Brain disease and molecular analysis in myotonic dystrophy.

Abnormal amplification of a CTG repeat on chromosome 19 is the molecular basis of myotonic dystrophy (DM). Expansion of the repeat has been correlated with severity of several clinical features of the disease. We performed extensive cognitive testing, cerebral magnetic resonance imaging (MRI) and a molecular analysis in 28 cases of DM to determine the relationship between the molecular defect and brain disease. Performance in two or more cognitive tests was pathological in 10 cases. Fourteen patients had subcortical white matter lesions on MRI, 14 had cerebral atrophy. Amplification of the CTG repeat showed a strong correlation with cognitive test deficits when exceeding a length of over 1000 trinucleotides. MRI lesions were associated with impaired psychometric performance, but MRI and molecular findings were only weakly related. Disease duration influenced the appearance and amount of white matter lesions on MRI. Quantification of CTG repeat size may allow an early estimate on the probability of brain involvement in DM; cognitive dysfunction is associated with white matter lesions and cerebral atrophy later on in the course.

The clinical and genetic correlates of MRI findings in myotonic dystrophy.

Amplification of an unstable CTG trinucleotide repeat sequence in a protein kinase gene on chromosome 19 has recently been recognised as the molecular basis of myotonic dystrophy (DM), a multi-system disorder with a wide spectrum of muscular and extramuscular manifestations. The CTG expansion of 40 patients was assessed by direct genotype analysis of the white blood cell DNA and correlated with MRI of the brain and muscles, and with functional clinical data. Cerebral pathology on MRI consisted of diffuse atrophy (68%), subcortical white matter lesions (65%), wide Virchow-Robin spaces (38%) and thickening of the skull (35%). Cerebral atrophy and extent of white matter disease correlated significantly with mental retardation, duration of disease and CTG fragment amplification. MRI of the muscular system showed fatty degeneration of different degrees in neighbouring muscles causing a mosaic pattern of the thigh in 38% and the calf in 44%. Muscular changes on MRI were strongly correlated with muscular impairment but less strongly with CTG expansion. Changes on MRI reflect the stage of development of tissue pathology in DM, modified by defect of the DM gene. Pathology on MRI is strongly correlated with functional deficits.

White matter lesions and cognitive deficits: relevance of lesion pattern?

Magnetic resonance imaging (MRI) permits efficient visualization of white matter lesions (WML). A growing body of literature deals with the correlation of WML and cognitive dysfunction with conflicting results. We studied the influence of lesion pattern as well as size by analyzing MRI and psychometric test performance in 2 patient collectives with different WML patterns. 22 patients with myotonic dystrophy (MD) and mainly subcortical WML were compared with 39 patients with multiple sclerosis (MS) and mainly periventricular lesions. 73% of MD patients had WML, the extent of which correlated with cognitive deficits. Severely impaired patients had psychometric findings compatible with "subcortical" dementia. In MS the extent of WML alone did not correlate significantly with cognitive deficits. Significant cognitive dysfunction was observed with extension of WML to areas of white matter immediately underlying cortex, but not with exclusively periventricular lesions. Cerebral atrophy had less impact. Comparison of MD and MS indicates that WML immediately subjacent to cortex are likely to cause significant cognitive deficits, whereas extensive periventricular demyelination may cause no major dysfunction. This may relate to early disturbance of associative fibers by subcortical lesions. Our results emphasize the significance of pattern as well as total extent of WML. Myotonic dystrophy is a useful model to study the effect of subcortical lesions, due to a typical lesion pattern unusual in other conditions.

[Myotonic dystrophy: magnetic resonance tomography and clinico-genetic correlations]. / Myotonische Dystrophie: Magnetresonanztomographie und klinisch-genetische Korrelationen.

Myotonic dystrophy (DM) is an autosomal dominant multisystem disorder involving muscle, brain, heart, eyes and endocrine organs, among others. The molecular basis is an unstable trinucleotide repeat at the 3'-untranslated end of the myotonin protein kinase gene on chromosome 19 q 13.3, and the number of repeats correlates with the severity of muscle weakness. We performed a clinical, psychometric and MRI study on 43 patients with DM and correlated findings with the molecular analysis. Nineteen patients had mild distal muscle weakness, 17 moderate und 7 severe weakness. Thirteen had marked cognitive deficits with reduced speed of cognition, low IQ, and apathy. MRI showed pathological muscle signal in 35 cases with a characteristic mosaic involving distal muscle groups, often sparing the posterior tibial muscle. Cerebral MRI showed significant subcortical white matter lesions in 20 cases and brain atrophy in 15 cases. Clinical and MRI findings of CNS and muscle both correlated with CTG repeat length, but did not parallel each other. DM is a significant disease of the brain as well as muscle, and several aspects of the disease correlate with molecular findings, with a threshold effect for repeats exceeding 1000 trinucleotides. The individual predominance of specific organ involvement probably depends on variable somatic mosaicism of the molecular defect.