“Introduction: GEMIN5 is a multifunctional RNA binding protein that controls SMN complex expression (o translation) and assembly. Pathogenic variants in GEMIN5 were mainly found in patients with developmental delay and ataxia associated to cerebellar atrophy. Three patients were reported to present a SMA-like phenotype with early death. De novo variants in KAT6B are associated with two distinct clinical syndromes (SBBYSS; MIM# 603736) (GPS; MIM# 606170) with intermediate phenotypes falling on a spectrum between these two syndromes. Here we present a patient harboring a novel homozygous GEMIN5 variant and a novel KAT6B variant with a clinical picture characterized by epileptic encephalopathy, progressive cerebral and cerebellar atrophy and peripheral neuropathy.
Case reports: Our patient was born by caesarean section and presented severe hypotonia with respiratory distress at birth. He also showed talipes and bilateral hip dislocation. Genetic analyses showed the novel homozygous c.2984T>A (p.Val995Glu) variant in GEMIN5 (ACMG class 3) and a de novo KAT6B variant (c.466G>A; p.Ala156Thr). At 2 months he started to present seizures and EEG disclosed a pattern of epileptic encephalopathy. Serial brain MRIs disclosed progressive cerebral and cerebellar atrophy with T2-hyperintense white matter signal. BAEPs were normal. Electroneurography showed a mixed sensorimotor polyneuropathy. Neurological examination at 2 years showed marked tetraparesis with absent reflexes and no ocular fixation and tracking.
Conclusions: Here we described an early onset phenotype with refractory epilepsy, progressive brain atrophy and peripheral neuropathy. Functional studies are needed to investigate the role of GEMIN5 and KAT6B variants in determining the phenotype.”