P345: Expanding the phenotype of an ultra-rare neurodevelopmental disorder associated with NACC1

NACC1 gene encodes Nucleus Accumbens Associated Protein 1 (NAC1), which is a ubiquitously expressed protein that contains a BTB/POZ domain and is primarily localized to cell nuclei, where it acts as a transcriptional regulator. It has been linked to multiple cellular processes, including cell cycle control and tumorigenesis, embryonic stem cell regulation, excitatory synaptic plasticity, as well as chromatin remodeling. It’s role in the progression, survival, and recurrence of numerous carcinomas has been extensively studied over the last years. More recently a recurrent de novo variant (c.892C>T) in NACC1 has been associated with a neurodevelopmental disorder. NACC1-related disorder or Neurodevelopmental disorder with Epilepsy, Cataracts, Feeding difficulties, and delayed brain Myelination (NECFM) is a relatively newly identified, rare genetic condition associated with severe neurodevelopmental delays and/or intellectual disability, hypotonia, feeding difficulties resulting in failure to thrive, acquired microcephaly, and in some cases, bilateral cataracts, epilepsy including infantile spasms, incapacitating episodic irritability of unclear etiology, repetitive stereotypic motor behaviors and sleep disorder. Some reported cases showed cerebral atrophy and delayed myelination on cerebral imaging. Very few affected individuals (16) have been reported in the literature to date. All patients presented with a highly similar phenotype and the same de novo variant (c.892C>T) in NACC1. Recently functional studies demonstrated that this variant impairs glutamatergic neurotransmission in a dominant negative manner. Here, we describe a 21-month-old female, who presented at 7 months of age with failure to thrive, poor feeding, acquired microcephaly, developmental delay, bilateral congenital cataracts, subcutaneous hemangiomas, and congenital dysplastic nevus. She was born to a healthy mother with unremarkable pregnancy and birth. Despite normal birth parameters, microcephaly manifested by 4 months, with subsequent developmental regression in gross motor skills and significant delays in other domains of development. Trio whole exome sequencing revealed a heterozygous, de novo, pathogenic variant in NACC1(NM_052876.4):c.892C>T p.(Arg298Trp). Brain MRI at 8 months showed lobal volume loss, thin corpus callosum, T2 hyperintensities and thinning of periventricular white matter, delay in myelination status, and prominent Virchow Robin spaces. At age 1, she developed startle myoclonus, especially triggered by light stimulus, sleep myoclonus, as well as clinical episodes consistent with tonic seizures. She also experienced episodes of irritability and inconsolability with no identifiable triggers lasting 3-5 days. EEG did not show hypsarrhythmia, epileptiform activity or a photoparoxysmal response, however, did demonstrate background slowing and intermittent rhythmic slow wave activity. Few patients with NECFM have been described in the literature to date. Our case contributes to the understanding of the clinical spectrum associated with NACC1-related disorder and highlights the need for comprehensive genetic evaluations in patients with neurodevelopmental disorders. In addition to the irritability and stereotypies consistent with the recent reports, we have witnessed non-epileptic startle myoclonus in our patient, who also presented with dysplastic nevus and vascular malformations that have not been previously described. Long-term follow-up is needed to further delineate the significance of each of these findings and any potential risks or additional features. Recently, functional studies have shown to impair glutaminergic transmission therefore treatments targeting this pathway may help ameliorate both the seizures as well as the irritability and can lead to more effective therapeutic strategies.

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