Carrier status diagnosis in Duchenne muscular dystrophy with "conformational" DNA polymorphism.
Explore the source record for details and available documents.
Autoradiography↗
Biomedical subjects
M Vanasse
Publications and source records attributed to M Vanasse.
Deletions in the dystrophin gene: analysis of Duchenne and Becker muscular dystrophy patients in Quebec.
We have analyzed patient DNA samples in 77 unrelated Duchenne (DMD) and Becker (BMD) muscular dystrophy families, 73 of which were of French Canadian origin. We show that the frequency (68%) and distribution of deletions within the dystrophin gene was neither random nor unique in this population. We localized 33% of the deletions to the proximal portion of the dystrophin gene while 63% involved the exons spanning introns 43 through 55 with breakpoint clusters occurring within introns 44 and 50. Whether the dystrophin open reading frame (ORF) is maintained constrains the distribution of DMD/BMD deletions such that BMD deletions tend to be strikingly homogeneous. Finally, the conservation of the dystrophin ORF and the severity of the clinical phenotype were concordant in 95% of the DMD/BMD deletions documented by this work.
Adolescent↗
Single-strand conformational polymorphisms (SSCP): detection of useful polymorphisms at the dystrophin locus.
We searched for DNA polymorphisms in seven amplified fragments of the dystrophin gene. Three fragments exhibited variable mobilities during nondenaturing strand-separating gel electrophoresis (SSGE). These variants were due to single base changes (three transversions and one transition). Three were intronic (upstream from exons 17, 15, and 48) and one was in exon 48. The frequencies of these sequence variants were determined in a sample of 54 normal X chromosomes of Caucasian origin. One of these DNA polymorphisms was observed in every 650 bp tested and the average heterozygosity was 0.05% per base pair (0.08% if exons were excluded). Such a detection density and the fact that single-strand conformational polymorphisms do not depend on the presence of any specific sequence makes them especially valuable as genetic markers. In the dystrophin locus this approach could allow simultaneous detection of frequent deletions.
DNA, Single-Stranded↗
Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.
We report the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of six patients with hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, an inborn error of ornithine metabolism. Pyramidal signs, decreased vibration sense, bucco-facio-lingual dyspraxia, and learning difficulties or subnormal intelligence were found in the majority. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common, and one patient had markedly abnormal white matter images on cranial magnetic resonance imaging. One patient had retinal depigmentation and chorioretinal thinning. The clinical severity varied greatly among patients; in general, the three younger patients had less neurologic and intellectual impairment than did the three older patients. Only two of our patients have had episodes of symptomatic hyperammonemia. We conclude that hyperammonemia-hyperornithinemia-homocitrullinuria syndrome can be associated with widespread manifestations in the central and peripheral nervous systems. Although the control of hyperammonemia is an essential element in the treatment of these patients, the relationship of hyperammonemia to the chronic neuropsychologic problems of these patients is unclear.
Adolescent↗
Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): confirmation of close linkage to D5S39 in French Canadian families.
Chronic childhood-onset spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. Recent linkage analyses have mapped this disease to 5q12-5q14. We show that chronic SMA (Types II and III) is tightly linked to the marker locus D5S39 (Zmax = 5.47 at theta = 0.02) in eight French Canadian families. In contrast to previously published results, we do not observe close linkage between chronic SMA and D5S6 (Zmax = 0.34 at theta = 0.18) or D5S78 (Zmax = 0.25 at theta = 0.21). Last, we present a family that appears to be discordant for this localization but may represent the first example of an incompletely penetrant individual.
Canada↗
Neurologic crises in hereditary tyrosinemia.
Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970. Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias.
Acute Disease↗
Utility of short-latency evoked potentials in the classification of progressive, early onset cerebellar ataxias.
In recent years, several authors have proposed new classifications of inherited ataxias, some of them being based on systematic clinical studies of large groups of patients. This methodic approach has led to the identification of new types of ataxias and helped the development of molecular biology research in these diseases. Up to now, nerve conduction velocity and evoked potential studies have not been considered in the classification of hereditary ataxias. We have studied the results of short latency evoked potentials in 102 patients affected by a early onset, progressive cerebellar ataxia. Based on the results of this study and a review of the literature on this subject, we will evaluate the utility of nerve conduction velocity and evoked potential recordings in the classification of this group of diseases.
