Unusual clinical, laboratory, and muscle histopathological findings in a family with myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is a multisystem degenerative disorder with distinctive clinical and electrophysiological features. Recently, genetic confirmation has become available with the identification of the molecular defect, an expansion of a CCTG repeat located in intron 1 of the zinc finger protein 9 (ZNF9) gene. We present two first-degree relatives with an athletic clinical phenotype, pathological evidence of subsarcolemmal vacuolation, and molecular genetic confirmation of DM2. When found in the proper clinical context, athleticism and pathological subsarcolemmal vacuoles should not dissuade the clinician from the possible diagnosis of DM2.     

CTG trinucleotide repeat length and clinical expression in a family with myotonic dystrophy

Unstable expansion of the CTG repeats in the 3′ untranslated region encoding a member of the protein kinase family in the 813.3 band on chromosome 19 is a mutation specific for myotonic dystrophy. To examine the correlation between clinical expression and CTG trinucleotide repeat length, we carried out Southern blot analysis in a family with myotonic dystrophy. In this pedigree, the expanded CTG repeats were transmitted maternally. The mother had three female children. The mother had about 200 CTG repeats, and the number of repeats for each child was about 800, 1500 and 1600 in birth order. The mother and the patient with 800 repeats were unaware of muscle weakness or myotonia. Symptoms were present from age 3 years in the patient with 1500 repeats and from birth in the one with 1600 repeats. Although the mother menstruated regularly, the patients with 800 and 1500 repeats both menstruated irregularly, and the one with 1600 repeats has never menstruated. The age of onset and severity of the disease were correlated with the size of the expanded repeats. Endocrinological studies revealed that the basal levels of the gonadotropins, PRL and E2 were within normal range, and a pituitary response to LHRH was observed. These data suggest that the amenorrhea and menstrual irregularities were caused by a suprahypophyseal dysfunction. When expanded CTG repeats are transmitted maternally, abnormal products resulting from the metabolic disturbance in the affected mother may harm the fetus in utero. A heterozygous fetus, who has more CTG repeats, may be unable to metabolize the pathologic products sufficiently and therefore may become more severely affected. This may explain the exclusive maternal transmission of congenital myotonic dystrophy.     

Neonatal myotonic dystrophy in a premature infant: clinical and morphological findings

We report a case of neonatal myotonic dystrophy in a premature infant of 34 weeks gestation. The striking pathological feature in muscle biopsy was severe generalized fiber hypotrophy. Histochemical stains for myofibrillar ATPase revealed a uniform fiber type of intermediate staining characteristics (Type II C). Oxidative preparations showed a light peripheral sarcoplasmic halo without enzymatic activity in most fibers. Ultrastructurally, fiber periphery consisted of a sarcoplasmic rim devoid of myofibrils and mitochondria and rich in glycogen granules and some vesicles. Satellite cells were numerous. Pathologic findings characteristic of the adult form of the disease were lacking. These morphological features were interpreted as a marked delay in fetal muscle maturation. The purpose in this paper is to present the unique pattern of myopathologic findings.     

Sweating deficiency in myotonic dystrophy

We evaluated local sweating function quantitatively in nine cases of myotonic dystrophy (MyD) aged 26 to 61 years (mean, 45.4 years) and 25 control subjects aged 24 to 71 years (mean, 50.1 years). MyD subjects were grouped into three clinical classes according to their severity (three mild cases; class 1, three moderate; class 2 and three severe; class 3). 10 mg of acetylcholine was injected intradermally on the dorsum of the foot. After stimulation the impressions of sweat droplets were obtained using vinyl silicon impression material and the number of sweat droplet impressions per square centimeter was counted and the diameter of each droplet was measured by an image processor using a microcomputer. The result showed statistically significant decrease in the number of sweat droplets in class 2 and 3 as compared with control group and class 1. The histogram of sweat droplet diameter disclosed tendency of progressive deficit in diameter in all three clinical classes of MyD. Various kinds of autonomic function test, besides sweat tests, and nerve conduction study done on class 2 and 3 failed to show any significant abnormalities. Skin biopsy study done on lower leg on four subjects of class 2 and 3 revealed atrophy of eccrine sweat glands. These results suggests that local sweating deficiency develops in MyD as the disease progresses and that this deficiency is caused by dysfunction of eccrine glands, and not of postganglionic autonomic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropsychological findings in myotonic dystrophy

