Ashley P.L. Marsh

Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR

Objective: To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia. Methods: Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs. Results: Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant. Conclusions: We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

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

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.

A novel AMPD2 mutation outside the AMP deaminase domain causes pontocerebellar hypoplasia type 9

A Novel AMPD2 Mutation Outside the AMP Deaminase Domain Causes Pontocerebellar Hypoplasia Type 9 Ashley P. L. Marsh, Patrick Yap, Tiong Tan, Kate Pope, Susan M. White, Belinda Chong, George Mcgillivray, Amber Boys, Sarah E. M. Stephenson, Richard J. Leventer, Zornitza Stark, and Paul J. Lockhart* Bruce Lefroy Centre For Genetic Health Research, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Genetic Health Service New Zealand (Northern Hub), Auckland City Hospital, Auckland, New Zealand Neuroscience Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Department of Neurology, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia

Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency

Objective: To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families. Methods: The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the intersection of the regions. Exome sequencing was performed on 1 affected patient with variant filtering and prioritization undertaken using these intersected regions. Results: Using a combination of sequencing technologies, we identified compound heterozygous mutations in HSD17B4 in all 5 affected patients. In all 3 families, peroxisomal D-bifunctional protein (DBP) deficiency was caused by compound heterozygosity for 1 nonsense/deletion mutation and 1 missense mutation. Conclusions: We describe 5 patients with juvenile DBP deficiency from 3 different families, bringing the total number of reported patients to 14, from 8 families. This report broadens and consolidates the phenotype associated with juvenile DBP deficiency.

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum and developmental split brain syndrome

The deleted in colorectal cancer (DCC) gene encodes the netrin‐1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss‐of‐function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss‐of‐function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss‐of‐function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype–phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus‐specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Teaching NeuroImages: Imaging features of DCC-mediated mirror movements and isolated agenesis of the corpus callosum

Two unrelated children were prenatally diagnosed with isolated agenesis of the corpus callosum (iACC) in otherwise uneventful pregnancies. Postnatal clinical assessments identified mirror movements in these offspring, their siblings, and their respective mothers. MRI (figure) showed characteristic features of complete (A, B) and partial (C, D) iACC, and abnormal crossing of the corticospinal tracts (E, F) on diffusion imaging. Sequencing revealed monoallelic missense mutations in the axon guidance receptor DCC.1 The association of iACC and abnormal corticospinal decussation is unique to only a handful of genes known to cause agenesis of the corpus callosum,2 and can provide a clinical clue towards a genetic diagnosis.

CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63

Abstract1. Name of Disease (Synonyms)Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63).2. OMIM# of the Disease615809 and 615686.3. Name of the Analysed Genes or DNA/Chromosome SegmentsAMPD2 at 1p13.3.4. OMIM# of the Gene(s)102771.