MORC2 Neurodevelopmental Disorder - a Mitochondrial Disease Masquerader Azzah Atiqah Ahmad, Sulekha Sivapatham, Chan Mei Yan Clinical Genetics Department, Hospital Kuala Lumpur. 1. OMIM® - Online Mendelian Inheritance in Man: MORC FAMILY CW-TYPE ZINC FINGER PROTEIN 2; MORC2 (OMIM: 616661) 2. Guillen Sacoto MJ, Tchasovnikarova IA, Torti E, et al. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. Am J Hum Genet. 2020;107(2):352-363. doi:10.1016/j.ajhg.2020.06.013 3. Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE, Modis Y, Lehner PJ. Hyperactivation of HUSH complex function by Charcot- Marie-Tooth disease mutation in MORC2. Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5. PMID: 28581500; PMCID: PMC5493197. References Differential diagnoses: • Leigh disease • Biotin-thiamine dependent basal ganglia disease • Viral encephalitis. Mitochondrial cocktail was prescribed and he showed an improvement in symptoms after initiation. • Dystonia resolved • Left sided weakness resolved • Swallowing improved • No more drooling • Able to swallow small amounts • Development forward progressing • Good head control in sitting position • Still unable to turn prone • Able to maintain tripod sitting posture • Pincer grip, object transfer • No speech MORC2 has a threefold function within the human body: • Epigenetic silencing by HUSH complex • Regulating ATP citrate lyase activity • Facilitating chromatin remodeling MORC2 encodes for an ATPase fundamental for epigenetic silencing by the human silencing hub (HUSH) complex. MORC2 mutations hyperactivates HUSH- mediated repression in neuronal cells CNS manifestations (eg: weakness, hyporeflexia, neuropathy) As MORC2 also binds to ATP citrate lyase which catalyses the formation of acetyl Co-A, this is the potential mechanism for mitochondrial-like disease features (Figure 2). MORC2 missense mutations • complex neurologic disorder • impaired motor and intellectual development, • hypotonia • poor overall growth • subtle dysmorphism • signs and severity are highly variable • hearing loss • pigmentary retinopathy • abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. Most common features of patients with MORC2 mutations (features in bold were also noted in the reported case) • Short stature • Microcephaly • Motor delay • Intellectual disability • Gait abnormalities • Hypotonia • Hyporeflexia Leigh syndrome-like lesions on MRI brain are present in approximately 28% of patients with MORC2 mutations. Discussion Conclusions REPLACE THIS BOX WITH YOUR ORGANIZATION’S HIGH RESOLUTION LOGO Introduction Mitochondrial disorders present in a myriad of ways. Tissues with the highest energy requirements are the most affected as mitochondria are the powerhouses of cells. Common organs affected include the brain, heart and skeletal muscle. Some conditions can mimic mitochondrial disorders in clinical presentation and radiological findings. Recognition of such conditions is important as accurate diagnosis is important for patient management and genetic counseling. Microrchidia CW-zinc finger type 2 (MORC2) gene mutations cause a newly described neurodevelopmental disorder with growth retardation and variable craniofacial dysmorphism (DIGFAN). The aim of this case report is to highlight the fact that other genetic conditions can masquerade as a mitochondrial disorder. Case description A 2 year-old Malay boy who was born to non consanguineous parents was referred for genetic evaluation of a possible Leigh syndrome. He was born at 36 weeks with birth weight of 1.9kg, and had a background of global development delay. Presented with • Hemiplegia • Dystonia • Neuroregression Physical examination • left upper motor neuron facial nerve palsy • left hemiplegia • hypotonia and hyporeflexia. Molecular anal