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Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A 2 -activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E 2 and cytosolic phospholipase A 2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E 2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E 2 and cytosolic phospholipase A 2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E 2 The non-functional phospholipase A 2 -activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Congenital recessive ichthyoses represent a vast and markedly heterogeneous group of diseases that have been mapped to at least seven distinct chromosomal loci. In this study, we ascertained two consanguineous families presenting with congenital ichthyosis. Using homozygosity mapping, we identified a 6.5 cM homozygous region on 12p11.2-q13 shared by all affected individuals. Multipoint logarithm of odds ratio (LOD) score analysis placed the new locus between markers D12S345 and D12S390 with a maximum LOD score of 4.79 at marker CH12SSR13. This region harbors PPHLN1, encoding periphilin 1, a protein involved in the cornification process. No deleterious mutations were identified within the coding region of this gene, suggesting the existence of another gene associated with epidermal differentiation on 12p11.2-q13.