Abstract

Although the literature contains several references to clinically apparent cognitive deficits in patients with myotonic dystrophy (MYD), efforts to support these observations with formal testing have been lacking. The current study compared 17 MYD patients with 25 normal controls on an expanded Halstead-Reitan Battery. The MYD group scored worse than the controls on nearly every neuropsychological measure. Significant neuropsychological impairment was present even when tests of motor skills were excluded. There was no relationship between general neuropsychological impairment and degree of weakness, myotonia, or muscle atrophy in the MYD patients. These findings suggest that cognitive impairment can be an important and relatively independent component of the disability in MYD, which should be considered in the clinical evaluation and counselling of persons with this disease.     

Proximal myotonic myopathy: clinical, electrophysiological and pathological findings in a family

Proximal myotonic myopathy (PROMM) is an autosomal dominant muscle disorder characterized by proximal weakness, myotonia, muscle pain and cataract. It resembles Steinert myotonic dystrophy (MD), but weakness is proximal, without facial muscle involvement, and the chromosome 19 CTG trinucleotide repeat expansion characteristic of MD is not present. We describe a further family with PROMM. Affected members complained of weakness of lower limbs or of myotonia. EMG revealed diffuse myotonic discharges. Muscle histology showed dystrophic abnormalities. The PROMM phenotype varies, even in the same pedigree, and may mimic MD or limb-girdle muscle dystrophy. EMG is particularly useful, since it may disclose myotonic discharges even in the absence of overt myotonia. Thus far it is not known whether PROMM is a single entity, or if it represents a heterogeneous group of disorders. This question will probably soon be settled through genetic analysis.     

Neurophysiological and radiological findings in myotonic dystrophy patients

Somatosensory evoked potentials (SEPs) and brainstem auditory evoked potentials (BAEPs) were recorded in 10 patients with myotonic dystrophy and in 20 sex and age-matched healthy controls. In all patients a brain MRI examination was also performed. In our results, the significantly longer absolute peak latencies of the SEPs and the abnormal increasing of the later components of the BAEPs suggest an involvement of the afferent sensory and central auditory pathways. Brain MRI showed white matter hyperintense lesions (WMHL) in eight patients (80%). No correlations were found between individual abnormal electrophysiological parameters or severity of WMHL and age, age at onset, disease duration or muscular impairment. The total number (SEP + BAEP) of electrophysiological abnormalities significantly correlated with muscular impairment ( p < 0.05) and MRI changes ( p < 0.05), suggesting a strict pathogenetic linkage between muscular and nervous system alterations in this disease.     

Cognitive and neuroradiological findings in myotonic dystrophy.

Cognitive functions were investigated in 37 patients with myotonic dystrophy (MD) and correlated with clinical and neuroradiological variables. The whole cognitive performance was at a low-average level; in about 1/3 of the subjects, in fact, the scores at the neuropsychological tests were below the normal range. There was a consistent trend for patients with inheritance on maternal side to perform worse on Wechsler verbal score and to present cerebral atrophy. In 7 out of 12 subjects focal white matter lesions were found at nuclear magnetic resonance. The significance of these findings and its relation to cognitive performance are discussed.     

Anticipation in myotonic dystrophy. II. Complex relationships between clinical findings and structure of the GCT repeat.

