Report of the 95th European Neuromuscular Centre (ENMC) sponsored International Workshop Cognitive Impairment in Neuromuscular Disorders, Naarden, The Netherlands, 13–15 July 2001
Article Outline
- 1. Introduction
- 2. Duchenne and Becker muscular dystrophies
- 3. Animal models and molecules interacting with dystrophin in the central nervous system (CNS)
- 4. Myotonic dystrophy
- 5. Congenital myopathies and sarcoglycanopathies
- 6. Mitochondrial encephalomyopathies
- 7. Conclusions
- Acknowledgements
- References
- Copyright
Keywords: Cognitive impairment, Neuromuscular disorders
1. Introduction
As many neuromuscular disorders involve brain as well as muscle, the European Neuromuscular Centre (ENMC) consortium on cognitive impairment in neuromuscular disorders held its first meeting in Naarden (The Netherlands) on the 13–15 July 2001. It was attended by 15 participants from the United Kingdom, France and Italy.
In his introductory remarks, Prof. N. Bresolin (Milan, Italy) convenor and chairman of the Consortium, outlined the objectives of the workshop: to gather a panel of experts (clinical, geneticists and basic scientists), to review the available scientific information and find a common strategy of clinical analysis, establishing the criteria of selection of the patients and to define the objectives of shared research projects.
Over the last 10 years several approaches concerning possible correlation between molecular defects in genes mainly responsible for muscular diseases and cognitive impairment or between neuroradiological analysis and mental retardation have been published. In order to identify the particular features of neurofunctional, cognitive, psychiatric and visual deficit in neuromuscular disorders, different groups reported their experience on a wide spectrum of patients. Possible correlations between gene/protein alterations and cognitive impairment were discussed in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy, limb-girdle muscular dystrophies, congenital myopathies and mitochondrial myopathies.
2. Duchenne and Becker muscular dystrophies
The first session was concentrated on the molecular basis of cognitive impairment in DMD and BMD and on the neuropsychological profile of Duchenne patients.
Duchenne himself had already noted a ‘caractere obtus’ in many of the children affected by the neuromuscular disease. More specific work in identifying the characters of this intellectual phenotype was done by Karagan and colleagues [1] in 1980: they found a basic language deficit. Leibowitz and Dubowitz [2] found significant impairment in word-reading ability. The presence of mental retardation and its possible correlation with dystrophin gene alterations in DMD patients has been well recognized since 1992 [3], about one third of DMD patients show reduction of intelligence quotient (IQ) associated with specific deficit in verbal rather than performance IQ. The cognitive impairment is not progressive and not correlated with the severity of muscle disease; no clear association has been found between DNA mutations and IQ scores [4].
The muscle disease is caused by the absence of dystrophin, a 427 kDa protein associated with the sarcolemma in skeletal and smooth muscle; since two alternative 427 kDa isoforms are also expressed in the cerebral neocortex and in the cerebellum, it has been hypothesized that they might be important for normal neuronal function or development. Previous studies revealed that intellectual impairment is more frequent in patients carrying deletions in the distal part of the gene (including exons 45–54). The discovery of two carboxy-terminal dystrophin proteins (Dp), Dp71 and Dp140, both expressed in the brain, in addition to the full-length central nervous system dystrophins, may be regarded as an explanation for these findings. Transcription of Dp71 is initiated between exons 62 and 63 [5] while Dp140 promoter and first exon are located upstream to exon 45 [6].
Dr Sironi (Bosisio, Italy) presented the result of genetic analysis concerning patients affected by DMD and BMD clinically followed at the E. Medea Institute and at the University of Milano, over the last 5 years.
