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

摘要

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. Callosal malformations include complete or partial agenesis, hypoplasia, and dysgenesis. 1 , 2 Clinical sequelae range from no or mild manifestations to severe neurodevelopmental disability. 3 , 4 The latter is more common when the callosal malformation is accompanied by other brain abnormalities, is part of a multiple congenital anomaly syndrome, or is secondary to a metabolic or degenerative disorder. 5 Agenesis of the corpus callosum (ACC) occurs in approximately 1:5,000 live births and >80 congenital syndromes, 6 , 7 although the etiology remains unknown for the majority. Pontocerebellar hypoplasia (PCH) syndromes are rare, usually autosomal recessive, disorders characterized by degeneration of the cerebellum and brainstem. The term “hypoplasia” is used although the changes are thought to reflect prenatal onset of atrophy. 8 Ten PCH syndromes have been described with additional features that variably include microcephaly, a movement disorder, epilepsy, optic atrophy, and axonal neuropathy. The combination of corpus callosum (CC) hypoplasia and PCH secondary to mutations in the gene encoding adenosine monophosphate deaminase 2 ( AMPD2 ) was recently reported (PCH type 9, Online Mendelian Inheritance in Man [OMIM] #615809). 9 The authors described 8 affected individuals from 5 families with severe disabilities, hypoplasia of the CC, and a characteristic midbrain “figure of 8” appearance on axial MRI. AMPD2 encodes 1 of 3 of adenosine monophosphate (AMP) deaminase homologs, which convert AMP to inosine monophosphate. Guanine nucleotide deficiency was shown to be central to the pathogenesis of PCH9 and associated with defective protein synthesis. 9 In this study, we characterize a large consanguineous Middle Eastern family and expand the phenotype of PCH9, describing the novel combination of complete ACC, PCH, and an axonal neuropathy.