Language disturbances in a group of participants suffering from Duchenne muscular dystrophy: a pilot study.

Results from several studies suggest that the process of language acquisition may be altered in patients suffering from Duchenne Muscular Dystrophy. In this study, a group of 8 male participants with Duchenne Muscular Dystrophy (M age = 16 yr., SD = 4.7) underwent an extensive neuropsychological and language assessment. They also performed a discourse production task. Results showed mild mental retardation associated with a specific deficit in Verbal rather than Performance IQ. At the linguistic assessment, 7 of 8 participants showed moderate to severe difficulties on oral language processing with particularly impaired morphosyntactic competence.

Long-term functional outcome measures in corticosteroid-treated complex regional pain syndrome.

AIM: The aim of this paper was to assess the effects of low-dose systemic corticosteroid therapy in complex regional pain syndrome (CRPS), to measure the long-term functional outcome, and to evaluate an arbitrary scale of severity of CRPS. METHODS: An evaluation of 31 consecutive subjects diagnosed with CRPS before and after they underwent corticosteroid therapy was carried out. The clinical and functional variables considered were evaluated at baseline, halfway through therapy, at the end and after 1, 6 and 12 months after the end of treatment. A clinical severity scale of CRPS was devised. RESULTS: The comparison between baseline and post-treatment data of the principal variables resulted in all cases significant (P<0.001), as did, in most cases, the changes in variables between successive time intervals (P<0.05), supporting the long-term efficacy of treatment. The score of the clinical severity scale of CRPS showed a significant improvement in the one-year follow-up. CONCLUSION: Corticosteroid therapy in CRPS provides a short-term response to the pain with a low risk of side effects. The improvement in all the variables considered persisted at one-year follow-up. The arbitrary scale of clinical severity of CRPS should be further tested in order to propose it as an instrument for use in following the course of CRPS.

Efficacy of glossopharyngeal breathing for a ventilator-dependent, high-level tetraplegic patient after cervical cord tumor resection and tracheotomy.

This case study was undertaken to describe the use and limitations of glossopharyngeal breathing (GPB) by a ventilator-dependent, tracheotomized patient after cervical tumor resection. A 6-yr, 8-mo-old, tracheotomized, ventilator-dependent boy, after cervical tumor resection, learned GPB on his own and used it for ventilator-free breathing. Over the next 16 yrs, his GPB efficacy improved to the point that, with a vital capacity of 670 ml, his GPB maximum single-breath capacity increased to 3300 ml. This was limited by the fact that at 2.9 l of lung volume, air began to leak around the tracheostomy tube walls and out of the stoma. Still, GPB permitted up to 12 hrs/day of ventilator-free breathing. Measurements of assisted peak cough flow and GPB lung insufflations exceeding vital capacity are the main measures that demonstrate adequate tube fit to permit effective GPB in the presence of an indwelling tracheostomy tube.

Two dystrophin proteins and transcripts in a mild dystrophinopathic patient.

Two muscle dystrophin transcripts and proteins were detected in a 17-year-old boy with a persistently elevated serum creatine kinase level. A decreased amount of full-length dystrophin and a 360 kDa polypeptide lacking the COOH-terminus were detectable in the patient's muscle biopsy; accordingly, transcript analysis revealed the expression of a wild type messenger RNA together with a shorter frameshifted one. No genomic DNA mutation was found and the presence of a somatic mosaicism was excluded. This dystrophinopathy may be caused by a novel dystrophin gene transcriptional defect, namely aberrant intraexonic splicing.

Electrophysiological analysis of cognitive slowing in subjects with mitochondrial encephalomyopathy.