A first neuropsychological evaluation and genetic analysis of the Dp140 transcription unit was performed on 12 Duchenne and 28 Becker muscular dystrophy patients carrying deletions of variable length either with a 3′-end breakpoint in exon 44 or with a 5′-end breakpoint in exon 45. Comparison of neuropsychological and molecular data showed a statistically significant relationship between loss of Dp140 first exon and mental retardation in BMD (P=0.008). Such a correlation was not evident in Duchenne muscular dystrophy patients but only showed a trend toward significance (P=0.063). It is noteworthy that no patient with normal intelligence showed a deletion involving the Dp140 regulatory region. In order to better clarify the contribution of Dp140 to mental retardation in DMD, a further 44 patients carrying deletions distributed along the gene were analyzed: as expected, there was a significant difference between the IQ scores of patients with proximal versus distal deletions and this latter group of patients displayed median FIQ, PIQ and VIQ values below 77. The same 44 patients were then divided according to the loss or preservation of Dp140 regulatory sequences: two patients with a deletion of Dp140 promoter and first exon and all patients with deletion spanning downstream to exon 51 were supposed to lack Dp140 function. Comparison of FIQ, VIQ and PIQ scores from this group versus the remaining patients showed higher significance than the previous association: 19 patients with normal Dp140 expression had a mean FIQ score of 96, while the 25 patients with altered Dp140 expression had a mean FIQ of 73.
In the sample, patients with deletions involving Dp140 gene region presented a median FIQ score lower than the one recorded in the whole group of patients with distal deletion indicating that lesions involving Dp140 gene region might be considered functionally distinct from general distal deletions.
Nonetheless, the study was including some exceptions. A patient with a proximal deletion (exons 17–19) displayed one of the lowest IQ scores in the mental retardation group and two subjects presented apparently identical deletions (exons 45–54) but significantly different FIQ scores (93 versus 61). In the sample, one of two untestable patients showed a splice-site mutation in intron 69. This patient, already tested for the absence of the Dp116 isoform, presumably also had an alteration in both Dp71 and Dp140 expression [7], [8]. This supports the hypothesis that mutations in the Dp71 gene region cause severe cerebral dysfunction, disrupting expression of all brain transcripts as suggested by Moizard et al. [9], [10].
Connecting this point, Dr A. Toutain (Tours Cedex-France) showed her group's results focused on Dp71 point mutation screening. As several investigations have shown that rearrangements in the second part of the dystrophin gene tend to be more commonly associated with cognitive impairment, and several reports have described point mutations in the Dp71 coding region in DMD retarded patients, her group screened for point mutations in the Dp71 coding sequence in DMD patients without detectable deletion or duplication in the whole dystrophin cDNA sequence. Point mutations were found in seven of the 14 patients tested.
All mutations were found in patients with cognitive impairment, particularly among the most severely retarded, and not in patients with normal cognitive abilities.
In a more recent investigation, they found two promoter-deleted Dp140 transcripts (total absence of Dp71 transcript for one patient and a nonsense mutation for the other one) respectively in four patients with severe cerebral dysfunction. Both patients with Dp140 deletion had a VIQ <70 and bad or no reading acquisition, whereas both patients with altered Dp71 transcripts were psychologically untestable because of severe mental retardation. Taken together, these findings suggest that cognitive impairment in some DMD is related to dysfunction of certain brain dystrophin isoforms and that cognitive impairment is more severe when the mutation is more distal.
To support this hypothesis, a group of 12 DMD patients without detectable deletion or duplication in the whole dystrophin cDNA sequence, was screened for point mutation in the Dp71 coding sequence. Four nonsense mutations and one splice (splice-site o splicing mutation) mutation were detected in five severely neuropsychologically impaired children.
The identification of the mutation is critical for: (1) genotype-phenotype correlation studies; (2) genetic counselling (carrier detection and prenatal diagnosis) in some families; and (3) possible therapeutic prospects.
Point mutation screening remains difficult due to the large size of the dystrophin gene and the great variety of molecular defects: on the other hand, Dp71 is expressed in blood cells and point mutation screening in the Dp71 region is therefore much easier, being feasible by reverse transcriptase-polymerase chain reaction on lymphoblastoid cell lines.
Dr Stefania Lilli (San Vito al Tagliamento-Pn-Italy) described a systematic investigation of language functions in seven patients with dystrophinopathy (six DMD, one intermediate phenotype DMD/BMD) who presented a lower verbal IQ than the performance IQ.
Analysis of the error percentage in language assessment of each patient shows that morphology is the most impaired linguistic level with the highest percentage of errors, followed by syntax and semantics.
