Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

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. Utilizing 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 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), with ages ranging from 1 to 50 years old, 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 localisation 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 Xenopus 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

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

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

Childhood epilepsy in Bangladesh: Clinical profile, predictors of outcome and randomized controlled trial of efficacy and side effect of drug treatment

Around 80% of the world's patients with epilepsy live in countries with limited resources, and are predominantly young, 90% of whom are not appropriately treated. Bangladesh is probably typical in this respect, with an estimated 6.5/1000 affected in the 2–9 years age group, but detailed information about childhood epilepsy is limited, and services are almost non-existent outside the 2 major cities. A study of childhood epilepsy was carried out in 3 stages. In the 1st, retrospective stage, an epilepsy profile was compiled in children aged 2 months to 15 years and predictors of poor seizure remission identified. Primary care physicians and multidisciplinary health workers were trained on short courses to diagnose and manage epilepsy and additional impairments. An extensive system of patient care, regular follow up and patient recall was set up in collaboration with a community service. The 2nd, prospective, stage was designed to validate the predictors of poor seizure remission using two groups of patients: those with newly diagnosed epilepsy from the community and the second from the child development centre (CDC) who were anticipated to have more neurodevelopmental impairments. In the 3rd stage, 108 patients from the 2nd stage study were enrolled in a randomized controlled trial (RCT) to compare the behavioural side effects of phenobarbitone (PB) and carbamazepine (CBZ). The pilot study of 151 children showed a high rate of neurodevelopmental disabilities (73% had cognitive and 57% had motor problems). Seizure remission was obtained in 45.7%, and predictors of poor seizure remission were multiple seizure types, cognitive impairment, and an abnormal EEG. The poor were under-represented in this study. The socio-economic profile of the newly recruited children in the 2nd stage was more representative of the general population, with around 60% from the poor, both urban and rural. As anticipated, the community group had less associated non-convulsive neurological-disorder(s) than that from CDC (38.8% vs 70.5% for motor and 47% vs 76.3% for cognitive impairment). After 12 months regular treatment, seizure remission was obtained in 77% who did not have additional non-convulsive disorder. In this population, multiple logistic regression analysis showed multiple seizure types (p<0.01), cognitive impairment (p<0.02) and associated motor disorder (p<0.04) predicted poor seizure remission. In the RCT there was no difference in efficacy between PB and CBZ, and no significant difference in behavioural problems between the two treatments. The study suggests that epilepsy outcome can be broadly predicted at first presentation using the 3 factors (associated motor disability, cognitive impairment and multiple seizure types), which could be applied by a community health care physician. A multidisciplinary service in a community health care setting is an appropriate model for managing childhood epilepsy in a developing country such as Bangladesh. The result from the RCT study suggests that and PB does not produce increased behavioural problems compared with CBZ

Non-convulsive Status Epilepticus in Children, Electro-Clinical Profile and Response To A Specific Treatment Protocol

Objective: Non-convulsive status epilepticus (NCSE) is an under-diagnosed neurological condition. We report the electroclinical profile and treatment outcome of children diagnosed with NCSE