Abnormal calcium metabolism in myotonic dystrophy as shown by the Ellsworth-Howard test and its relation to CTG triplet repeat length

Abstract

Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by peculiar clinical features. Its molecular basis is the unstable expansion of a CTG triplet repeat in the gene encoding myotonin protein kinase (Mt-PK), the nucleotide sequence of which has extensive homology to the cyclic AMP (cAMP)-dependent protein kinase gene. Extensive efforts have been made to clarify the signal transduction pathway in which the responsible gene operates, but confirming evidence has yet to be obtained. Because some symptoms in DM are similar to those in hypoparathyroidism, we divided 24 DM patients into two groups on the basis of their serum calcium levels; Group 1, those with normocalcemia (11 patients), and group 2, those with hypocalcemia (13 patients). The highly sensitive parathyroid hormone (HS-PTH) plasma levels in group 1 were within normal limits, whereas those in group 2 were abnormally high. Laboratory findings for the group 2 patients resembled those for pseudohypoparathyroidism (PHP), whereas those for group 1 patients were normal. The Ellsworth-Howard (EH) test was used to determine which type of PHP the group 2 patients belonged to. Both the phosphaturic (delta P) and urinary cAMP (UcAMP) responses were estimated. The delta P responses in group 2 were significantly lower than those in group 1, but their UcAMP responses did not differ. This is evidence that group 2 patients had PHP type II, whereas group 1 patients were normal. We also investigated whether the disease severity differed between the groups. Cataracts, ectopic calcifications, and ossifications, which are associated with PHP, were more frequent in group 2. In addition, the mean IQ in that group was significantly lower. Clinically, the group 2 signs agreed well with those of PHP, whereas for group 1 there was only a slight similarity. These results are additional evidence that the patients in group 2 have abnormal calcium metabolism, the abnormality being in the postadenylate cyclase-cAMP pathway in the renal tubular cells. The degree of (CTG)n expansion, the so-called expanded DNA fragment (EF) size, was determined by standard Southern blot analysis. The allelic EF sizes in both groups were greater than in the healthy controls. Moreover, those in group 2 were significantly longer than those in group 1. We therefore investigated whether EF size is correlated with the serum calcium and plasma PTH levels, the delta P responses in the EH test, and IQ. All these items were significantly correlated with EF size. Our findings show that the expanded DNA fragment size in DM is correlated with the degree of abnormal calcium metabolism.

CTG triplet repeat expansion in a laryngeal carcinoma from a patient with myotonic dystrophy

“…7 CTG repeat expansion in somatic cells of DM patients generally is considered to occur during gametogenesis or early embryonic development, but CTG repeat expansion size is reported to increase over the lifetime of DM patients, 21,24 and both disease severity and CTG repeat size may increase over the course of the illness. 13 These and our findings support the hypothesis that elongation of the CTG repeat occurs during acquired cell proliferation. This paper was presented at the American Academy of Otolaryngology-Head and Neck Surgery Annual Meeting in San Antonio, Texas, September 1998.…”

Saccadic slowing in myotonic dystrophy and CTG repeat expansion

“…Several recent reports have shown that the size of the CTG triplet repeat is correlated quantitatively with such clinical indexes of DM as the phosphaturic response in the Ellsworth-Howard test [21,27], intelligence quotient [11,21,27], apnoea index [21] and cardiac functions [42]. We found a significant negative correlation between EF sizes and horizontal saccadic velocity.…”

Stapedial reflex in myotonic dystrophy type 1 and CTG repeat expansion

“…A few studies have reported quantitative or semiquantitative analysis of the correlation between muscle involvement and (CTG)n length in DM1 patients [10,13,27]. Kinoshita et al [13] and Jaspert et al [10] grossly evaluated the muscle status of DM1 patients based on the muscular disability rating scale (MDRS) of Mathieu et al [17] or the muscle disability test described by Stuart et al [26] and reported a significant correlation between the extent of muscle weakness and (CTG)n length.…”

“…Recent studies have shown that the severity of various clinical symptoms of DM1 is closely related to (CTG)n length [2,3,13,14,22]. Findings of neuro-otological examinations, including eye movement and the SR, can contribute to a quantitative evaluation of muscle involvement in DM1.…”

“…Kinoshita et al [13] and Jaspert et al [10] grossly evaluated the muscle status of DM1 patients based on the muscular disability rating scale (MDRS) of Mathieu et al [17] or the muscle disability test described by Stuart et al [26] and reported a significant correlation between the extent of muscle weakness and (CTG)n length. Tohgi et al [27] studied biceps brachii muscle strength using the manual muscle test [5] and found that muscle strength in DM1 patients had a significant inverse correlation with (CTG)n length.…”