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.

Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly.

DEAF1 encodes a transcriptional binding factor and is a regulator of serotonin receptor 1A. Its protein has a significant expression in the neurons of different brain regions and is involved in early embryonic development. In addition, its role in neural tube development is evident from the knockout mouse as many homozygotes have exencephaly. Heterozygous mutations of this gene have been linked to intellectual disability in addition to the gene's involvement in major depression, suicidal tendencies, and panic disorder. In this clinical report, we describe two children from a consanguineous family with intellectual disability, microcephaly, and hypotonia. The brain MRI of both patients showed bilateral and symmetrical white matter abnormalities, and one of the patients had a seizure disorder. Using whole exome sequencing combined with homozygosity mapping, a homozygous p.R226W (c.676C>T) mutation in DEAF1 was found in both patients. Furthermore, sequencing analysis confirmed complete segregation in tested family members and absence of the mutation in control cohort (n = 650). The mutation is located in a highly conserved structural domain that mediates DNA binding and therefore regulates transcriptional activity of its target molecules. This study indicates, for the first time to our knowledge, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability.

A case of extreme prematurity and delayed diagnosis of pyridoxine-dependent epilepsy.

Pyridoxine-dependent epilepsy presents early in life, even in utero. It is usually refractory to conventional antiepileptic medications and responds only to lifelong pyridoxine supplementation. Seizures are usually generalized tonic clonic. We report a 3-year-old child that was born prematurely at 25 weeks of gestation. He presented with abnormal movements in the second month of life. At 10 months of age he presented with status epilepticus, which was refractory to multiple antiepileptic medications and was controlled with intravenous pyridoxine. An elevated level of a-aminoadipic semialdehyde excretion in the urine supported the diagnosis of pyridoxine-dependent epilepsy. Subsequently, a c.1195G>C homozygous mutation in the 5q31 aldehyde dehydrogenase 7A1 gene was confirmed. This case calls for considering pyridoxine-dependent epilepsy and its early management in cases with resistant seizures; even in the presence of extreme prematurity with its neurological consequences.

Consensus Statement on the Management of Duchenne Muscular Dystrophy in Saudi Arabia During the Coronavirus Disease 2019 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused overwhelming challenges in healthcare worldwide. During such an outbreak, some needs of high-risk groups who require regular follow-ups and long-term management are not met. The vulnerable populations include patients with Duchenne muscular dystrophy (DMD). Duchenne muscular dystrophy is characterized by respiratory complications caused by muscle weakness. Hence, patients with this condition are at high risk of severe diseases including COVID-19. Methods: To standardize care and provide optimal treatment to DMD patients in Saudi Arabia during the COVID-19 pandemic, a panel of experts including neurologists and pediatricians consolidated recommendations for healthcare professionals and caregivers. Results: During this pandemic, substituting unnecessary clinic visits with virtual clinic services was highly recommended, if possible, without compromising clinical outcomes. Duchenne muscular dystrophy patients with respiratory complications should be closely monitored, and those with cardiovascular complications must continue taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Moreover, individualized home-based rehabilitation management was preferred. Glucocorticoid and new gene correction therapies should be continued. However, new gene correction therapy must be post-poned in newly diagnosed patients. A multidisciplinary decision was required before the initiation of hydroxychloroquine based on the COVID-19 treatment protocol. Conclusion: COVID-19 has caused challenges and transformed access to health care. However, these limitations have provided opportunities for the health care system to adapt. Further, telemedicine has become a reliable platform for follow-up appointments that should be conducted by a multidisciplinary team including physicians, dieticians, and physical therapists.

Acute hemiplegia as a rare presentation of infantile Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) usually presents in a symmetrical ascending fashion of weakness. We present a 6-month-old male infant who presented to our emergency room with acute left-sided limb weakness and head lag 3 days after a febrile upper respiratory tract infection. A diagnosis of GBS was established by confirming high cerebrospinal fluid protein, motor nerve reduced amplitude, and prolonged conductions, and MRI T2 high signal intensity affecting the ventral roots of the spinal cord. He showed remarkable clinical and neurophysiological improvement after intravenous immunoglobulin and intensive physiotherapy. The occurrence of infantile acute hemiplegia as a presentation of GBS is rare. This report highlights the importance of considering GBS in the differential diagnosis so that early effective treatment may be started.