Abstracts

Rationale: TBC1D24 gene mutations were first described in an Italian family with a recessive form of idiopathic epilepsy subsequently named familial infantile myoclonic epilepsy. Via whole-exome sequencing, novel TBC1D24 mutations have been shown to cause a range of disorders. We describe two brothers with distinct cerebrocerebellar syndromes, born to non-consanguineous parents, each with epilepsy of varying severity and variable phenotypic expression. Methods: Case 1: 18 year old RH dominant male with brief jerks, GTCs, and staring events since 3 months old. He has 2 seizures per year. He has rotary nystagmus since 2 y/o and is legally blind. He has poor balance and large amplitude upper extremity tremor. He wears bilateral AFOs and is wheelchair bound. Case 2: 15 year old RH dominant male who was seen at 12 y/o. He has rare twitches of the extremities and 2-3 GTCs per year. He has dysarthria and a jerky tremor. He walks independently and is independent in limited ADLs. Results: UOA, serum AA were unremarkable. Normal pyruvate, lactate, Hu/Yo/Ri antibodies. Ammonia slightly elevated at 99 (case 2) Optho: Circular nystagmus. Difficult funduscopic exam due to near constant nystagmus, some evidence of optic atrophy. Retinoscopy did not reveal significant refractive error (case 1) Audiometry: sensorineural hearing loss at 250-500 hz (case 1) Cardiac Evaluation: no cardiac pathology EEG: 1 generalized onset seizure. Generalized, multifocal (right frontocentral max) IEDs (case 1) Theta/delta slowing and spikes, right temporoparietal (case 2) EMG/NCS: mild proximal myopathy w/o denervation. No evidence of large fiber polyneuropathy (case 1) Muscle biopsy: pending sleep study for clearance per pulmonary Whole exome sequencing (WES) was performed on both cases and their parents. Both brothers have a homozygous variant of unknown significance (VUS) c.845C>G of TBC1D24 gene. The parents are carriers. A hemizygous variant of unknown clinical significance c.5393A>T in the x-linked DMD gene associated with Duchenne muscular dystrophy was also found. Mother is heterozygous for the VUS. Conclusions: The TBC1D24 gene is located on the short (p) arm of chromosome 16 at position 13.3. In situ hybridization analysis revealed that TBC1D24 is mainly expressed at the level of the cerebral cortex and the hippocampus. The prevalence of these disorders is very low. They are autosomal recessive conditions which comprise a continuum of recognized phenotypes such as DOORS syndrome, familial infantile myoclonic epilepsy, progressive myoclonus epilepsy, early infantile epileptic encephalopathy (EIEE16), autosomal recessive nonsyndromic hearing loss (DFNB86), and autosomal dominant nonsyndromic hearing loss (DFNA65). The brothers have TBC1D24 related disorders, which have not been described to date. Case 1 manifests with symptomatic generalized epilepsy, dysarthria, vision loss, rotary nystagmus, imbalance, DD/ID, OSA, obesity, fatigability, hepatic steatosis, hypotonia, hyporeflexia, mild proximal myopathy. His presentation and neurologic decline is more severe than his brother. He has controlled focal epilepsy, milder DD/ID, dysarthria, OSA, morbid obesity, hypotonia, and hyporeflexia. Both have cerebellar atrophy/dysfunction (tremor, dysmetria, dysdiadochokinesia, ataxic gait). In case 1, cerebellar atrophy was marked in the inferior medial cerebellum, whereas in case 2, there was diffuse cerebellar atrophy, with restricted diffusion abnormalities in the right anteromedial cerebellum. TBC1D24 related disorders encompass various phenotypes which are poorly characterized. Identifying these disorders will allow us to provide appropriate genetic screening, counseling, treatment of associated manifestations, and surveillance Funding: N/A