Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

Abstract

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay

“…Autosomal recessive mutations in TBC1D24 (MIM613577) lead to epilepsy (familial infantile myoclonic epilepsy (FIME), MIM 605021; early-infantile epileptic encephalopathy 16 (EIEE16), MIM 615338), non-syndromic hearing loss (either recessive, DFNB86, MIM 614617, or dominant, DFNA65, MIM 616044) or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures, MIM 220500). We noted that carriers of TBC1D24 mutations may have a susceptibility to epilepsy notably in the mother of a patient with DOORS syndrome who carries a loss-of-function mutation [1], and this was eventually noted in other families (detailed in Banuelos et al [2]). We thus sought to identify the phenotype associated with microdeletions of TBC1D24 and surrounding genes.…”

Emerging Monogenic Complex Hyperkinetic Disorders

“…In a recent review of new and published cases, 39/48 (81%) presented mild to profound intellectual disability, which therefore appears to be a frequently encountered clinical feature. Moreover, dystonia (sometimes with a hemisomatic distribution) was reported in 7/48 (14.5%) of patients as well as in a recently published case with a complex phenotype including epilepsy, infantile-onset parkinsonism, cerebellar signs, and psychosis [ 85 ]. Cortical myoclonus affecting lower limbs with gait impairment has also been reported [ 86 ].…”

Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene

“…Therefore, a combined secondary etiology (progressively decreasing vascular reserve capacity of the basal ganglia and drug-induced aggravation of signs) is suggested as an explanation for the Parkinsonian syndrome, and its relationship with DOORS syndrome cannot be proved. Of note, Parkinsonism was reported previously to be associated with mutations in the most common causative gene for DOORS syndrome (15). In addition, individuals with TBC1D24 mutations were also noted to have dystonia and other movement disorders (16).…”