We studied the expansion of the GCT repeats within the myotonic dystrophy protein kinase gene in nine myotonic dystrophy (DM) kindreds. Southern blot and polymerase chain reaction analyses of the repeat region demonstrated the expansion in all 62 patients with the diagnosis of DM. Among 43 DM parent-child pairs, age of onset in the child was earlier than in the parent in 36 pairs, in the same decade as the parent in five, and undetermined in two. The clinical anticipation observed in the 36 pairs accompanied an increase in the fragment size in 32, a decrease in two, and no apparent change in two pairs. In the remaining pairs without documented clinical anticipation, the fragment size increased in four, decreased in two, and was apparently unchanged in one. Overall, the size of expansion showed an inverse correlation with the age of onset (p < 0.001). In all seven pairs in which the fragment did not increase in size, the affected parent was male. Two congenital DM children born to affected mothers had expanded DNA greater than 4.5 kb. The differences between parent and child in age of onset significantly correlated with the differences in the expansion size among father-child pairs (p < 0.001) but not mother-child pairs (p > 0.5). Our data suggest that the expansion of the GCT repeats plays an important role in anticipation although other factors, including the sex of the affected parent, may have significant effects on molecular mechanisms of anticipation.     

Serum carbonic anhydrase III in myotonic dystrophy

Serum carbonic anhydrase III (CAIII) levels were determined by means of an enzyme immunoassay method and were compared with serum creatine kinase (CK) and muscle-specific enolase (MSE) levels in 33 patients with myotonic dystrophy. Serum CAIII levels were elevated in all 33 patients, whereas serum CK and MSE levels were elevated in 12 and 10 patients, respectively. Serum CAIII levels showed a good correlation with CK levels, but a poor one with MSE levels. There was no obvious correlation between the serum CAIII level and the duration of illness or the age of the patient. These results suggest that serum CAIII is probably a more sensitive marker than CK and MSE in myotonic dystrophy and may also reflect the type 1 fiber abnormality more predominantly observed in myotonic dystrophy.     

Recombinant DNA study of Duchenne muscular dystrophy occurring in a myotonic dystrophy family

A recombinant DNA study was performed in a three-generation family with 8 typical cases of late onset myotonic dystrophy (DM) and with one case of Duchenne muscular dystrophy (DMD). The study with DNA markers for chromosome 19 showed linkage of DM locus to the 3.8 Kb allele of apolipoprotein C2 (APOC2) probe and to 9 Kb allele of pSC11 probe (APOC2 lod score = 0.69 at theta = 0). The 21-year-old DMD patient showed no myotonic signs. His clinical history revealed onset with weakness around 4 years of age, progressive course with wheelchair confinement at 11, and cardiomyopathy. His karyotype was normal (46, XY). The study with 10 DNA markers for the chromosome X found a deletion limited to XJ 1.1, XJ 1.2, and XJ 2.3 probes. His 22-year-old sister with typical clinical, EMG and recombinant DNA findings characteristic for myotonic dystrophy was also a carrier of DMD deletion.     

P300 and respiratory findings in myotonic muscular dystrophy

Ten patients with myotonic muscular dystrophy (MD) were examined by auditory event-related potentials (P300 ERPs), spirometric and blood gas analyses: arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2) and arterial oxygen saturation (SaO2). The aim of the study was to analyse the frequency of ERP abnormalities in this disease and to determine whether the neurophysiological evidence of cognitive impairment might be related to the ventilatory function abnormalities frequently described in MD. The mean P300 latency was significantly altered in MD patients compared with controls; P300 latencies did not correlate with spirometric parameters, blood gas values or with age, age at onset, duration or clinical status of the disease. This study provides neurophysiological evidence of cognitive impairment in MD patients. The cognitive deficits are not related to alveolar hypoventilation and appear to be a non progressive feature of the disease.     

