Subacute Neuropsychiatric Syndrome in Girls With SHANK3 Mutations Responds to Immunomodulation

Abstract

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

FIGURE 1

Sickness behavior as a hypothetical model for conceptualizing SHANK3’s interface with the immune system. SHANK3 functions as an important scaffolding protein for neurotransmitter receptors (see 1). A, In experimental models, systemic inflammatory stimuli can decrease SHANK3 expression via nuclear factor κ–light-chain enhancer of activated B cells (NF-kB)-related signaling pathways (see 8). B, A variety of stereotyped behaviors occur as codified responses to nonhomeostatic physiologic states (eg, acute illness), each using unique molecular pathways to manifest adaptive, stimuli-specific behavioral responses. C, Alteration of proteins within these pathways, such as via genetic variants that confer a gain or loss of function, would be hypothesized to alter the associated behavioral response. The diverse behaviors that accompany states of acute infection, known as sickness behaviors, which include irritability, depressed mood, and social withdrawal, offer a template for conceptualizing the molecular and behavioral phenomena that may result from systemic inflammation and, conversely, be modified by its resolution (see 17). Considered together with our case histories, the combined observations offer a reasonable hypothesis implicating SHANK3 as a candidate protein involved in 1 or more molecular pathways regulating clinically relevant sickness behaviors in humans. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mGluR, metabotropic glutamate receptor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMDAR, N-methyl-D-aspartate receptor; NP₀, common variant of a hypothetical neurobehavioral protein; NP₁, gain of function variant of neurobehavioral protein; NP₂, loss of function of neurobehavioral protein; NP, neurobehavioral protein.