Pure psychiatric presentation of Fragile X‐associated tremor/ataxia syndrome

Abstract

Fragile X syndrome is a leading cause of intellectual disability in childhood related to the presence of more than 200 repeats of CGG triplets in the FMR1 gene [1]. By contrast, premutation carriers (number of CGG triplets between 55 and 200) have normal development but are at high risk of developing in their late adulthood the so-called Fragile Xassociated tremor/ataxia syndrome (FXTAS) [2]. This syndrome is characterized by late-onset cerebellar ataxia and intention tremor often associated with executive dysfunction. Other frequent clinical manifestations are parkinsonism, psychiatric symptoms, peripheral neuropathy and lower limb weakness [2–4]. The case of a patient affected by FXTAS whose presentation was psychiatric, without tremor and without ataxia, is reported. A 66-year-old right-handed man was referred for behavioural disturbances. He had been in good health until 10 years ago when he presented a first major depressive episode that lasted several months under antidepressant drugs. Three years before admission, his wife began complaining of short lasting episodes of sudden irritability and aggressive behaviour. He was treated by tianeptin and bromazepam for ‘atypical’ depression, but the symptoms kept worsening. His wife became frightened to stay alone with him. Antipsychotic drugs were prescribed with partial efficacy. A few weeks before admission, the patient saw an ear, nose and throat specialist for brief episodes of vertigo. A benign paroxysmal positional vertigo was diagnosed and a brain MRI was systematically prescribed, which revealed symmetrical abnormalities in the cerebellum. The patient was referred to our neurological department. He was kind and alert. His speech was adapted and coherent. He had no particular complaint but admitted having difficulties controlling himself on some occasions. On examination, motor and sensory testing was unremarkable. He had no rest, postural or intention tremor in either hand. He had no truncal or segmental ataxia but a slightly wide-based gait. Tandem walking was possible. Muscle tone and oculomotor movements were normal. There was no dysarthria, sphincter disturbances or orthostatic hypotension. Mini-mental state examination score was 28/30. He performed the clock drawing test well but otherwise showed mild dysexecutive symptoms and reduction of speed processing. Evaluation by a psychiatrist revealed no personality disorder but some elements of delusional jealousy, without depressed mood. The aspect of brain MRI was that of global brain atrophy with large ventricles and typical hyperintense signal in both middle cerebellar peduncles (Fig. 1). The diagnosis of FXTAS was considered. Data about the patient’s family were scarce as they were living in Algeria. He was an only child, but his mother had two daughters and two sons from another marriage. One of his half-brothers had three daughters, one of whom had two sons with severe behavioural disturbances in childhood. The other one had two daughters, one of whom had a son with severe intellectual disability. Genetic testing with both PCR and southern blot methods confirmed a premutation in the FMR1 gene with 95 repeats of the CGG triplet. The potential links between FMR1 premutation and psychiatric comorbidities are under debate [5]. Here, the appearance after the age of 50 of atypical psychiatric symptoms strongly suggests a causal link with the presence of the premutation. More generally, physicians must pay attention to familial history of both psychiatric and neurological symptoms when facing late-onset atypical psychiatric symptoms. Because the prevalence of the Fragile X premutation is high in the general population (estimated around one in 813 in males and one in 259 in females [2]), general neurologists should be aware of this diagnosis. Genetic counselling does not only involve the patient but also his whole family, as his daughters are obligate carriers. This was particularly true in the present case, as two of his daughters were actively considering pregnancy.