[Show abstract][Hide abstract] ABSTRACT: Medical records and follow-up data were reviewed in 297 genetically proven myotonic dystrophy type 2 (DM2) patients. Patients were selected by the criteria of cardiac sudden death before age 45. Sudden death occurred in four patients, three of whom were cardiological asymptomatic, and one with a history of heart failure. Cardiac histopathology showed dilated cardiomyopathy in all, and conduction system fibrosis in two patients. Pathogenetic CCUG ribonuclear inclusions were demonstrable in cardiomyocytes.
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy type 2 (DM2) is caused by a dominantly transmitted CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene on chromosome 3q. DM2 patients with two mutant alleles have not been reported so far. In one large consanguineous family from Afghanistan, we found three homozygotes for the DM2 mutation. The oldest patient was clinically more severely affected, compared with the two younger homozygotes, but for the clinical course of symptoms all three homozygotes were within the range expected for heterozygotes. Further investigations, such as mutation repeat length, muscle histology, anti-muscleblind-like 1 stainings or brain imaging studies, at least at short-term observation, showed no differences between heterozygotes and homozygotes. Twenty of 24 children, aged 2-21 years, were available for clinical examination. None of these children have signs or symptoms of disease until the age of 18 years. Homozygosity for the DM2 expansion does not seem to alter the disease phenotype as compared with the heterozygous state.
[Show abstract][Hide abstract] ABSTRACT: We evaluated muscle biopsies from 57 patients with genetically confirmed myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM). Light microscopy showed myopathic together with "denervation-like" changes in almost all biopsies obtained from four different muscles: increased fiber size variation, internal nuclei, small angulated fibers, pyknotic nuclear clumps, and predominant type 2 fiber atrophy. Quantitative morphometry in 18 biopsies that were immunostained for myosin heavy chain confirmed a predominance of nonselective type 2 fiber atrophy. These histological changes were similar in all patients regardless of the site of biopsy, the predominant clinical symptoms and signs, and the clinical course. It is likely that, in a number of undiagnosed patients, DM2 is the underlying disorder. With a better understanding of the histopathological pattern in DM2, biopsies from patients with undiagnosed neuromuscular disorders can now be reevaluated.
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.
The American Journal of Human Genetics 10/2003; 73(4):849-62. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Proximal myotonic myopathy is an autosomal dominant multisystem disorder with a recently defined CCTG expansion on chromosome 3 in the major subgroup (myotonic dystrophy type 2). Cardiac rhythm disturbances have been described in patients with this disease, but it is not known whether myotonic dystrophy type 2/proximal myotonic myopathy patients suffer from dysautonomia and whether cardiac arrhythmias relate to autonomic dysfunction.
To investigate cardiovascular autonomic function in myotonic dystrophy type 2/proximal myotonic myopathy patients with and without cardiac arrhythmias.
Standard autonomic function tests (heart rate responses to Valsalva manoeuvre, deep breathing and active change of posture, and blood pressure responses to active change of posture and sustained handgrip), resting heart rate variability in the time- and frequency-domain, and the corrected QT interval length were determined in 16 patients with genetically defined myotonic dystrophy type 2/proximal myotonic myopathy and compared to the results obtained in 16 age- and sex-matched healthy control subjects.
Standard autonomic tests yielded similar results in both groups. Measures of heart rate variability tended to be lower in myotonic dystrophy type 2/proximal myotonic myopathy patients compared to healthy controls, but reached statistical significance only for the number of R-R intervals exceeding 50 ms (p50) and the power spectrum density in the low-frequency range (low-frequency power). Four patients (25%) suffered from mild cardiac rhythm disturbances encompassing paroxysmal tachycardia, sinoatrial block, right bundle branch block, ventricular premature beats and bradycardia. The autonomic responses of these patients were essentially similar compared to those without cardiac arrhythmias, apart from a decreased heart rate response to deep breathing in the patients with cardiac arrhythmias.
We found no major abnormalities of cardiovascular autonomic function in patients with myotonic dystrophy type 2/proximal myotonic myopathy, neither in the whole study group nor in the subgroup of patients with cardiac rhythm abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic myopathy PROMM) are dominantly inherited disorders with unusual multisystemic clinical features. The authors have characterized the clinical and molecular features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene.
Three-hundred and seventy-nine individuals from 133 DM2/PROMM families were evaluated genetically, and in 234 individuals clinical and molecular features were compared.
Among affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes, and 19% cardiac involvement. Because of the repeat tract's unprecedented size (mean approximately 5,000 CCTGs) and somatic instability, expansions were detectable by Southern analysis in only 80% of known carriers. The authors developed a repeat assay that increased the molecular detection rate to 99%. Only 30% of the positive samples had single sizeable expansions by Southern analysis, and 70% showed multiple bands or smears. Among the 101 individuals with single expansions, repeat size did not correlate with age at disease onset. Affected offspring had markedly shorter expansions than their affected parents, with a mean size difference of -17 kb (-4,250 CCTGs).
DM2 is present in a large number of families of northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and cardiac conduction defects. An important distinction is the lack of a congenital form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level.
