The fra(X) syndrome: Neurological, electrophysiological, and neuropathological abnormalities

Abstract

We have evaluated 62 fragile X syndrome [fra(X)] individuals (55 males and 7 females) with different degrees of developmental disabilities that were clinically non-progressive and non-focal in character. The mean age for the 55 males was 23.1 years +/- 14.3 SD with a range of 2-70: for the 7 females, the mean age was 15.7 years +/- 3.5 SD with a range of 10-20 years. Mental retardation (MR) was found in 53 males (8/53 [15.1%] mild, 26/53 [49.1%] moderate, 14/53 [26.4%] severe, and 5/53 [9.4%] profound). Learning disabilities were found in 2/55 (3.6%) of males. One of the 7 females had mild and one had moderate MR: the other 5 were learning disabled. Autistic stigmata were present in 10/62 (16%) of the patients. Only 14/62 (23%) had a history of seizures, all of which were controlled with anticonvulsants. In 36/62 cases, an electroencephalogram (EEG) was performed. We compared these data with that of others. Brain stem auditory evoked response (BAER) was performed in 12 cases. Abnormalities were found in only 5/12. Neuroimaging and computerized cranial transaxial tomography (CT scan) were performed on 21/62 (34%) of the patients. Only 8 of these 21 (38%) studies were abnormal. One patient died; neuropathological studies showed mild brain atrophy, with light microscopic and ultrastructural abnormalities. Rapid Golgi dendritic spine patterns showed that the proximal apical segments were abnormally developed. Very thin, long tortuous spines with prominent terminal heads and irregular dilatations were present. Marked reductions in the length of the synapses, as determined on EPTA-postfixed tissue where noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…However, at the single-neuron level (using the Golgi impregnation technique on postmortem brain tissue), cortical neurons in several regions have abnormal dendrites, with spines showing excessive numbers and length [Rudelli et al, 1985;Hinton et al, 1991;Wisniewski et al, 1991;Irwin et al, 2001]. Similar studies in the Fmr1 mutant mouse confirmed these findings, as well as excessive dendritic branching [Comery et al, 1997;Irwin et al, 2002;Galvez et al, 2003].…”

Dendritic spine instability and insensitivity to modulation by sensory experience in a mouse model of fragile X syndrome

“…An overabundance of immature-appearing, long, and thin spines are frequently observed in Fmr1 KO mice and in FXS patients (15,16). To examine whether the larger pool of transient spines in Fmr1 KO mice is related to immatureappearing spines, we compared the size of newly formed and eliminated spines to spines that persisted for at least two imaging sessions by measuring several parameters of spine morphology, including adjusted spine head brightness (a measure of volume), head diameter, and spine neck length.…”

“…Despite these behavioral abnormalities, the gross structure of the brain is largely intact in FXS patients and in the mouse model of the disorder. The most consistent anatomical finding is an abnormal profile of dendritic spines, postsynaptic protrusions that receive the vast majority of excitatory input in the brains of diverse species (14)(15)(16)(17).…”

“…Despite these behavioral abnormalities, the gross structure of the brain is largely intact in FXS patients and in the mouse model of the disorder. The most consistent anatomical finding is an abnormal profile of dendritic spines, postsynaptic protrusions that receive the vast majority of excitatory input in the brains of diverse species (14-17).In FXS, the adult dendritic spine phenotype includes increases in spine density and spine length and the number of immaturelooking spines in the various brain regions examined (15,16,18). Similarly, in the visual and somatosensory cortices of adult Fmr1 KO mice, pyramidal neurons show higher dendritic spine density and more immature, long, and thin dendritic spines than those in WT brains (4,19,20).…”

Synaptogenesis and heritable aspects of executive attention

“…This protein is locally translated in synaptic spines in response to neuronal stimulation [Weiler et al, 1997]. Golgi-histochemical studies of post-mortem tissue from patients with FMR show no gross anatomical disturbances, but rather abnormalities in the quantity and morphology of dendritic spines in pyramidal cells [Wisniewski et al, 1991]. An excess of dendritic spines in fragile X patients indicates a deficit in synaptic pruning.…”