Adult↗
Maturation of short latency somatosensory evoked potentials by median nerve stimulation: a cross-sectional study in a large group of children.
We have conducted two studies to evaluate the maturational changes of SEP in 206 subjects from neonatal period through adulthood. The first study was done with a cephalic reference electrode and included 137 subjects from 41 weeks (conceptional age) to 9 years of age, divided in 5 different age groups. In the second study, we used an extracephalic reference electrode and recorded SEPs in 69 normal subjects aged from 4 to 34 years, divided in 3 age groups. Our results show that there is a highly significant correlation between age and height in all the age groups studied. Peripheral and central components of SEP mature at different rates with adult values being reached for central conduction times (N9-P14, N9-N20, N13-N20 and P14-N20) between 4 and 9 years of age. Male and female subjects were compared in both studies and no significant differences were found in any of the age groups for any of the wave latencies or interpeak latencies analyzed.
Adolescent↗
Normal brainstem auditory evoked potentials in adult hypothyroidism.
Nervous system dysfunction and hearing loss are part of the clinical picture of hypothyroidism. Several studies on visual evoked potential and two brainstem auditory evoked potential studies have shown abnormalities in this disease that are reversible with treatment. It has been suggested that visual evoked potential and brainstem auditory evoked potential could be useful to evaluate the effects of hypothyroidism on the central nervous system and to monitor the response to treatment. We recorded brainstem auditory evoked potentials in 15 adult hypothyroid patients immediately before treatment. All patients were women, ranging in age from 34 to 82 years. Fourteen also had an audiometric study. In five patients, both tests were repeated 20 to 22 months after treatment. Audiometry showed that hearing loss increased with age, suggesting that hearing loss in these patients could be secondary more to aging than to hypothyroidism. When compared to sex-matched controls of similar ages, our patients showed no statistically significant differences in brainstem auditory evoked potentials before treatment. Brainstem auditory evoked potential values were not modified in the five patients whose tests were repeated after treatment. The normality of these results raises serious objections to the clinical use of brainstem auditory evoked potential for central nervous system evaluation and therapy monitoring in adult hypothyroidism.
Adult↗
Evoked potential studies in Friedreich's ataxia and progressive early onset cerebellar ataxia.
We recorded somatosensory evoked potentials (SEP) in 15 patients affected by Friedreich's ataxia (FA) and in 9 patients with progressive early onset cerebellar ataxia (PEOCA). Brainstem auditory evoked potentials (BAEP) were also recorded in 14 FA patients and in five PEOCA patients. SEP results showed clear differences between groups of FA, evidence of peripheral involvement was seen in all patients, with absence of the N9 potential or a major reduction of its amplitude. In patients in whom central responses could be recorded, conduction velocity was normal or near normal up to the brainstem but was reduced from brainstem to cerebral cortex. Four patients with PEOCA had SEP abnormalities similar to those seen in FA. In the five other patients, the amplitude and latency of N9 were normal but conduction velocity was reduced from brainstem to cerebral cortex. In FA, BAEP were abnormal in all patients with a disease duration of four years or more but were normal in four of the five PEOCA patients. Systematic evoked potential recording is useful in the investigation of hereditary ataxias.
Adolescent↗
Somatosensory evoked potentials and auditory brain-stem responses in congenital hypothyroidism. II. A cross-sectional study in childhood. Correlations with hormonal levels and developmental quotients.
We report the results of somatosensory evoked potentials (SEPs) and auditory brain-stem responses (ABRs) done in 48 congenital hypothyroid (CH) treated children, early detected and aged 18 months, 3 and 5-9 years of age. We report also the results of SEP and ABR done in 9 3-year-old CH children, before and after a 1 month therapy interruption to reassess the thyroid status. The more frequent abnormalities were increased wave I latencies for 18 month and 3-year-old CH children. In some children, these increases were not associated with signs of otitis media. No significant difference was seen between CH children and controls for SEP latencies and ABR and SEP interpeak latencies (IPLs). Similarly, no significant difference was seen between the two recording sessions in the 9 3-year-old CH children for ABR and SEP. On an individual basis, we observed abnormalities of central conduction time for ABR and SEP in several CH children. Moreover, significant partial correlations were found between ABR and SEP IPLs and thyroxine (T4) serum levels at diagnosis and thyrotropin (TSH) serum levels at the time of recording. There was also a significant partial correlation between N19-P22 IPLs and the practical reasoning scale of the Griffiths test considering the whole group of CH children. These results indicate that SEP might eventually be used to detect CH children at risk of presenting developmental abnormalities.
