We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguishes it from other movement disorders.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P ¼ 0.0096), hypertension (P ¼ 0.0020), seizures (P ¼ 0.0077), peripheral neuropathy (P ¼ 0.0040), and fibromyalgia (P ¼ 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P ¼ 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS. ß

There was a high (14.5%) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly outpatients. The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201-300 pg/mL compared with patients with low cobalamin levels (< or = 200 pg/mL) had markedly elevated metabolites which fell with cobalamin treatment. Additional studies will be required to define the full clinical benefit from treatment with Cbl in elderly subjects.