At the morphological level the patients showed difficulties in ‘derivational morphology’ and ‘morphological opposites’; they mainly made inflectional errors: agreement in gender and number, verb conjugation. They made omissions, additions or substitutions of free grammar and bound morphemes.
At the semantic level difficulties in ‘lexical decision’ were as common as verbal and phonemic paraphasias. Some patients show also word-retrieval difficulties, which are shown by pauses within the utterance, clearly related to difficulties in lexical access.
Analysis of spontaneous speech revealed that the greater difficulty was sentence construction (propositioning). Word order (very rare in Italian) and omission of parts of speech such as subjects and verbs were the most frequent morphosyntactic errors. In conclusion, all patients except one showed a discrepancy between PIQ and VIQ and language difficulties. Some of the patients showed difficulties related to morphology, others to syntax and still others to lexical access.
These linguistic deficits in DMD sample may suggest that the genetic defect responsible for severe dystrophinopathies is also responsible for specific alterations of particular corticocerebral and cerebellar structures that subserve the organization of language function.
Our patients’ relevant difficulties with sentence construction, morphosyntax, lexical access and syntactic comprehension may be explained in terms of altered planning and organization skills which are associated with an altered functioning of the left frontal and left temporoparietal structures. All these data bring to the conclusion that the presence of language disorders in some subjects with dystrophinopathy is associated with a probable neurofunctional alteration of the left hemisphere and some cerebellar structures [11].
Professor Bushby (Newcastle, United Kingdom) presented data from Newcastle upon Tyne on the relationship between the position of the deletion in the dystrophin gene and IQ.
As with other studies, a relationship between the presence of distal deletions and overall lower IQ was noted, with no 5′ deletions being found in DMD patients with IQ <70 [12].
Several important questions remain however.
The first relates to the discrepancy in the IQ score between boys with apparently the same deletion. This could be very variable indeed.
The second relates to whether the boys with proximal deletions and normal IQ still had the typical verbal-performance deficit reported across the whole group. If this were present in this group despite the presence of a normal IQ, then it might indicate that there are a number of different mechanisms contributing to the cognitive involvement observed in dystrophinopathies.
Limited data were also presented for patients with BMD, which suggested that, overall, this group tended to underachieve relative to their peers. This is in keeping with a general observation that the BMD group often runs into problems with behavior especially in the teenage years which may present a challenge for management. This contrasts with the observation for other similarly disabled groups where different behavioral phenotypes may be observed. The need for further structured research in this area was highlighted to confirm or refute these observations and potentially allow some conclusions about how to help in the management of these complications.
Dr J. Chelly (Paris-France) reported his studies on X-linked mental retardation. X-linked mental retardation include a variety of different disorders, vastly heterogeneous, in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment.
So far, seven X-chromosomal genes responsible for non-specific mental retardation have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPNH1 and Pak3. The products of some genes have been implicated in neuronal plasticity by controlling the activity of small GTPase of the Rho family; others are involved with cell migration, axon guidance, dendritic outgrowth. Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that the ARHGEF6 (a new MRX gene, also known as αPIX or Cool 2, encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases) was disrupted by the rearrangement. Mutation screening of 119 patients with non-specific mental retardation revealed a mutation in the first intron of the gene in all affected males of a large family.
Dr J. Chelly gave as well the compelling evidence that the methyl-CpG-binding protein 2 (MECP2) gene is involved in X linked mental retardation. He reported mutations in two families that co-segregate with non-specific magnetic resonance (MR) phenotypes which affect only males. In view of these data, they screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA (Fragile X locus A) CGG repeat and reported the identification of mutations in four sporadic cases of MR.
All these data suggest that more systematic screenings of some genes in MR patients result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.
3. Animal models and molecules interacting with dystrophin in the central nervous system (CNS)
The second part of the workshop was devoted to animal model studies and to new molecules possibly interacting with dystrophin at the neuronal and glial level.
Behavioral studies in mdx mice led to the conclusion that a deficiency in full-length dystrophin induces specific and moderate learning and memory deficits, characterized by slower procedural learning and impaired long-term consolidation in non-spatial learning tasks [13], [14].
