Jose T. Bras

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Purpose:Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.Methods:Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.Results:All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.Conclusion:This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45–52.

CLN6 disease caused by the same mutation originating in Pakistan has varying pathology

The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative diseases in children, are characterised by storage of autofluorescent material that has a characteristic ultrastructure. We report two families with variant late infantile NCL, both originating from Pakistan. Probands from both families were homozygous for the same mutation (c.316dupC) but had variable pathology to that currently thought to be typical for CLN6 disease, late infantile variant. The observed pathology of one proband resembled condensed fingerprints, previously described in late infantile CLN7 and CLN8 diseases, and pathology from the second proband was thought to be absent even after repeated skin biopsy, but observed after review. This mutation is the most common NCL mutation in families originating from Pakistan and could be prioritised for testing. Finally, this report contains the first prenatal diagnosis for late infantile CLN6 disease, initially made on the basis of EM and now confirmed by mutation analysis.

An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides. We report that soluble oligomers were specifically detected in the dogs blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-Aβ specific binders. Importantly, our results reveal the potent neurotoxic effects of the dogs CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human Aβ. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed.

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Studies of monogenic heritable pain disorders provide valuable insights into human pain mechanisms. Habib et al. show that a point mutation in the gene ZFHX2 causes an autosomal dominant form of pain insensitivity. Modulating ZFHX2 and/or downstream genes may present a new strategy for the treatment of chronic pain.

CLN8 disease caused by large genomic deletions

The presence of deletions can complicate genetic diagnosis of autosomal recessive disease.