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August 2015

Fragile X Tremor Ataxia Syndrome With Rapidly Progressive Myopathy

Author Affiliations
  • 1Department of Neurology, NYU School of Medicine, New York
JAMA Neurol. 2015;72(8):946-948. doi:10.1001/jamaneurol.2015.0812

In this report, we describe a patient with clinically definite fragile X–associated tremor/ataxia syndrome (FXTAS)1 who experienced rapidly progressive, painless, noninflammatory proximal and distal myopathy after surgery with general anesthesia.

Report of a Case

A right-handed man in his 60s presented with a 10-month history of rapidly progressive motor impairment. His medical history was significant for type 1 diabetes mellitus, peripheral neuropathy, diabetic amyotrophy of the left lower extremity, and complex partial seizures. He also reported a 20-year history of slowly progressive, bilateral hand tremor with action and intention. Family history was significant for fragile X syndrome in his sister’s son.

Ten months earlier, he had undergone total left hip arthroplasty under general anesthesia. After this, he developed rapidly progressive gait and limb ataxia, diffuse muscle weakness and atrophy, impairment of manual dexterity, head tremor, increased hand tremor, dysarthria, mild dysphagia, myoclonic jerking, and frequent falls. He reported orthostatic lightheadedness, nocturia, and erectile dysfunction but no myalgias or muscle cramps and no changes in cognition, motivation, or mood.

Examination showed moderate bilateral dysdiadochokinesis; dysmetria on finger-nose-finger and heel-knee-shin tests; and overshoot on finger follow. There was also mild dysarthria, titubation with standing, and mild-moderate gait ataxia. Extraocular movements were significant for saccadic pursuits and hypometric saccades; square wave jerks and nystagmus were absent. A bilateral jerky hand tremor was present with action and intention; no rest or postural tremor was observed. There was also mild cervical dystonia with left head turn, right head tilt, and a positional yes-yes head tremor. There was no parkinsonism. Diffuse proximal and distal muscle atrophy was noted in all 4 extremities. There was bilateral scapular winging, and right greater than left weakness (4− to 4+ power) in the biceps, finger extensors, and intrinsic hand muscles, particularly the right opponens digiti minimi. There was also weakness (4− to 4+ power) in the left greater than right iliopsoas, of bilateral plantar flexion, and of left ankle and great toe dorsiflexion. Spasticity and fasciculations were absent. There was diffuse hyperreflexia but the ankle jerks were absent. The plantar responses were flexor. There was mild impairment of distal vibratory sensation. The Montreal Cognitive Assessment score was 26 of 30, with impairment of repetition, abstraction, and delayed recall.

Genetic testing showed a fragile X premutation, with 90 CGG repeats in the fragile X mental retardation 1 gene. Brain magnetic resonance imaging showed mild cerebral and cerebellar volume loss and mild T2/fluid-attenuated inversion recovery hyperintensities in the pons and periventricular white matter. The middle cerebellar peduncle and corpus callosum splenium signs were absent. Electrodiagnostic testing of the right arm and leg showed evidence of a clear nonirritative myopathy affecting the proximal and distal muscles and a moderate to severe large-fiber axonal peripheral neuropathy. No active denervation was found. Muscle biopsy from the right quadriceps showed findings consistent with myopathy, including fiber size variation, but no definite signs of mitochondrial dysfunction (Figure). The following test results were all normal: complete blood cell count; electrolytes; renal, hepatic, and thyroid function tests; creatine kinase; erythrocyte sedimentation rate; anti–glutamic acid decarboxylase antibodies; celiac laboratories; other autoimmune and paraneoplastic serologies; vitamin B12 level; heavy metal testing; human immunodeficiency virus test; Lyme antibody; VDRL; serum protein electrophoresis; immunofixation electrophoresis; and cerebrospinal fluid studies. The rheumatoid factor level was 54 IU/mL. Magnetic resonance imaging of the cervical and thoracic spine; computed tomographic scan of the chest, abdomen, and pelvis; and testicular ultrasonography were unrevealing. DaTscan (GE Healthcare) showed no evidence of a dopaminergic deficit.

Muscle Biopsy Findings
Muscle Biopsy Findings

A, Hematoxylin-eosin stain shows muscle fiber size variation and scattered atrophic fibers consistent with myopathy (black arrowheads) compared with a normal fiber (white arrowhead; original magnification ×10). B, A few of the atrophic fibers appear in small groups, indicating a minor neurogenic component (black arrowhead; original magnification ×10). C, Gomori trichrome stain did not show ragged red fibers, but some fibers show subsarcolemmal accumulations (white arrowhead; original magnification ×40). D, Adenosine triphosphatase pH 9.4 stain demonstrates that atrophic fibers are of type 1 and type 2; no definite fiber type grouping was observed (original magnification ×10). Oxidative stains, including reduced nicotinamide adenine dinucleotide (E; original magnification ×40) and succinate dehydrogenase (F; original magnification ×40), show increased subsarcolemmal enhancement (black arrowheads), as well as a few fibers with increased central pallor (white arrowhead). No intranuclear inclusions were observed.2,3


To our knowledge, this is the first report of documented myopathy in FXTAS. Prior studies have described leg weakness in FXTAS1 and fibromyalgia symptoms in female carriers of the FXTAS premutation4,5; however, the current study is the first to demonstrate the presence of myopathy. The myopathy observed in this case was not an incidental finding, but rather one of the major and most disabling features of his presentation. Together, these observations broaden the spectrum of clinical manifestations of FXTAS4,6 and underscore the potential risks of surgery with general anesthesia1,7 in this population.

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Article Information

Corresponding Author: Melissa J. Nirenberg, MD, PhD, Department of Neurology, NYU School of Medicine, 240 E 38th St, 20th Floor, New York, NY 10016 (melissa.nirenberg@nyumc.org).

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Nirenberg receives funding from the New York Stem Cell Foundation. Dr Roda receives support from an internal NYU School of Medicine startup grant. This funding is unrelated to the current article.

Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

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