Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2)

Abstract

A previous study in proximal myotonic myopathy (PROMM/DM-2) and myotonic dystrophy type 1 (DM-1) using brain positron emission tomography demonstrated a reduced cerebral blood flow in the frontal and temporal regions associated with cognitive impairment. The objective was to investigate further cognitive and behavioural aspects in a new series of patients with DM-1 and PROMM/DM-2. Nineteen patients with genetically determined PROMM/DM-2 and 21 patients with moderately severe DM-1 underwent neuropsychological testing and neuropsychiatric interviews. DM-1 and PROMM/DM-2 patients had significantly lower scores on tests of frontal lobe function compared to controls. Neuropsychiatric interviews demonstrated an avoidant trait personality disorder in both patient groups. Brain single photon emission computed tomography showed frontal and parieto-occipital hypoperfusion. The results suggest that there is a specific cognitive and behavioural profile in PROMM/DM-2 and in DM-1, and that this profile is associated with hypoperfusion in frontal and parieto-occipital regions of the brain.

Introduction

The myotonic dystrophies (myotonic dystrophy type 1, DM-1 and myotonic dystrophy type 2, PROMM/DM-2) are highly variable autosomal dominant, multisystem disorders characterised by the involvement of the neuromuscular, cardiovascular and the endocrine systems as well as by cognitive abnormalities in cognition and personality [1], [2], [3], [4]. While mental retardation of some degree is a constant feature of the maternally transmitted congenital DM-1 [1], there is no general agreement as to the type and degree of brain involvement in the adult or juvenile forms of DM-1 [5], [6], [7], [8], [9], [10], [11], [12]. Estimates of the incidence of mental retardation (IQ<70%) or of abnormal scores on measures of general intelligence (such as Standard Progressive Matrices) vary from 20 to 80% [1], [5], [6], [7], [8], [9], [10], [11], [12] and have been reported to be associated with an abnormally large CTG repeat size (>1000) [6], [7]. Abnormal scores on measures of visual or verbal memory have been reported by some authors [5], [8] but not by others [9]. Rubinsztein et al. [5] suggested that memory function may be more sensitive to small CTG repeat expansions than general intelligence in the mild forms of DM-1. In the adult or juvenile form of DM-1 estimates of the deterioration of frontal lobe and perceptual-motor functions range between 50 and 90% of patients [5], [13], [14], [15], [16], [17]. Intelligence scores in the juvenile form of DM-1 have been reported to be lower than average, although better than in children with congenital myotonic dystrophy [13]. Equivocal results have also been found in the neuropsychiatric evaluation of patients with DM-1. A high incidence of depressive symptoms has been described by some authors [15], [16], [17], [18], [19] and has been related to the somatic concern of the disabling medical condition rather than being a direct expression of DM-1 [16], [17]. Estimates of personality disorders as defined by DSM-IV criteria range from 30 to 40% [20]. A high incidence of dependent tendencies has been observed by some authors [16], while others have found a homogeneous personality cluster C profile (avoidant, obsessive–compulsive, passive–aggressive) [20].

It is unclear whether the spectrum of brain manifestations observed in DM-1 occurs in PROMM/DM-2. Is there a congenital form of myotonic dystrophy type 2? Do the same cognitive and behavioural abnormalities observed in DM-1 appear in PROMM/DM-2 [21] and are any of these mental changes affected by gender? [16], [22].

In a previous study, we evaluated 20 patients with proximal myotonic myopathy (PROMM/DM-2) and 20 patients with DM-1 [23]. At the time of the study it was possible to demonstrate linkage to chromosome 3q21 in only three of six families. Direct testing by CCTG expansion has now revealed the DM-2 mutation in all of these PROMM/DM-2 patients. These two groups of PROMM/DM-2 and DM-1 patients had neuropsychological tests, structural neuroimaging (brain CT or MRI scans), and rCBF with H215O PET. In this previous study, we demonstrated a relatively selective alteration in visual–spatial function in DM-1 patients and, to a minor degree in PROMM/DM-2. This cognitive abnormality did not correlate with structural abnormalities on brain MRI. However, functional neuroimaging with PET demonstrated a similar pattern of hypoperfusion in both groups, and a reduction of regional cerebral blood flow in the temporal cortex and in the ventral and mesial aspects of the frontal lobes.

In the light of these alterations in brain function and cerebral blood flow we decided to perform an in-depth study of frontal lobe function and of the neuropsychiatric profile in a new series of patients, to better characterize cognitive and neurobehavioural abnormalities in patients with DM-1 and PROMM/DM-2. We have also correlated the neuropsychological and neuropsychiatric test scores in the present study with the size of the (CTG)n and (CCTG)n repeat expansions.