We report in this paper the first volumetric study of the neurodevelopment associated with Coffin–Lowry syndrome (CLS). These are very preliminary data based on case studies. However, as CLS and many other XLMR disorders occur infrequently, case studies offer a novel opportunity to investigate the potential impact of particular X-linked genes on neurodevelopment. We compared brain morphological findings from individuals with CLS with those from age- and gender-matched typically developing controls.
The most consistent finding across individuals with CLS was the reduced total brain volume compared to controls (). Decreased brain volume in CLS is likely to stem from disruption of core RSK2
protein functions associated with mutations of this gene. The RSK2
protein activates the transcription factor cyclic AMP response element binding protein (CREB) [17
], which in turn, regulates neuronal survival factors and is required for axonal growth, neuro-protection, and synaptic plasticity associated with long-term memory. Abnormalities in CREB function may result in increased apoptosis [19
]. Accordingly, our present results suggest that diffuse reduction in brain volume may be a neuroanatomical marker for decreased neuronal survival within the developing CLS brain.
Our findings further suggest that development of the temporal cortex, cerebellum, and hippocampus may be particularly affected by RSK2
is known to be highly expressed in the human cerebellum and hippocampus [6
]. The present study offers the first evidence, albeit preliminary, of morphological abnormalities of these structures in association with CLS. In Family 1 of the present study, the 8-year-old affected male child had disproportionately enlarged cerebellum, whereas his affected brother did not. The brothers’ cognitive abilities were similarly impaired, but the 8-year-old child demonstrated a 33% lower finger-tapping score, a measure of fine motor function [21
]. Additionally, in family 2, the female carrier twin 2 (T2; and ) appeared to have more serious morphological abnormalities compared to her sister, who also showed disproportionately enlarged cerebellum. Although finger-tapping scores were not available for this individual, she did demonstrate much lower IQ than her sister who did not demonstrate disproportionately large cerebellum volume. Therefore, abnormalities of cerebellum morphology in CLS may be associated with greater risk for certain cognitive deficits. However, replication of these findings with larger samples and more specific cognitive testing are required.
The impact of RSK2
on the temporal lobe, particularly the hippocampus, may involve signaling pathways responsible for learning and memory. Persistent neuronal stimulation activates a cascade of molecular components that results in transcription and translation of new proteins, which strengthen and increase the number of synapses [18
]. The RSK2 protein is directly involved in these signaling pathways [23
]. Thus, alteration of RSK2 protein function resulting from mutations in CLS may disrupt the mechanisms necessary for the development and maintenance of new synapses in the hippocampus, a structure characterized by high synaptic activity, which is crucial for cognitive function.
However, variation from normative hippocampus morphology was not consistent across the two families with CLS, with family 1 members manifesting enlarged volume (absolute and proportional) and family 2 relatives showing reduced absolute volume (; reduction in proportional hippocampus volume in the 4-year-old affected male child in family 2 approached our definition of significance: z
=−1.39). This interfamilial resemblance of hippocampus morphology may initially suggest some genetic influence common to each family (unrelated to RSK2
), although previous studies have shown that hippocampus volume is less heritable than other brain volumes [25
] and is likely to be influenced by factors such as environmental stimulation and cortisol function [26
]. It is possible that these divergent morphological findings may also be due, in part, to different RSK2
mutations giving rise to variations of RSK2
protein function in the two families. Family 1 relatives demonstrated a mutation of the N-terminal kinase catalytic domain of RSK2
, while the mutation in family 2 was in close proximity to the ERK docking domain. CREB and ERK pathway function have both been directly implicated in hippocampus development and function [27
]. While a hypothesis linking differences in RSK2
mutations to neuroanatomical variation is speculative at this point, further genotype–brain phenotype studies in CLS may provide more definitive data in the future.
Although hippocampus morphology was different between the two families, it is interesting to note that the correlation of the absolute value of hippocampus z
scores (i.e., the magnitude
of deviation from the control group mean) with IQ approached significance when examined across
both families (r
=0.06, Supplementary Fig. 1
). This finding suggests that in CLS, the degree
of hippocampus abnormality, rather than the direction (i.e., increased or decreased volume), most accurately predicts functional outcome. Although the small sample size of the combined CLS group greatly limits the interpretability of these results, they are broadly consistent with the occurrence of hippocampus volume abnormalities in multiple populations with cognitive deficits, including Alzheimer’s disease, schizophrenia, and Down’s syndrome [32
]. These findings are very preliminary and require replication with larger samples but give direction for future studies involving the brain morphology and cognitive outcome of CLS as well as other XLMR syndromes.
RSK2 mutations may modulate the risk for cognitive impairment in CLS through altered early neurodevelopment (i.e., reduced or enlarged volumes) in combination with disruptions in ongoing neural organization and plasticity via the learning and memory signaling pathways. It will be essential to study the morphology and function of specific brain regions involved in learning and memory (e.g., hippocampus, prefrontal cortex) to determine the potential impact of disrupted neuronal plasticity in CLS. Additionally, studies involving assessment of neuroanatomy, mutation type, and cognitive-behavioral outcome in CLS are required to elucidate essential links among gene, brain, and cognition. Continued studies combining genetic analysis, neuroimaging, and cognitive outcome with larger CLS samples hold promise for improving our understanding of the influence of X-linked genes on brain development and function.