Using electrophysiological methods in hippocampal slices, Dr Vaillend and colleagues also investigated several calcium-dependent forms of synaptic plasticity involved in the basic mechanisms of memory processes (e.g. long-term potentiation or LTP) [15]. They found that dystrophin deficiency in mdx mice enhances NMDA receptor (NMDAr)-mediated short-term potentiation of excitatory neurotransmission, without affecting the 1st h of LTP expression [16]. This effect was prevented by NMDAr or GABAAr antagonists. Although the specificity of such alterations remains to be further investigated, this is in keeping with the role of dystrophin in the clustering of GABAAr at the neuronal membrane [17] and with the possible interaction between dystrophin and proteins associated with the NMDAr [18]. A suggestive explanation of the memory impairment in mdx mice is given by a role for neuronal dystrophin in NMDAr and/or GABAAr function, which might modulate neuronal excitability and network activity.
However, the moderate learning impairments in mdx mice cannot entirely reflect the profound deficits observed in some DMD patients. Can stronger cognitive deficits be expected in mdx3Cv mice lacking Dp71 and Dp140? Although a mild impairment in procedural learning may be a common alteration in the mdx and mdx3Cv mutants, the latter showed weaker learning impairments and no overt electrophysiological alteration [14], [15], [16], [17], [18], [19]. These results do not support the hypothesis of a crucial role for Dp71 and Dp140 in the occurrence of a cognitive impairment in DMD, although they may well be explained by the development of compensatory mechanisms in mdx3Cv mice [20]. Interestingly, mdx3Cv mice, unlike the mdx mice, showed enhanced anxiety-related behaviors as compared to controls. The possible correlation between such behavioral features and mutations affecting Dp71 and/or Dp140 might be an unsuspected feature of the DMD syndrome, which might explain, at least in part, the variable severity of the cognitive deficits.
This work in mouse models of DMD indicates that deficiency in full-length dystrophin alone may be responsible for specific learning and memory deficits independent of motor disturbances. The role of Dp71 and Dp140 in the genesis of the cognitive deficits associated with DMD remains to be demonstrated in mice lacking these proteins, and would benefit from the study of new genetic models displaying mutations which might prevent compensatory mechanisms by dystrophin homologues.
Dr Derek Blake (Oxford, United Kingdom) presented data on the molecular identification of dystrophin-associated proteins in the brain.
The dystrophin-related proteins, alpha- and beta-dystrobrevin are differentially distributed in the brain; alpha-dystrobrevin is localized to glia whereas beta-dystrobrevin is neuronal. Consistent with this idea beta-dystrobrevin forms a complex with dystrophin and is enriched at postsynaptic densities. Using the yeast two-hybrid system, a number of beta-dystrobrevin binding proteins have been identified and are currently being characterized. Dysbindin is a novel coiled-coil containing protein that binds to beta-dystrobrevin in brain and also to alpha-dystrobrevin in muscle. In the brain, dysbindin is found associated with axon terminals and also in some neuronal cell bodies. Whilst little is known about the functional significance of the beta-dystrobrevin: dysbindin interaction; dysbindin is localized to the short arm of chromosome 6 to a region containing an important quantitative trait locus for developmental dyslexia.
Dr Blake also showed that, under certain conditions in vitro, beta-dystrobrevin could be preferentially targeted to mitochondria. This targeting is mediated by the interaction between beta-dystrobrevin and a protein that is part of the mitochondrial membrane system called mitofilin. Dr Blake proposed the idea that some of the cognitive defects seen in patients with DMD could be, in part, due to mitochondrial dysfunction in dystrophin or Dp71-deficient neurons.
Dr Blake also showed that Dp71 is found in both neurons and glia and could therefore explain why mutations in the Dp71 region of the DMD gene are very frequently associated with severe mental retardation [21], [22].
It is now recognized that dystrophins, dystrophin-related proteins (DRP) and the dystrophin associated protein complex (DAPC) play important roles not only in muscle but in CNS and other non-muscle tissues. The laboratory of Alvaro Rendon (Strasbourg-Cedex-France) has been carrying studies in retina, which is considered as a structural model of the CNS. DMD gene mutations generate in DMD patients and mdx3cv mice strain a clear and defined abnormal electroretinogram (ERG).
