A 33-Year-Old Woman With Rigidity and Stereotypies

James Robert Brasic, MD, MPH

Disclosures

April 25, 2017

Fragile X syndrome is an X-linked dominant genetic disorder and is considered the most common etiology for inherited intellectual disability and autistic behaviors. Both males and females can be affected, but the impact on cognitive ability differs between the sexes: Males are more seriously affected and have moderate intellectual disability, whereas females have mild impairment. In the United States, fragile X syndrome affects about 1 in 4000 males and 1 in 8000 females.[23]

Females with fragile X syndrome have a normal appearance, whereas affected males have distinctive phenotypic features. Salient craniofacial findings include macrocephaly; a long face; prominent forehead and chin; and large, protruding ears. Macroorchidism is seen in postpubertal males. Delayed motor development, language delay, hyperactivity, and autistic mannerisms are described in affected males with moderate intellectual disability.[24,25]

Fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome (Xq27.3). For patients, the severity of the syndrome is determined by the number of trinucleotide repeats (CGG) present within the FMR1 gene. Expansion of CGG repeats leads to an inability to produce the FMR protein, a protein involved in cerebral neuronal function.

Early intervention programs to address intellectual deficits in patients with fragile X syndrome can help facilitate optimal growth and development. Newborn screening for fragile X syndrome is being considered, although at present, it is not available as part of the newborn screening program in the United States. Medications to address behavioral concerns and improve quality of life for patients with fragile X syndrome are being investigated, Presently, 22 controlled studies have been cited; 19 of the 22 (86%) are registered on the National Institute of Health website.[24,25,26]

Figure 3.

The female patient in this case challenge participated in an investigation to examine acetylcholine in the brains of women with Rett syndrome and healthy men and women.[27] Men with Rett syndrome are extremely rare. Because males have only one X chromosome, the defect of this X-linked condition is apparently lethal in utero, leading to miscarriages. The density of the acetylcholine vesicular transporters in the living human brain can be estimated by single-photon emission computed tomography after the administration of (-)-(2R,3R)-2-hydroxy-3-(4-phenylpiperidino)-5-[123I]iodotetralin, (-)-5-[123I]iodobenzovesamicol ([123I]IBVM).[27] The scans of the patient and three other women with Rett syndrome exhibited reduced uptake in the brain, in contrast to the scans of eight healthy men and women (Figure 3).

The lower panels in the image demonstrate the average representations of the women with Rett syndrome, whereas the upper panels show the averaged images of the healthy adults. The right side of each picture corresponds to the right side of the brain. The top of each image corresponds to the anterior (front) of the brain. The panels represent transverse images at the level of the cerebellum (left), striatum (middle), and cingulate gyrus (right). Reduced uptake is demonstrated in the vermis (left lower panel), the striatum (middle lower panel), and in bilateral precentral cortices (left lower panel) and middle cingulate (right lower panel). The changes do not attain statistical significance, probably owing to the small sample sizes.[27]

Although this patient has the ability to feed herself and to walk without assistance, most patients diagnosed with Rett syndrome require assistance with eating, walking, dressing, toileting, and other basic activities of daily living. People with Rett syndrome typically require assistance and supervision for their entire lives owing to their profound intellectual disability, as is the case with the patient described in this case.

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