Vitamin D deficiency in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder affecting, among others, the endocrine system, with derangement of steroid hormones functions. Vitamin D is a steroid recognized for its role in calcium homeostasis. In addition, vitamin D influences muscle metabolism by genomic and non-genomic actions, including stimulation of the insulin-like-growth-factor 1 (IGF1), a major regulator of muscle trophism. To verify the presence of vitamin D deficit in DM1 and its possible consequences, serum 25-hydroxyvitamin D (25(OH)D), calcium, parathormone (PTH), and IGF1 levels were measured in 32 DM1 patients and in 32 age-matched controls. Bone mineral density (BMD) and proximal muscle strength were also measured by DXA and a handheld dynamometer, respectively. In DM1 patients, 25(OH)D levels were reduced compared to controls, and a significant decrease of IGF1 was also found. 25(OH)D levels inversely correlated with CTG expansion size, while IGF1 levels and muscle strength directly correlated with levels of 25(OH)D lower than 20 and 10 ng/ml, respectively. A significantly higher percentage of DM1 patients presented hyperparathyroidism as compared to controls. Calcium levels and BMD were comparable between the two groups. Oral administration of cholecalciferol in 11 DM1 patients with severe vitamin D deficiency induced a normal increase of circulating 25(OH)D, ruling out defects in intestinal absorption or hepatic hydroxylation. DM1 patients show a reduction of circulating 25(OH)D, which correlates with genotype and may influence IGF1 levels and proximal muscle strength. Oral supplementation with vitamin D should be considered in DM1 and might mitigate muscle weakness.     

Unusual clinical and magnetic resonance imaging findings in a family with proteolipid protein gene mutation

BACKGROUND: Pelizaeus-Merzbacher disease (PMD) and a complicated form of familial spastic paraparesis (spastic paraplegia 2 [SPG2]) are X-linked development disorders of myelin formation caused by a mutation in the proteolipid protein (PLP) gene. Spastic paraplegia 2 is allelic to PMD. The wide range of PLP mutations results in a corresponding large spectrum of clinical severity in PMD, with a continuum of signs and symptoms to SPG2. OBJECTIVE: To report the results of genetic, neurophysiologic, and neuroimaging investigations performed in a child affected by a mild ataxic and spastic form of PLP-related disorder and in his relatives. RESULTS: A missense mutation in exon 6 of the PLP gene (Q233P) was found in the proband and in the female obligate carriers. In the proband, evoked potentials were altered and remained unchanged during the 7 years of follow-up. Magnetic resonance imaging of the child demonstrated patchy hyperintensities of the paraventricular white matter, with microcystic components. These latter findings, along with pallidal calcium deposition, were also present in 2 females heterozygous for PLP mutation. CONCLUSION: The unusual genetic, magnetic resonance imaging, and clinical findings of this family confirm the wide variability of PLP-related disorders.     

Brain magnetic resonance image changes in a family with congenital and classic myotonic dystrophy

We present the clinical manifestations, brain magnetic resonance images (MRI), and genetic analysis of a family with 2 siblings with congenital myotonic dystrophy type 1 (DM1) and 4 patients with classic DM1. These 2 patients with congenital DM1 had severe mental retardation and a characteristic feature of hyperintensity of white matter at the posterior-superior trigone (HWMPST), in addition to ventricular dilatation in T2-weighted images (T2WI) of brain MRI. In 2 of the 4 classic DM1 patients, brain T2WI MRI showed hyperintensity lesions in the bilateral frontal and/or temporal regions, which were absent in congenital DM1. In conclusion, we suggest that the HWMPST in brain MRI is a characteristic finding in congenital DM1, and that the severe cognitive impairments are not only attributable to the subcortical white matter lesions. In congenital DM1, the cognitive function is a diffuse impairment, which is different from that in classic DM1.     

IgG deficiency and expansion of CTG repeats in myotonic dystrophy

Objectives

Expansion of CTG repeats in myotonic dystrophy (DM1) alters the regulated expression of numerous genes. It is considered to explain the major clinical features of DM1. IgG deficiency is common in DM1 and is due to altered FcRn-related hypercatabolism. We hypothesized that the IgG catabolic rate is correlated with CTG repeat expansion.

Methods

Correlations between serum immunoglobulin levels, peripheral lymphocyte subset counts and CTG repeat numbers were performed in 52 DM1 patients.

Results

Serum IgG and IgG1 levels were below the normal limit respectively in 54% and 72% of patients. Increasing CTG repeat numbers were significantly correlated with decreasing serum IgG and IgG1 levels, and with decreasing CD3⁺ T-cell and CD3⁺-CD8⁺ cell counts. An abnormal immunoglobulin profile at protein electrophoresis was found in 4 patients.

Conclusion

We conclude that the catabolic rate of IgG is linked to expanded CTG repeats, possibly involving an altered immune response.