Brain Stem↗
Priorities in adolescent health care: the teenager's viewpoint.
The purpose of this study was to determine what issues teenagers want discussed or covered when they visit primary care physicians and to assess to what extent such discussion takes place. A questionnaire was administered to 1,564 students aged between 13 and 18 years in six high schools. Mean participant age was 15.3 years; 801 were male and 763 were female. Questions were drawn from both physical and psychosocial aspects of teenage life. The teenagers answered as to whether they would like to discuss the suggested topics on visits to physicians, and whether in fact such a discussion had taken place. The three topics of most interest to teenagers were physical fitness, nutrition, and growth. Teenagers wanted to discuss these topics in over 80 percent of the visits, and they indicated that actual discussion took place in just under 50 percent of the visits. Discussion of sexually transmitted disease was desired by teenagers 70 percent of the time, with a discussion rate of only 18 percent; contraception at 66 percent with a physician discussion rate of only 22 percent. If physicians discuss exercise, nutrition, and growth with teenage patients, in over 80 percent of cases they will be providing the patient with valued information. This initial dialogue will establish a base of communication that may allow for the discussion of issues teenagers often find more difficult (such as contraception, sexually transmitted disease, depression, drugs, and drinking).
Adolescent↗
Somatosensory evoked potentials and auditory brain-stem responses in congenital hypothyroidism. I. A longitudinal study before and after treatment in six infants detected in the neonatal period.
We report the results of a longitudinal study of auditory brain-stem responses (ABRs) and somatosensory evoked potentials (SEPs) performed in 6 children with congenital hypothyroidism. These infants were detected by the Quebec Network for Genetic Medicine and treated early. ABRs and SEPs were recorded both before and 2 weeks after the initiation of therapy and at 6 months of age. Before treatment, for SEP, we found increased wave N19, P22 latencies and N13-N19, N19-P22 interpeak latencies (IPLs) in congenital hypothyroid (CH) children. For ABR, there were increased wave I latencies with normal I-V IPLs. Substitutive therapy improved these abnormalities although this improvement was more evident after a shorter period of time for ABRs than for SEPs. Even at 6 months, 2 CH children still showed increased N13-N19 IPLs. Both had very low serum T4 levels at the time of diagnosis and one had also a very small knee surface area, both criteria indicating a severe hypothyroidism. It will be interesting to verify if initial and persisting increase of N13-N19 IPL is associated with later neuropsychological problems.
Congenital Hypothyroidism↗
Auditory brainstem response audiometry in congenitally hypothyroid children under early replacement therapy.
Using auditory brainstem response audiometry, we evaluated 34 congenital hypothyroidism children under thyroid hormone therapy and 24 age- and sex-matched controls between 5 and 12 yr of age. Two main auditory brainstem response abnormalities were encountered: first, prolonged wave I latencies, secondary to a peripheral impairment, were found in seven congenital hypothyroidism children (20%): three of these showed signs of serious otitis media, unilaterally in two and bilaterally in the other, at the time of the evaluation. Second, shortened I-V interpeak latencies were observed in 10 children (29%). No correlation was found between the interpeak latencies and the L-thyroxine serum values at the time of the test or just prior to treatment initiation. Also, there was no correlation with estimated bone age at treatment initiation or with the Griffiths global mental development quotients assessed at 5 yr of age. These preliminary results suggest a significant incidence of auditory brainstem response abnormalities in treated hypothyroid children.
Audiometry↗
EMG and needle muscle biopsy studies in arthrogryposis multiplex congenita.
