Dataset Information

Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, Cirrhosis, and Renal Failure in ACBD6-Associated Syndrome: A Case Report.

ABSTRACT:

Objectives

Neurodevelopmental disorders (NDDs) are a group of conditions that are clinically and etiologically heterogeneous. Biallelic variants in ACBD6 were previously reported in 7 patients with NDDs. Unfortunately, their clinical information remains very limited with descriptions of only their neurologic and craniofacial features. The purpose of this report is to expand the clinical phenotype of the ACBD6-associated NDDs.

Methods

We identified 2 Thai siblings with NDDs. Clinical and radiologic features of the proband were described. The affected siblings and parents underwent whole-exome sequencing and PCR-Sanger sequencing.

Results

Clinical manifestations that have never been previously reported include morbid obesity, pancytopenia with severe infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Molecular studies identified a novel homozygous 1 base-pair duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene.

Discussion

This study reported 1 novel single base-pair duplication, expanding the mutational spectrum, and described the clinical features establishing the entity of ACBD6-associated NDDs.

SUBMITTER: Yeetong P

PROVIDER: S-EPMC9709716 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, Cirrhosis, and Renal Failure in <i>ACBD6</i>-Associated Syndrome: A Case Report.

Yeetong Patra P Tanpowpong Natthaporn N Rakwongkhachon Supphakorn S Suphapeetiporn Kanya K Shotelersuk Vorasuk V

Neurology. Genetics 20221129 1

<h4>Objectives</h4>Neurodevelopmental disorders (NDDs) are a group of conditions that are clinically and etiologically heterogeneous. Biallelic variants in <i>ACBD6</i> were previously reported in 7 patients with NDDs. Unfortunately, their clinical information remains very limited with descriptions of only their neurologic and craniofacial features. The purpose of this report is to expand the clinical phenotype of the <i>ACBD6</i>-associated NDDs.<h4>Methods</h4>We identified 2 Thai siblings wit ...[more]

PMID: 36457943

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Project description:The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.