A 74 year-old man, a retired bank clerk, presented with hand tremors that had started five years earlier and worsened over the last year. The tremors were more severe when the patient had to hold objects with his hands or when he was worried. He also complained of gait disturbance attributed to previous traumatic lesions of the ankle and knee joints that occurred during his lifetime as a football (soccer) player. Recently, he had manifested several episodes of urinary incontinence and a few incidents of fecal incontinence. His wife reported that he had become progressively more forgetful over the last five years, with difficulties in remembering appointments, messages or where he had kept his things. In the last month he had presented episodes of misinterpretations of TV programs as real events and of not recognizing his house as his own. No other physical illness was reported. His mother had a similar tremor when she was very old. She died at the age of 94, but after 89 years she began to show cognitive decline. One of his sisters also has hand tremors but no memory complains, whereas his other sister and brother were apparently unaffected. He had two daughters and the only offspring of one of the daughters was a 7-year-old mentally deficient boy. His two sons were clinically normal.
On examination his blood pressure was 140 x 80 mm Hg, and there were signs of arthrosis in both ankle and knee joints. His gait was slightly ataxic and action (postural and kinetic) tremors in upper extremities, left greater than right, were evident. Rest tremor as well as bradykinesia and rigidity were absent. The hand tremors made it difficult to evaluate the coordination of the upper extremities, whereas no coordination problems were present in his legs. The subject also had voice tremor.
He scored 20 on the Mini-mental State Examination (MMSE), a low score given his 16 years of schooling, in spite of his incapacity for drawing or writing because of the tremor (Figure 1). He was easily distracted and was unable to accurately repeat sentences from the MMSE or to obey the simple commands involved in the test. In the memorization of drawings from the Brief Cognitive Battery, he showed more severe learning than delayed recall impairment demonstrated by his score of 5 out of the 10 items in the learning test, while in the delayed recall test he was able to recall 4 of the 5 items. In the Dementia Rating Scale he scored 88, with low performance across all subtests (drawing and writing incapacities further reduced his score). He scored 3 on the Digit span in both direct and reverse order. In the Logical Memory of the Wechsler Memory Scale he attained the 6th percentile on immediate recall, but was able to reach the 10th percentile after 30 minutes. Semantic verbal fluency was low for animals in one minute (5 animals) as well as for supermarket items (6 items). Phonemic verbal fluency was also very low, with a total score of 4 for the letters F, A and S together, and 2 for the letter P. His score on the Stroop Color Test was poor with 22 errors (1.8 standard deviations below the mean for his age). His score on the Questionnaire of Functional Activities was 7 (scores higher than 5 are indicative of impairment in instrumental activities of daily living, often observed in dementias).
Routine laboratory tests were normal except for a high serum level of triglycerides. EKG was normal. Brain MRI images were acquired on a 1.5T MR system (Signa Excite - GE - Milwaukee - USA) using an 8 Ch head coil. Axial T2-weighted FSE (TR: 2200 ms / TEef: 90 ms / NEX: 1), axial FLAIR (TR: 11000 ms / TEef: 104 ms / TI: 2200 ms / NEX: 1); pre and post Gadolinium axial MTC T1-weighted (TR: 500 ms / TE: 19 ms / TI: ms / NEX: 1 / MT offset: 1200 Hz) images were collected as per routine investigation. There was marked ventricle enlargement, with slight augmentation of the remaining CSF spaces. Diffuse T2 and FLAIR white matter hyperintensities were found in both superior and infratentorial compartments, with a distinct distribution, being symmetrical in the middle cerebellar peduncles (MCP), splenium of the corpus callosum, middle pontine region and periaqueductal grey matter - and most of the bi-hemispheric white matter and periventricular regions (Figure 2). These lesions did not exhibit contrast enhancement and had no corresponding MR signal alterations on the Magnetization Transfer Contrast images. Additionally, an area of tissue loss located in the anterior vermis (at the culmen and declive lobules) was detected indicating a possible earlier infarct.
Analysis of the FMR1 gene showed a premutation with (CGG)90. The presence of the premutation in this patient prompted the genetic counseling of his two daughters, obligate permutation carriers. The examination of his mentally retarded grandson revealed the FMR1 full mutation, thus establishing the diagnosis of fragile X syndrome.
He was treated with primidone 100 mg/day associated with propranolol 40 mg/day with partial improvement in the tremor, making eating and shaving easier for him.
An informed consent form was signed by the patient's son authorizing the publication of the case for medical and scientific purposes.