From Regression to Revelation: SHANK3-related Phelan-McDermid Syndrome Presenting as Lennox-Gastaut Syndrome
Jose Ortega Tola1, Mikaela Camacho Olalla1, Julianne Mallinger2, Sayed Naqvi3
1Larkin Community Hospital, 2Florida International University, 3Neurology, Nicklaus Children's Hospital
Objective:
To describe a case of a 19-year-old patient initially diagnosed with Lennox–Gastaut syndrome during childhood, later found to harbor a pathogenic SHANK3 mutation, highlighting the evolving role of genetic testing in redefining epilepsy syndromes once attributed to idiopathic or developmental etiologies.
Background:
Phelan-McDermid Syndrome (PMS) is a rare neurodevelopmental disorder caused by SHANK3 haploinsufficiency on chromosome 22q13.3. It is characterized by global developmental delay, autism spectrum features, hypotonia, and variably dysmorphic traits. SHANK3 encodes a synaptic scaffolding protein essential for glutamatergic transmission and cortical connectivity; its disruption leads to widespread neurodevelopmental impairment. Advances in genetic testing have improved recognition of PMS and its overlap with epilepsy syndromes such as Lennox–Gastaut, underscoring the importance of early genetic evaluation in refractory epilepsy.
Design/Methods:
A 19-year-old male with a history of Lennox–Gastaut syndrome, autism spectrum disorder, and cerebral palsy presented with increased seizure frequency and emesis due to small bowel obstruction, requiring surgical intervention. Seizures began at age nine, consisting of brief tonic episodes with bilateral arm flexion and upward gaze, occurring in clusters lasting 3–5 seconds. Examination revealed microcephaly, gingival hypertrophy, nystagmus, spastic quadriparesis, low axial tone, and dyskinetic movements. EEG showed diffuse slowing with rare right central and left temporal discharges, and one generalized seizure. Brain MRI demonstrated mild diffuse atrophy with stable ventricular prominence.
Results:
Extensive prior genetic and metabolic workups were negative. Rapid whole-genome sequencing later identified a heterozygous pathogenic SHANK3 variant, confirming the diagnosis of Phelan-McDermid Syndrome.
Conclusions:
This case illustrates that SHANK3-related Phelan-McDermid Syndrome may phenotypically mimic Lennox–Gastaut syndrome. Incorporating advanced genetic testing in patients with developmental regression and refractory epilepsy can uncover underlying syndromic etiologies, guiding prognosis, management, and family counseling. To our knowledge, this is the first reported case in which Phelan-McDermid Syndrome was identified in adulthood following an earlier diagnosis of Lennox–Gastaut syndrome.
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