Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect

Abstract

MBOAT7 gene codes O‐acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild‐to‐moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome‐wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173‐54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile

“…In general, this rare disease appears to be slowly progressive, in which behavioral problems and cognitive decline worsen over adolescence. Her phenotype overlaps with many of the features already described in other reports (Jacher et al, 2019; Johansen et al, 2016; Yalnızoǧlu et al, 2019). In particular, she presents global developmental delay, motor and speech delay, motor incoordination with ataxic gate, very early‐onset age of seizures (2 months of age), and similar facial dysmorphic features.…”

“…LPIAT1 is expressed in the cerebral cortex and the Mboat7 knockout mice show abnormal cortical lamination (Lee et al, 2012). Indeed, specific common brain MRI findings, such as cerebellar atrophy, disorganized cerebellar folia and prominent perivascular spaces are described in patients with MBOAT7 defect (Yalnızoǧlu et al, 2019). Our patient's brain MRI was normal until age 7, when cerebellar atrophy and dilations of the bilateral subcortical perivascular spaces were first detected.…”

“…In 2016, Johansen et al (2016) reported for the first time 16 patients from six different consanguineous families harboring homozygous inactivating variants in the MBOAT7 gene (OMIM 606048). Since then, other 27 patients with MBOAT7 defects were identified (Hu et al, 2019; Jacher, Roy, Ghaziuddin, & Innis, 2019; Khan et al, 2019; Santos‐Cortez et al, 2018; Yalnızoǧlu et al, 2019). As summarized by Khan et al (2019), 13 different MBOAT7 variants in 18 families have been described until now, of which 5 are frameshift mutations, 2 are splice, 1 is nonsense, 3 are missense, 1 is a 21 bp in frame deletion, 1 is a 11,549 bp deletion.…”

“…As summarized by Khan et al (2019), 13 different MBOAT7 variants in 18 families have been described until now, of which 5 are frameshift mutations, 2 are splice, 1 is nonsense, 3 are missense, 1 is a 21 bp in frame deletion, 1 is a 11,549 bp deletion. Almost all these patients were born from consanguineous parents and share a specific clinical phenotype characterized by intellectual disability (ID), speech impairment, autistic features, early onset epilepsy, abnormal motor coordination, and similar facial features (Jacher et al, 2019; Johansen et al, 2016; Yalnızoǧlu et al, 2019).…”

Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families

“…Recently homozygous pathogenic variants within MBOAT7 have been identified in 16 families (15 consanguineous and 1 reported as non-consanguineous, although both parents were from the same village in Lebanon) as a cause of a neurodevelopmental disorder (autosomal recessive mental retardation type 57 (MIM 617188) characterized by seizures, moderate to severe ID with significant psychomotor retardation (several individuals are non-verbal and never walked, usually occurring with seizure onset), truncal hypotonia, appendicular hypertonia, features of autism spectrum disorder (ASD), below average head circumference and characteristic facial features [6–10]. The MBOAT protein family consists of five acyltransferases; lysophosphatidylinositol acyltransferase 1 (LPIAT1) encoded by the MBOAT7 gene is known to transfer arachidonic acid (AA) from arachidonoyl-CoA to lysophosphatidylinositol [11].…”