Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X

Patient 2.

A 63-year-old right-handed grandfather of two children with FXS, with a PhD in education, had gradual onset of shaking in his right hand at age 55, which interfered with writing. The tremor worsened and become bilateral. Over the past 2 years his wife noticed a resting tremor in his right hand and a general slowing of movement. His activities of daily living took longer to perform. He had difficulty with balance, and fell occasionally. Memory problems were present for 2 years. He took sertraline for depression, anxiety, and obsessive–compulsive symptoms. Neurologic examination revealed a mild postural tremor of the right upper extremity, and a 4- to 6-Hz intention tremor with finger-to-nose testing. The tremor was most pronounced with handwriting, which was large and poorly legible. He had masked facies, diminished amplitude of finger tapping, mild rigidity, and an intermittent slow resting tremor in the right upper extremity. Vibration sense was reduced in his great toes.

Patient 3.

A 62-year-old right-handed grandfather of a boy with the full mutation, this patient had consumed alcohol heavily, stopping at age 57 years, when he noticed a tremor in his right arm. The tremor became much more apparent and disabling when he stopped drinking, and progressed to bilateral involvement by age 58. For the past 2 years he drank liquids through a straw because of difficulty holding a cup; his wife cut his foods, his writing was illegible, and he required assistance with buttons and dressing. He switched from using his right hand primarily to his left at age 58, and stopped driving at age 61. He was unsteady, sometimes listing to the right, with frequent stumbling in the forward direction and occasional falls. He had used a cane for the past 2 years and a walker for the past year.

Examination of the cranial nerves showed facial masking, mild saccadic pursuit, monotone speech, and bilateral hearing loss. With finger-to-nose testing he had a bilateral, upper extremity, 4- to 6-Hz, large-amplitude intention tremor and dysmetria. A resting and a static, postural tremor were present in both arms. He was unable to write. There was loss of check in the upper extremities and dysdiadochokinesis. Heel-to-shin movements were ataxic. He had slight cogwheel rigidity in the right arm and mild rigidity in both legs. His gait was wide-based and slow, his steps were short, his arm swing was reduced, and he turned en bloc. Muscle stretch reflexes were reduced in all extremities and absent at the ankles. Vibration sense was markedly reduced in the right great toe and absent in the left. MR images from Patient 3 are shown in the figure.

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Figure. (A and B) Patient 3. T1 axial and sagittal images demonstrate prominent ventricles with cerebral, brainstem, and cerebellar atrophy. Note the particularly severe frontal and parietal atrophy, which has lead to excess fluid graying the sulci seen frontally on sagittal view.

Patient 4.

This case was identified retrospectively. The patient, who died in 1988, was the grandfather of a boy with FXS. As his daughter had 75 CGG repeats and his wife was negative for the FMR1 mutation, Patient 4 was therefore an obligate premutation carrier. He had first experienced an intermittent intention tremor in his left hand at age 57 years while working as a professor in Nigeria. His handwriting became tremulous, and he found it difficult to button clothing and tie shoelaces. His wife noted the gradual development of memory and concentration problems.

Thought to have PD with left-sided rigidity, the patient was given carbidopa and l-dopa, which improved his tremor and rigidity. His condition continued to deteriorate, and by age 64 he had developed a marked resting and intention tremor bilaterally, cogwheeling in his lower extremities, and dementia. His diagnosis was modified to atypical PD. His symptoms gradually worsened and he eventually became bedridden before dying from complications of a kidney infection at age 69.

Patient 5.

Patient 5 was a 70-year-old, right-handed former college professor and grandfather of two children with FXS. At age 61 years he first noticed a tremor in his right hand, which subsequently developed in the left hand and began interfering with his handwriting. Over the past 3 years his tremor was present daily with movement, and intermittently at rest. At age 66, he found it difficult to get a key into the car door lock because of his tremor. Within the past year, he had problems with spilling liquids. Over the past 4 years he had fallen occasionally, and his gait sometimes drifted to one side. His wife noticed that he had mild short-term memory problems and compulsive hand washing. Results of his neurologic examination were similar to those of the first three cases, including impaired vibration and position sense in the distal lower extremities. The cerebellar and parkinsonian findings are described in the table.