From 1979 to 1983, EMG and/or muscle biopsy studies were done in twenty-one of twenty-two patients seen in our institution for the first time for arthrogryposis multiplex congenita (AMC). Most of the muscle biopsies were done with a needle. As expected, the final diagnosis in these patients was very heterogeneous since it is well recognized that AMC can be due to any factor that interferes with fetal mobility. We found however a surprisingly high number of patients (9/22) affected by a myopathic disease. Based on these results, we feel that needle muscle biopsy should be included as a routine procedure in infants affected by AMC since by clarifying the diagnosis it helps in improving genetic counselling and prognosis in these patients. It is now widely accepted that arthrogryposis multiplex congenita (AMC) is not in itself a disease but is secondary to any factor that interferes with fetal movements. The joint deformities seen in these children can be due to mechanical factors (oligohydramnios for example), central or peripheral nervous system disorders, muscle diseases... (Dubowitz 1978, Hageman and Willemse 1983, Hall 1981, Swinyard 1982). However, the relative frequency of each etiologic factor remains unclear since in spite of the abundant literature on the subject, we found only three reports describing the findings of electromyographic (EMG) and muscle biopsy studies done systematically in unselected groups of children affected by AMC (Amick et al 1967, Bharucha et al 1972, Dastur et al 1972, Kullmann and Szijj 1973). Furthermore, each article reached different conclusions in regard to the occurrence of these various etiologies in their respective patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Arthrogryposis↗
A progressive neurological syndrome associated with an isolated vitamin E deficiency.
Several authors have recently reported a neurological disorder associated with chronic vitamin E deficiency in man. Except in one patient, this deficiency has always been secondary to an underlying disease resulting in lipid malabsorption. We report a second case of such a neurological syndrome in a patient in whom vitamin E deficiency was an isolated finding. The clinical picture in our patient was characterized by a diffuse muscle weakness most prominent distally and in the lower limbs, generalized areflexia, a decrease in proprioception and vibration sense and slight limb and gait ataxia. His condition improved on alpha tocopherol therapy so that it is very likely that vitamin E deficiency is responsible for his neurological deficit. Since in our patient as well as in several other reported cases this condition has been treatable, it is important that this syndrome be recognized in children presenting a suggestive clinical picture even if they do not have lipid malabsorption.
Ataxia↗
Friedreich's ataxia: malic enzyme activity in cellular fractions of cultured skin fibroblasts.
We have measured the activity of malic enzyme NADP+ dependent in the nuclear, mitochondrial, lysosomal and cytosolic fractions of cultured skin fibroblasts from twelve patients with Friedreich's ataxia and nine control subjects. Hexosaminidase, cytochrome-C-oxidase, lactate dehydrogenase and malic enzyme NAD+ dependent were used as marker enzymes. The activity of malic enzyme NADP+ dependent was not significantly reduced in the mitochondrial fraction of patients with Friedreich's ataxia as compared with controls. When corrected for possible contamination between mitochondrial and cytosolic fractions, malic enzyme NADP+ dependent activity was still not significantly reduced in patients with Friedreich's ataxia. Unless critical methodological differences were overlooked in this or previously published studies, we conclude that mitochondrial malic enzyme deficiency is not the primary genetic defect underlying Friedreich's ataxia.
Adolescent↗
The Andermann syndrome: agenesis of the corpus callosum associated with mental retardation and progressive sensorimotor neuronopathy.
Andermann et al. described in 1972 an autosomal recessive inherited syndrome which associates agenesis of the corpus callosum, mental deficiency, and a peripheral motor deficit. We had the opportunity to study in detail 15 patients affected by this syndrome. As in the cases previously reported, the families of these children all originated from Charlevoix County and the Saguenay-Lac St-Jean area in the Province of Quebec. Clinically, these patients have a characteristic facies and moderate mental retardation associated with a progressive motor neuropathy leading to loss of ambulation by adolescence and progressive scoliosis. In 13 of these 15 patients, neuroradiological investigation has shown either total or partial agenesis of the corpus callosum. In every patient in whom these tests were done, sensory nerve action potentials were absent and motor nerve conduction velocities reduced. We also found neurogenic abnormalities both on EMG and neuromuscular biopsies. These abnormalities are similar to those described in Friedreich's ataxia and in hereditary motor and sensory neuropathy type II, although in our patients the motor deficit is much more severe than in these diseases. The pathogenesis of the peripheral nervous system involvement is still unknown since there have so far been no autopsy studies of this syndrome.
Adolescent↗