The purpose of this article is to provide an overview of the behavioral phenotype of FMR1 mutations, including fragile X syndrome (FXS) in order to better understand the clinical involvement of individuals affected by mutations in this gene. FXS is associated with a wide range of intellectual and behavioral problems, some relatively mild and others quite severe. FXS is the most common cause of inherited intellectual disability and one of the most prevalent genetic causes of autism spectrum disorder. Learning difficulties, attentional problems, anxiety, aggressive behavior, stereotypies, and mood disorders are also frequent in FXS. Recent studies of children and adults have identified associations between FMR1 premutation and many of the same disorders. We examine the neurobehavioral phenotypes of FXS and FMR1 premutation as they manifest across the lifespan of the individual.

Summary KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A ,a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport in vivo by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity.

KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified group of rare neurodegenerative conditions caused by variants in KIF1A, a member of the kinesin-3 family of microtubule (MT) motor proteins. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in regions involved with ATP and MT-binding: the P-loop, switch I, and switch II. For a subset of identified variants, we generated recombinant mutant proteins which we used to assess transport in vivo by assessing neurite tip accumulation, and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all patient variants result in defects in transport, and describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The molecular rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a new way to describe KAND subtypes to better capture the breadth of disease severity.

Although it is suspected that anxiety modifies the clinical presentation of autism in fragile X syndrome (FXS), neuropsychiatric co-morbidity profiles of these two disorders have not been extensively studied. The National Fragile X Survey was completed for 1,027 males with FXS, for whom yes/no information regarding the presence of several disorders is provided. Although the survey exhibited limited depth and lacked validation by standardized measures, this exploratory study was conducted to take advantage of the data as an opportunity for identifying future lines of inquiry. We addressed the following questions: (i) how do the co-morbidity profiles of FXS males with both autism and anxiety compare to those without anxiety?; (ii) do individuals with autism exhibit specific co-morbidity profiles compared to FXS males with anxiety only, or without either autism or anxiety?; (iii) how do co-morbidity profiles in children ages 3-11 differ from profiles of individuals >12 years? The group with autism and anxiety reported the highest prevalence of attention problems, hyperactivity/impulsivity, self-injurious behavior and aggressiveness. In addition, the lowest prevalence rates of these conditions were often observed in non-anxious groups regardless of autism status. Overall, this exploratory analysis generated several hypotheses for further study: (i) anxiety increases the severity of autism in FXS, particularly through additional behavioral abnormalities; (ii) some neuropsychiatric and behavioral conditions (i.e., attention problems, hyperactivity/impulsivity, aggressiveness) are primarily related to comorbid anxiety, not autism; (iii) prevalence of behavioral abnormalities increases with age. Future studies evaluating these hypotheses should incorporate validated neurobehavioral assessments, and control for cognitive level.