebellum, pons and brain stem only slightly increased in size postnatally. Supratentorial brain volume also showed reduced growth compared to the healthy controls. Differences between patients and controls could already be seen at birth but became more significant during childhood. Validation of the method showed high precision and reproducibility.ConclusionsIn a genetically very homogenous group of children with PCH2 severely hypoplastic infratentorial structures, the hallmark of the disease, showed only slight increase in volume postnatally. Supratentorial brain structures, which are considered normal at birth, also showed smaller volumes neonatally and a lower growth rate compared to controls, leading to severe microcephaly. Volume loss, however, could not be observed during the first years of life. This argues for a severe disruption of the cerebellar-cerebral networks during pre- and postnatal development caused by a primary cerebellar dysfunction, rather than postnatal neurodegeneration. The developmental progress in these children, although little, further supports this.

Dataset Information

Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

Publications

Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

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