Mitochondrial encephalomyopathies (MEs) are multisystemic inherited disorders affecting tissues with high energy requirement such as the muscle, retina and central nervous system. Progressive external ophthalmoplegia and myopathy are the most common features in adults, and cognitive impairment is rare. In many neurodegenerative disorders, ERPs have been effectively performed to record cognitive slowing on tasks with different amount of information. To analyze the evidence for possible cognitive slowing, a standard auditory oddball paradigm with a button-press response was applied. Participants were 11 non-demented patients affected by mitochondrial encephalomyopathy and 14 age-matched normal controls. This hypothesis was tested using two tasks of different difficulty (pure tone vs. phonetic stimuli). Reaction time (RT), performance (P) and event-related potentials (ERPs) were measured. RT and P were not significantly different between the groups. Patients showed significantly increased N2 latency and reduced P3 amplitude on both tasks. No difference was found in pure tone and phonetic task conditions. Results were interpreted as electrophysiological signs of cognitive slowing--particularly in relation to stimulus evaluation--irrespective of sensory problems, response selection and cognitive load. These findings suggest that in ME patients, there may be a possible dysfunction of neural mechanisms underlying cognitive events and ERP generation.

Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

Transcriptional activation of the non-muscle, full-length dystrophin isoforms in Duchenne muscular dystrophy skeletal muscle.

Despite promoter tissue specificity, up-regulation of the brain and Purkinje cell type dystrophin isoforms was described in skeletal muscle of X-linked dilated cardiomyopathy (XLDCM) and BMD affected individuals. An extended population of 11 Duchenne muscular dystrophy (DMD) and 11 Becker muscular dystrophy (BMD) patients was investigated to determine whether ectopic muscle expression of the two full-length non-muscular isoforms is a common event in dystrophinopathies and if it has functional significance. Up-regulation of the two non-muscle-specific isoforms was detected in four DMD patients but in none of the BMD affected individuals or non-dystrophic controls. This is the first report of an expression of these two isoforms in DMD skeletal muscle. Ectopic expression is not confined to regenerating or revertant fibers and does not correlate with age at biopsy, clinical phenotype, cardiac involvement, deletion size or location. We consider that muscle ectopic expression of the brain and Purkinje cell-type isoforms has no favorable prognostic significance in DMD and BMD patients.

Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy.

BACKGROUND: Mental retardation is a clinical feature of Duchenne dystrophy (DD) and affects about one-third of patients. No clear association has been found between DNA mutations, protein expression, and IQ scores, although distal deletions in the dystrophin gene have been reported in association with intellectual impairment. A role for the brain distal dystrophin isoform Dp140 was suggested. OBJECTIVE: To explore the possible association between cognitive impairment and DNA macrodeletions in the distal part of the gene, including Dp140 gene region. METHODS: Sixty-six patients with DD received general intelligence assessment by Wechsler Intelligence Scales measuring full, verbal, and performance IQ. PCR analysis was performed to detect deletions in the dystrophin gene, and the Dp140 regulatory region was analyzed in a subgroup of 12 patients. Statistical analysis was performed by nonparametric Wilcoxon rank signed and rank sum tests. RESULTS: Comparison of neuropsychological and genetic data revealed an association between distal macrodeletions and cognitive impairment (p < 0.001). Comparing deletions involving the Dp140 gene region with deletions presumably not altering Dp140 expression resulted in even greater significance. CONCLUSIONS: These data suggest that in DD, distal dystrophin deletions are associated with intellectual impairment. This study highlights a possible role for the brain distal isoform Dp140 in normal cognitive development.

Loss of Dp140 regulatory sequences is associated with cognitive impairment in dystrophinopathies.

Mental retardation is a clinical feature present in both Duchenne and Becker muscular dystrophy patients and its pathogenesis is still unknown. Dp140 is a dystrophin isoform with predominant expression during foetal brain development. Its promoter and first exon lie in the large intron between exon 44 and 45, a region that is commonly deleted in dystrophinopathic patients. We performed neuropsychological evaluation and genetic analysis of the Dp140 transcription unit on 12 Duchenne muscular dystrophy and 28 Becker muscular dystrophy patients carrying deletions in this critical region. Comparison of neuropsychological and molecular data showed that there is a statistically significant relationship between the loss of Dp140 transcription unit and mental retardation in Becker muscular dystrophy patients (P = 0.008). Such a correlation is not evident in Duchenne muscular dystrophy patients but only shows a trend towards significance (P = 0.063). It is worth noting that both Duchenne muscular dystrophy and Becker muscular dystrophy patients with normal intelligence do not show deletions in the Dp140 regulatory regions. In the light of these findings, we suggest that impairment of cognitive abilities in Duchenne muscular dystrophy and Becker muscular dystrophy patients might be related to a dysfunction of Dp140 brain isoform.

Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations.

Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the beta sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaffected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of alpha and gamma sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in alpha and gamma sarcoglycans, we show for the first time that the condition can also be caused by mutations in the beta sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.

Focal cognitive impairment in mitochondrial encephalomyopathies: a neuropsychological and neuroimaging study.

Mitochondrial encephalomyopathies (ME) are a multisystemic group of diseases characterized by a wide range of biochemical and genetic mitochondrial defects with a variable mode of inheritance. We studied the neuropsychological profile, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) data in a group of ME patients in order to look for common or specific cognitive defects and a possible correlation with related brain areas. Three main cognitive areas were assessed: general intelligence, memory functions and visuo-perceptual skills. Our sample included 16 ME patients (nine males, seven females) aged 25-68 years (mean age 45.2, SD 13.0). No sign of mental deterioration was found in the group of elderly subjects. Despite subjects showing no global cognitive impairment they scored lower in nonverbal versus verbal tasks. Visuo-spatial skills and short-term memory were selectively impaired. There was no correlation between neuropsychological results and age, illness duration, age of onset, clinical phenotypes, genetic mitochondrial alterations and pharmacological therapy. The most frequent SPECT pattern observed was the hypoperfusion of temporal lobes, with a direct localization in the temporal cortex and with prevalent mesial involvement. The neuropsychological profile and SPECT imaging revealed similarities with focal defects.

Sarcoglycan deficiency in a large Italian population of myopathic patients.

Autosomal recessive limb-girdle muscular dystrophies are a heterogeneous group of genetic diseases with a wide spectrum of clinical severity and age of onset; mutations in the gene encoding the dystrophin-associated sarcoglycan proteins (alpha, beta, gamma and delta) have recently been shown to cause some cases of these myopathies (primary sarcoglycanopathies, types 2D, 2E, 2C and 2F, respectively). In this study we have examined a large population of Italian myopathic patients to determine the frequency of (alpha-, beta- and gamma-sarcoglycan deficiency and to correlate molecular defects with clinical phenotypes; to exclude the presence of primary dystrophinopathies both genetic and immunological analysis of dystrophin was performed. We report 12 patients (10 male and 2 female) with deficiency of either one or more sarcoglycan proteins. They were aged 8-56 years with onset between 4 and 30 years of age; they all presented with either mild, moderate or severe limb-girdle involvement associated with elevated blood creatine kinase levels and myopathic pattern at EMG; one was also affected with a mild dilation cardiomyopathy. All patients, except one, showed pathological muscle histological changes. Absence of all three proteins always correlates with severe forms, whereas mild protein deficiencies or isolated partial alpha-sarcoglycan deficiency correlate with either severe, moderate or mild forms.

Cognitive impairment in Duchenne muscular dystrophy.

Cognitive function and dystrophin gene mutations were investigated in 50 DMD patients (mean age 11.1 yr; range 3.5-20.3). General intelligence assessment showed 31% of patients with Wechsler full intelligence quotient (FIQ) lower than 75 (normal values: 100 +/- 14), and only 24% with appropriate FIQ level. Modal distribution of Wechsler verbal, performance, and FIQs, and Raven IQs was normal. Verbal IQ was more affected than performance IQ (PIQ) only in the younger group of subjects. Low PIQ correlated with the presence of macroglossia, detected in 13 out of 50 patients. Impairment of productive language was of non-dysphasic nature and correlated with defects of short-term memory, which was also affected in non-verbal skills. DMD patients shared the same spectrum of neuropsychological defects, regardless of whether they were or were not mentally retarded. The proportion of patients with dystrophin gene deletions was 64%. No statistically significant correlations were found between genetic data and psychometric assessment. Finally, (18F)-fluorodeoxyglucose positron emission tomography studies demonstrated cerebellar hypometabolism in all the DMD patients examined and variable involvement of associative cortical areas. These findings suggest a possible role of the cerebral and cerebellar hypometabolism in the cognitive impairment of DMD.