Individuals with pontocerebellar hypoplasia 6 (PCH6) typically present with global developmental delay, abnormal brain structure, and neonatal-onset seizures that are poorly responsive to treatment. Acquired microcephaly, intellectual disability, hypotonia, feeding difficulties, ataxia, hyperreflexia/spasticity, elevated lactate in the blood or cerebrospinal fluid, neonatal hypoglycemia, and lower levels of mitochondrial enzyme activity are also common features. Less frequently reported phenotypes include dystonia, edema, optic atrophy, apneic episodes, and facial dysmorphisms such as full cheeks and deep-set eyes.
Recently, milder forms of RARS2-associated developmental epileptic encephalopathy were described in patients who initially demonstrated normal early development. Developmental concerns and features suggestive of a movement disorder (i.e., myoclonus, abnormal eye movements, dysarthria, and ataxic gait) arose in early childhood, followed by seizure onset. In contrast to the classic PCH6 presentation, epilepsy in some of these individuals responded favorably to anti-seizure therapy, further suggesting a continuum of RARS2-associated disease severity that correlates with variant severity.
RARS2