The main aim is to elucidate the function of the dystrophins and the DAPC in the retina. This might not only help us to understand information processing in the CNS but might also lead to better ways of approaching the muscle therapy of DMD patients.
They identified four DMD gene products in rat retina: the 427 kDa dystrophin (Dp427), Dp260, Dp140 and Dp71. Their study was focused on the determination of their cellular localization. They showed that Dp260 was expressed in photoreceptor cells and Dp71 in Müller glial cells. They have characterized in Müller cells the presence of the DAPC, namely alpha and beta-dystroglycan, delta and gamma-sarcoglycans and alpha-1 syntrophin. They also show that beta-dystroglycan is associated with dystrobrevin-1 and PSD (Post Synaptic Derivatives)-93. By overlay experiments they also found that Dp71 and alpha-dystroglycan from Müller cells could bind to actin and laminin, respectively. These data suggest that the DAPs complex may participate in both structural and signalling functions in Müller cells.
Nevertheless, the type as well as the cellular distribution of DAPs (but β-dystroglycan) in mouse retina is still unknown as well as how mdx3cv mutation might affect the complex dystrophin-DAPs.
To this end they characterized the expression and localization of DMD gene products and DAPC. They findings indicated that only the dystroglycan complex is affected by mdx3cv mutation, specifically at the outer plexiform layer [23].
To clarify the importance of Dp71 they examined the ERG of Dp71 knockout mice [24] as well as the repercussion of the absence of this protein on the localization of members of the DAPC. The ERGs studies did not reveal significant differences either in implicit time or in the b-wave amplitude with respect to the wild strain. Since replacing its first and unique exon with a beta-gal reporter gene specifically inactivated the expression of Dp71, they therefore could evaluate by this mean the expression of Dp71. They found an inner limiting membrane (ILM) localization.
The analysis of the localization of members of the DAPC indicates that only the dystroglycan complex was affected at the ILM. Interestingly, the absence of Dp71 seems to affect exclusively the localization of beta-dystroglycan without any effect on alpha-dystroglycan.
In summary, it is clear from the comparison of the observations reported above in Dp71 knock-out mice and the fact that neither mdx (lacking dystrophin) nor Dp260 knock-out mice present a reduction in the b-wave amplitude, that is only the mdx3cv mutation with a severe reduction of all the dystrophin gene products that affects the ERG.
4. Myotonic dystrophy
In the last part of the workshop some of the neuromuscular disorders different from DMD and Becker muscular dystrophy have been discussed.
Dr K. Murphy (London-United Kingdom) presented a review of the brain effects of myotonic dystrophy.
MD is the most common form of adult muscular dystrophy; it is a pleiotropic autosomal dominant disease involving skeletal muscles, lens, heart, lungs, gastrointestinal tract, bone, skin, CNS and PNS (peripheral nervous system) [25]. The disorder is caused by an amplification of an unstable trinucleotide (CTG) repeat in the 3′-untraslated region of a transcript encoding a serine/threonine kinase (DMPK) [26] on chromosome 19.
There is a clear correlation between number of trinucleotide repeats and phenotype: between 50 and 99 repeats the patients are asymptomatic or poorly symptomatic, over 100 they present the typical features of MD.
DMPK belongs to a relatively new protein serine/threonine kinase family, sinaptically localized at the cerebellum, midbrain, hippocampus and medulla, at the apical membrane of the ependyma and plexus chorioid and post-sinaptically at the neuromuscular junction of skeletal muscle, at the intercalated discs of cardiac tissue [27].
A study performed on rat brain and spinal cord [28] showed that DMPK expression begins after birth and increases gradually proceeding to the adulthood, with a localization within adult spinal motor neurons to the endoplasmic reticulum and dendritic microtubules, suggesting a role in the membrane trafficking and secretion within neurons associated with cognition, memory and motor control. It has also been demonstrated that the triplet repeat expansion in MD leads to decreased levels of DMPK messenger RNA and protein brought about by decreased chromatin sensitivity in the region of repeat expansion [29].
There is a consensus that people with myotonic dystrophy have reduced IQ levels, and this is particularly marked in the congenital onset group. In addition, there appears to be some evidence for a characteristic cognitive profile in affected individuals with specific impairments in tests of the frontal and parietal lobes, as reduced visuo-spatial performances, constructional and frontal lobe performances.