[Show abstract][Hide abstract] ABSTRACT: Rippling muscle disease is a rare autosomal dominant disorder first described in 1975. Recently, it could be classified as a caveolinopathy; in European families, mutations in the caveolin-3 gene were revealed as causing this disease. Although clinical symptoms were almost all described in adulthood, we are now reporting clinical data of seven children with rippling muscle disease owing to mutations in the caveolin-3 gene. Initial symptoms were frequent falls, inability to walk on heels, tiptoe walking with pain and a warm-up phenomenon, calf hypertrophy, and an elevated serum creatine kinase level. Percussion-/pressure-induced rapid contractions, painful muscle mounding, and rippling could be observed even in early childhood. The diagnosis can be confirmed by molecular genetic analysis. Muscle biopsy must be considered in patients without muscle weakness or mechanical hyperirritability to differentiate between rippling muscle disease and limb-girdle muscular dystrophy 1C.
Journal of Child Neurology 08/2002; 17(7):483-90. · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the cause of sporadic rippling muscle disease (RMD) in a 24-year-old patient.
RMD is a rare myopathy characterized by percussion-induced rapid muscle contractions (PIRC), muscle mounding, and rippling waves. We have recently found that autosomal dominant RMD is caused by mutations in the caveolin-3 gene (CAV3) on chromosome 3p25. Possibly, increased activity of neuronal nitric oxide synthase (nNOS) contributes to the clinical characteristics of increased mechanical muscle hyperexcitability.
Clinical examination, mutational analysis, and immunohistochemistry of muscle tissue were performed in a patient with sporadic RMD.
The authors observed a de novo CAV3 missense mutation Arg26Gln. Immunohistochemistry showed reduced caveolin-3 surface expression in a muscle biopsy. In addition, the authors found normal sarcolemmal nNOS expression and a reduced expression of alpha-dystroglycan in muscle fibers.
These data confirm that RMD is caused by CAV3 mutations. Moreover, there is evidence that CAV3 mutations may also be found in patients without a positive family history of RMD.
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.
[Show abstract][Hide abstract] ABSTRACT: Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.
[Show abstract][Hide abstract] ABSTRACT: Recently, myotonic dystrophy type 2 has been described as a separate disease entity that is distinctive from classical Steinert's disease since it lacks a CTG repeat expansion on chromosome 19q. A gene locus for myotonic dystrophy type 2 has been mapped to chromosome 3q. Independently, proximal myotonic myopathy has been recognized as yet another form of a multisystem myotonic disorder. Its relationship to myotonic dystrophy type 2 remains to be clarified. In our linkage study of 17 German proximal myotonic myopathy families nine of them mapped to the myotonic dystrophy type 2 locus (LOD score 18.9). However, two families with a typical proximal myotonic myopathy phenotype were excluded from this locus (LOD score -7.4). These results confirm genetic heterogeneity in the proximal myotonic myopathy syndrome. Furthermore, in the majority of the proximal myotonic myopathy families the disease phenotype may be caused by allelic mutations in the putative myotonic dystrophy type 2 gene.
[Show abstract][Hide abstract] ABSTRACT: Core features of the dominantly inherited myotonic dystrophies are myotonia, muscle weakness and cataract. Classic myotonic dystrophy (Steinert's disease) has been defined as a genetic entity by the underlying CTG repeat expansion on chromosome 19q13.3 (= DM1 locus). Later on, another disorder similar to but different from myotonic dystrophy was described as proximal myotonic myopathy (PROMM). The majority of PROMM families have been linked to a recently discovered locus on chromosome 3q21 (= DM2 locus).--This article analyses the clinical features of 70 patients from 14 German PROMM families linked to the 3q locus. In contrast to Steinert's disease, these patients did not reveal mental deficiency; no congenital type was found; weakness was mainly located in the proximal leg muscles; clinical myotonia was very mild and sometimes absent; episodes of pain occurred. In the majority of patients, the disorder seems to be more benign compared to Steinert's disease. However, life threatening cardiac involvement is possible; rarely, muscle weakness may progress until the patient is bedridden.--Some families with a PROMM-like phenotype do not link to the locus on 3q. The group of the myotonic dystrophies will get new members in the future.
[Show abstract][Hide abstract] ABSTRACT: To investigate anticipation in proximal myotonic myopathy (PROMM).
PROMM is a recently described autosomal dominantly inherited disorder similar to but distinct from myotonic dystrophy (DM). DM belongs to the group of inherited disorders with anticipation caused by an unstable trinucleotide repeat expansion. In PROMM, no mutation has been identified, although PROMM has recently been mapped to a gene locus on chromosome 3q.
We investigated 10 German families with the PROMM phenotype and linkage to chromosome 3q. We based our analysis of anticipation on the age of disease onset. Anticipation was assumed if the offspring had first symptoms earlier in life than his or her affected parent. For statistical analysis Independence Estimating Equations (IEE) and a Monte-Carlo bootstrap were used.
In 27 affected living parent-offspring pairs from these 10 families, the mean difference of disease onset was 18.8 years with either statistical analysis (p < 10-14 and p < 10-15). The mean disease onset interval in years was greater in father-offspring as compared to the mother-offspring pairs (p < 0.05; IEE).
Our findings suggest the occurrence of anticipation in parent-offspring pairs from families with the PROMM phenotype and linkage to chromosome 3q. The different disease onset intervals in mother-offspring and father-offspring pairs could indicate a mild parent-of-origin effect. These observations are compatible with the suggestion that PROMM, like DM, may be a trinucleotide repeat associated disorder. In contrast to DM, anticipation in PROMM is milder, a congenital form does not seem to occur, and fertility does not appear to be affected.