A case of fragile X premutation tremor/ataxia syndrome with evidence of mitochondrial dysfunction

The fragile X premutation tremor/ataxia syndrome (FXTAS) is a recently described adult-onset neurodegenerative disorder1 characterized by cerebellar ataxia and/or intention tremor and other documented symptoms such as short-term memory loss, executive function deficits, cognitive decline, Parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction in various combinations. Magnetic resonance imaging (MRI) findings in affected individuals include increased T2 signal intensity in the middle cerebellar peduncles and cerebellar peridentate white matter, cerebellar cortical atrophy, cerebral atrophy, and thinned corpus callosum.2,3 A 58-year-old man was referred to us because of rest and action tremor and ataxic gait. He had no family history of neuropsychiatric disorders, except a late-onset tremor in his maternal grandfather. At the age of 45, he developed major depression with severe anxiety and social phobia. He experienced onset of right arm tremor by the age of 48, followed by right leg tremor, intermittent tongue tremor, mild right bradykinesia, and gait instability by the age of 53. At the age of 56, tremor extended to the left side and he started complaining of memory loss. At the age of 58, he had developed severe ataxia with falls. Neurological examination showed bilateral rest, postural, and action tremor; mild right bradykinesia; left Babinski; reduced deep tendon reflexes at the patellae and absent at the ankles; and ataxic gait. Neuropsychological testing documented short-term and long-term memory loss and executive function deficits without dementia. IQ score was normal (total IQ 90). Copper; HIV markers; lysosomial enzymes studies; genetic testing for spinocerebellar ataxias type 2, 3, and 6; and cerebrospinal fluid investigations (including oligoclonal bands) were all normal. MRI scans showed symmetrically decreased T1 and increased T2 signal intensity in the middle cerebellar peduncles, peridentate white matter, and periventricular and subependymal cerebral white matter. Mild cerebral and cerebellar cortical atrophy and thin corpus callosum with hyperintense genu and splenium were also present (Fig. 1A–D). Genetic testing disclosed a CGG expansion in the FMR1 (fragile X mental retardation 1) gene in the 55to 200-repeat range (91 3 CGG repeats on Southern blot analysis), termed premutation. The diagnostic criteria proposed by Jacquemont and colleagues for definite FXTAS were fulfilled.2 Proton (1H-MRS) and phosphorus (31P-MRS) magnetic resonance spectroscopy (MRS) studies were performed in a 1.5T GE Medical Systems Signa Horizon LX whole-body scanner. Single voxel 1H-MRS spectra were acquired using the PRESS sequence in the left cerebellar hemisphere (including the dentate nucleus and the peridentate white matter with abnormal signal intensity on MRI), in the normalappearing left parieto-occipital white matter, in the midbrain parietal– occipital cortex (TE 35 msec; TR 4,000 msec) and in the lateral ventricles (TE 288 msec; TR 1,500 msec; Fig. 1E). Peak areas for N-acetylaspartate (NAA), creatine–phosphocreatine (Cr), choline (Cho), and lactate were calculated using the time domain fitting program AMARES/MRUI. 31P-MRS spectra were acquired at rest from the left calf muscles as previously described4 with a repetition time of 5 seconds (128 FIDs), and phosphocreatine, inorganic phosphate (Pi), and ATP were quantified using AMARES/MRUI. Ten healthy sexand age-matched subjects were also studied. Reduced cerebellar NAA/Cr (1.21; normal range, 1.31–1.68) and abnormally increased lactate in ventricles (Fig. 1F), undetectable in controls, were found in the patient. No metabolic alterations were found in the other cerebral regions studied. Muscle 31P-MRS in the patient detected an increase in Pi to ATP ratio (0.78; normal range, 0.44 – 0.62). Ventricular lactate accumulation and increased Pi to ATP ratio in the resting calf muscles found in our patient are typical findings in mitochondrial encephalomyopathies5–7 and point to a dysfunction of oxidative phosphorylation. Several findings indicate an RNA-mediated pathogenesis for FXTAS.8 The main molecular abnormality in this disease is the twoto fivefold increase in FMR1 mRNA with lownormal or mildly decreased levels of FMRP (fragile X mental retardation protein).9 Mechanisms of pathogenesis could be similar to that of myotonic dystrophy (DM), where abnormal RNAs with the CTG trinucleotide expansion accumulate in ribonuclear foci and alter the regulation or localization of different forms of RNA-binding protein, leading to aberrant splicing of several transcripts.10,11 Of interest, the 31P-MRS study of patients with DM disclosed an impairment of oxidative phosphorylation.12 In FXTAS, excess binding of some proteins to mRNA with CGG expansion has been hypothesized to trigger the accumulation or abnormal processing of proteins by the proteasomal degradation pathway, inducing intranuclear inclusion formation, and to deplete the protein cellular pool, leading to a loss of their normal functions in other regulatory processes.8 Unlike DM, no aberrant transcripts are known in FXTAS. In both, however, one of the final events due to RNA toxic gain-offunction could be a dysfunction of the respiratory chain. Our MRS findings in a single patient could be coincidental, but if further studies confirm mitochondrial dysfunction in FXTAS, as well as in DM, they would shed more light on all pathogenic mechanisms in these diseases.