In addition, while there is general agreement that people with myotonic dystrophy have high rates of hypersomnolence, apathy and fatigue, data on rates of depression are inconsistent between studies. As a consequence of the neuropsychological and psychiatric phenotype, a reduced educational level is specific of most of DM patients.
Neuroimaging studies have recently allowed a much more detailed examination of how the brain is affected in myotonic dystrophy. Although limited studies have been performed, several reports suggest that, consistent with the cognitive findings, the frontal and parietal lobes appear particularly affected.
The disease is characterized by an impaired glucose penetration into many tissues, including brain [30]. Following studies by positron emission tomography showed that cortical glucose use is reduced by 20% and by single photon emission computed tomography (SPECT) a reduction of brain perfusion, mainly at frontal and temporoparietal areas. MR performed in patients affected by MD showed either cortical (atrophy) either subcortical white matter alterations especially in the anterior portion of the temporal lobes [31].
Actually in literature, the neuroradiological and neuropsychological studies, showing language disturbance, memory deficit, visuo-spatial function alteration [32], [33], together with personality alterations with obsessive-compulsive traits and passive-aggressive traits have always been performed separately.
Preliminary data were then presented on a sample of people with the adult-onset form of myotonic dystrophy who attended a Behavioral Genetics Clinic at the Institute of Psychiatry, King's College London.
The need for standardized protocols for the assessment of these individuals to facilitate collaborative work between centers was then discussed.
C. Chisari (Pisa-Italy) described his group experience in 22 MD patients subdivided in subgroup according to sex, age, extent of muscular involvement and sex of affected parent. They submitted the patients to an extensive neuropsychological assessment, evaluating: language, memory and ‘frontal’ function.
Their results did not show any difference between patients and controls with regard to language tasks. Impairment in all ‘frontal lobe’ tasks and in immediate, spatial and verbal memory emerged in MD. No correlation with sex, muscular involvement and sex of affected parent was found.
Their data confirm a cognitive impairment in MD patients but show a partially different neuropsycological pattern. In fact they did not find a prevalent visuospatial function alteration.
The ‘frontal’ pattern observed in this study could suggest, according to MRI (magnetic resonance imaging) studies, a subcortical involvement in MD cognitive impairment.
5. Congenital myopathies and sarcoglycanopathies
Moving to the subject of the congenital myopathies, Andrea Martinuzzi and Emanuela Russo, from ‘E. Medea’ Scientific Institute, Conegliano Research Centre, described their studies in a small group of patients.
Congenital myopathies are a heterogeneous group of muscle diseases in which cognitive status can be affected even severely. Correlation with a specific molecular however is lacking, especially for those forms for which no molecular definition is available.
Patients with congenital non-progressive myopathies have a high probability to attain adulthood.
The consequences of the motor, cognitive, behavioral alterations on social ability and quality of life have not been explored in patients with this group of diseases. These issues are of particular importance considering that most of these patients do not have a significant limitation of life span.
They have studied 6 patients with merosin-positive congenital dystrophy (CMD: three males and three females, age 21.6±12, three patients non-ambulant) and seven patients with structural congenital myopathies (four males and three females, age 7.6±3.9, two patients non-ambulant). Half of the CMD patients showed borderline to mild cognitive impairment (IQ 70–85), but there was no correlation between cognitive status and behavioral problems (present in one patient) or social difficulties (reported for two patients). Only one patient with congenital fiber type disproportion showed borderline mental retardation, which was associated with significant behavioral problems.
Quality of life perception (SF-36 or CBCL) reflected very well the motor disability in the ‘physical activity’ domain, but was otherwise quite positive for all the other domains even in presence of significant impairment in activity, implying a positive adjustment for most patients with their functional status with no or only marginal limitation in participation.
Cognitive and behavioral problems can be part of the clinical picture of CMD, and occasionally can be found in some forms of structural myopathies. Quality of life assessment is an important aspect of the evaluation in these patients, since it shows in most cases a satisfactory adjustment with the disease.
