Rationale:
Progressive myoclonic epilepsy (PME) is a collection of rare genetic and clinical disorders characterized by generalized epilepsy, myoclonus, and progressive neurological decline, which manifests in early adolescence to late childhood. Progression to severe motor debilitation, ataxia, and dementia may occur and PME is resistant to various treatment modalities.
Several types of PMEs have been identified; the most common being Unverricht-Lundborg disease (ULD). Genetic studies have been a crucial aid to diagnosis along with EEG. Many of the genes implicated in PME express an autosomal recessive inheritance pattern, like those seen in
Cystatin B or
Laforin gene mutations. Overall, PME has a poor prognosis. Here we present the 7
th reported case of PME type 12 due to
SLC7A6OS gene, which maps to chromosome 16q22.1, and
is highly expressed in the developing human brain.
Methods:
This is a single case study.
Results:
A 34 year-old female with learning disability developed myoclonus and generalized tonic-clonic (GTC) seizures around age 12 years. Her myoclonic seizures worsened after pregnancy at age 20 years and progressed to multiple daily jerks involving upper and lower extremities. Her generalized tonic-clonic seizures have occur less than once a month mostly in sleep. She identified menstruation as a trigger.
While the patient began walking at an appropriate age, as her myoclonic epilepsy progressed, her ability declined and she has been wheelchair dependent for the last 10 years. Anti-seizure medications (ASM) tried include valproate, levetiracetam, lacosamide, clobazam, topiramate, cannabidiol, and cenobamate. Video EEG studies revealed multiple myoclonic jerks and bilateral clonic seizures with generalized polyspike and wave discharges (Figure 1A and B).
There was no family history of epilepsy or other risk factors. But, whole genome sequencing revealed the following:
- Homozygous likely pathogenic variant of the: SLC7A6OS: NM_032178.3:c.191A >G (p.Gln64Arg). This gene has been implicated in autosomal recessive PME 12.
- Heterozygous variant of uncertain significant [NPRL3: NM_001077350.3: c.1516A >T; p.Asn506Tyr; rs202015937], a gene which is associated with autosomal dominant familial focal epilepsy with variable foci, which was likely incidental.
Conclusions:
Mazzola et al described six cases in two families of PME 12 caused by
SLC7A6OS splicing defect found by exome sequencing and confirmed by Sanger sequencing. The gene defect resulted in marked (~50%) reduction in decreased transcription and protein product, consistent with a loss-of-function effect. The majority of patients had bilateral GTC seizures beginning between ages 11 to 21 years which progressed to myoclonic seizures over time. Two-thirds of patients also had deterioration in walking resulting in wheelchair use before age 30. We described the seventh case of PME 12 with many similarities. Like our patient, the seizures were refractory to various ASM.
PME is a debilitating disorder that can be difficult to treat. Earlier identification through genomic sequencing may allow for treatment trials similar those performed in patients with ULD, such as ketogenic diets, different ASM, Ropinerole, and IVIg.
Funding: None