Dr M.G. D'Angelo (Milano-Italy) described a case of a 12 years old boy affected by a β-SG (sarcoglycan) deficiency with unusual presentation of exercise-induced myoglobinuria; the β-SG gene analysis demonstrated a compound heterozygous for an A→T base pair substitution at nucleotide 85 in exon 2 (A85T) and a C→T base pair substitution at nucleotide 271 in exon 3 (C271T).
The father and one sister were presenting a heterozygous status for the A85T, the mother and another sister were presenting the heterozygous status for the C271T mutation [34].
The Wechler Intelligence Scale for Children Revised showed an important discrepancy between verbal IQ (62) and performance IQ (113), global IQ was 84.
Following psycholinguistic studies, showed a disturbance in the language articulation; a very poor structural sentences organization, reading and comprehension problems, suggesting an involvement of β-SG in language development, similar to the one already shown in DMD.
The SPECT analysis revealed an asymmetrical signal, with an hypoperfusion of the left temporal and frontal lobe, strongly supporting the neurofunctional alteration of the left hemisphere (frontal, temporoparietal region) and the cerebellum in language disturbances.
The precise function of sarcoglycans is currently not completely understood, especially β-sarcoglycan alone serves an important functional role in non-muscle tissues, as suggested by the presence of β-SG in several tissues. In the brain, β-SG may be part of the dystroglycan complex and this could be particularly intriguing in relation to the involvement of DG (dystroglycan) in the synapse formation.
6. Mitochondrial encephalomyopathies
Dr A.C. Turconi (Bosisio P-Italy) presented a neuropsychological and neuroimaging study in 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.
With the aim to study the presence of a common and specific cognitive defects and the possible correlations with related brain areas, a group of ME patients underwent neuropsychological tests and MR imaging (MRI) and SPECT in order to look for. Three main cognitive areas were assessed: general intelligence, memory functions and visuo-spatial skills.
The sample was including 16 patients ME (nine males, seven females), with a range of age from 25 to 68 years (mean age 45.2). No signs of mental deterioration were found in the group of elderly patients. Despite subjects showing no global cognitive impairment they scored lower in non-verbal 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, mitochondrial genome alterations and pharmacological therapy. The most frequent SPECT pattern observed was the hypoperfusion of the temporal lobes, with a direct localization in the temporal cortex and with prevalent mesial involvement. In non-demented patients the association of mild temporal perfusion and moderate reduction of amnesic/attentional performance can be considered as a localization marker of ME cortical damage, not necessarily associated with large neuronal loss.
However, SPECT results confirm that cognitive defects associated with ME are more diverse and unique to each individual with this disease [35].
7. Conclusions
The avalanche of interesting data already present in the literature, needs a formal organization; our proposal for this workshop on cognitive impairment in neuromuscular disorders aimed to gather a panel of experts, to review the available scientific information and find a common strategy of analysis of the patients, establishing the criteria of selection of the patients and to define the objectives of the common research project.
The participants agreed to organize themselves in groups having the common aim to work on ‘CNS impairment in dystrophinopathies’. The objectives will be to understand the basis of CNS impairment in DMD and BMD. They all agreed on the following tasks:
Aims
Acknowledgements
This Workshop was made possible thanks to the financial support of the ENMC and ENMC main sponsors: Association Française contre le Myopathies (France); Deutsche Gesellschaft für Muskelkranke (Germany); Telethon Foundation (Italy); Muscular Dystrophy Campaign (United Kingdom); Muskelsvinfonden (Finland); Prinses Beatrix Fonds (The Netherlands); Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland); Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria); and Vereniging Spierziekten Nederland (The Netherlands). And ENMC associate member: Muscular Dystrophy Association of Finland. List of Participants: Prof. N. Bresolin; Dr M.G. D'Angelo (Italy); Dr A. Turconi (Italy); Dr C. Chisari (Italy); Dr K. Murphy (UK); Dr A. Toutain (France); Dr K. Bushby (UK); Dr A. Martinuzzi (Italy); Dr F. Leturcq (France); Dr K. Murphy (UK); Dr S. Lilli (Italy); Dr D. Blake (UK); Dr M. Sironi (Italy); Dr C. Vaillend (France); Dr A. Rendon (France); Dr J. Chelly (France); and Prof. Andoni Urtizberea (ENMC).
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