RESUMO
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy worldwide. With increasing survival, there is now a greater awareness of associated neurodevelopmental co-morbidities. Despite this, there is currently a limited understanding of how these co-morbidities might potentially impact on health outcomes. This study reviewed the characteristics of 37 adults with DMD who died between 2011 and 2022. The median age of death was 22.25 years, and those with neurodevelopmental co-morbidities had statistically poorer survival than those without a neurodevelopmental disorder. Notably, the proportion of patients within this cohort with a diagnosis of a neurodevelopmental disorder was higher than previously reported studies in living cohorts. This study suggests that patients with a co-morbid neurodevelopmental disorder may have worse health outcomes than those who do not.
Assuntos
Distrofia Muscular de Duchenne , Humanos , Adulto , Adulto Jovem , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/diagnóstico , Estudos Retrospectivos , Comorbidade , Cooperação do PacienteRESUMO
Duchenne muscular dystrophy is a progressive muscle wasting disease caused by pathogenic variants in DMD. Gastrointestinal involvement is increasingly recognised in older patients and can manifest as life-threatening bowel dysmotility. We describe a series of adults with Duchenne muscular dystrophy who developed either severe colonic pseudo-obstruction or sigmoid volvulus requiring urgent assessment and intervention. The presentations varied in their clinical picture and outcomes, but together highlight the complexity of managing gastrointestinal complications in this cohort of patients. Key considerations include pre-existing cardiorespiratory compromise and the increased risk associated with surgery and general anaesthesia. We also outline a role for home parenteral nutrition in the long-term management of associated bowel dysmotility.
Assuntos
Distrofia Muscular de Duchenne , Humanos , Adulto , Idoso , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/patologia , Atrofia MuscularRESUMO
Anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) myopathy is an immune-mediated necrotising myopathy. Atypical presentations hinder its recognition and its prompt treatment. We present two patients with atypical clinical or pathological features. A 45-year-old woman had an asymptomatic serum creatine kinase (CK) of ~10 000 IU/L and muscle biopsy showing minimal changes. She then developed slowly progressive proximal weakness, diagnosed as limb-girdle muscular dystrophy but with negative genetics. Twelve years later, now with severe proximal weakness, her MR scan of muscle showed diffuse asymmetrical fatty degeneration, with conspicuous hyperintense STIR signal abnormalities. HMGCR antibodies were positive and she partially improved with immunosuppression. The second patient developed slowly progressive proximal limb weakness with a high serum CK (~4000 IU/L); muscle biopsy showed a lymphocyte infiltrate with angiocentric distribution suggesting vasculitis. Serum HMGCR antibodies were positive. Anti-HMGCR myopathy can present as a slowly progressive myopathy with atypical pathology. HMGCR antibody screening is indicated for people with suspected limb-girdle muscular dystrophy or atypical inflammatory muscle conditions.
Assuntos
Doenças Autoimunes , Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Miosite , Feminino , Humanos , Pessoa de Meia-Idade , Autoanticorpos , Doenças Musculares/diagnóstico , Doenças Musculares/patologia , Miosite/diagnóstico , Miosite/tratamento farmacológicoRESUMO
Due to their frailty and cardiorespiratory compromise adults with DMD are considered extremely vulnerable and at high risk of severe infection should they contract COVID-19. We report 7 adults with DMD aged 17-26 years who tested positive on a nasopharyngeal PCR swab for SARS-CoV-2. Despite long term corticosteroid treatment, severe respiratory compromise requiring night-time ventilation and receiving treatment for moderate to severe cardiomyopathy, none of the patients developed moderate to severe symptoms; in fact two remained asymptomatic and two developed only anosmia and reduced sensation. The remaining three developed transient fever with or without sore throat, cough and runny nose. All recovered fully without complication and no patient required hospitalization.
Assuntos
COVID-19/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , COVID-19/diagnóstico , COVID-19/epidemiologia , Comorbidade , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/epidemiologia , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions.
Assuntos
Glucosiltransferases/genética , Doença de Depósito de Glicogênio/genética , Glicoproteínas/genética , Atrofia Muscular/genética , Doenças Musculares/genética , Idoso de 80 Anos ou mais , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Humanos , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Doenças Musculares/diagnóstico , Mutação/genética , Estudos RetrospectivosRESUMO
BACKGROUND: In Huntington's disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas. OBJECTIVES: The objective of this study was to explore the ability to synchronize activity in a motor network using transcranial magnetic stimulation and to relate this to timing of motor performance. METHODS: We examined synchronization in oscillatory activity of cortical motor areas in response to an external input produced by a pulse of transcranial magnetic stimulation. We combined this with EEG to compare the response of 16 presymptomatic Huntington's disease participants with 16 age-matched healthy volunteers to test whether the strength of synchronization relates to the variability of motor performance at the following 2 tasks: a grip force task and a speeded-tapping task. RESULTS: Phase synchronization in response to M1 stimulation was lower in Huntington's disease than healthy volunteers (P < .01), resulting in a reduced cortical activity at global (P < .02) and local levels (P < .01). Participants who showed better timed motor performance also showed stronger oscillatory synchronization (r = -0.356; P < .05) and higher cortical activity (r = -0.393; P < .05). CONCLUSIONS: Our data may model the ability of the motor command to respond to more subtle, physiological inputs from other brain areas. This novel insight indicates that impairments of the timing accuracy of synchronization and desynchronization could be a physiological basis for some key clinical features of Huntington's disease. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Mapeamento Encefálico , Sincronização Cortical/fisiologia , Potencial Evocado Motor/fisiologia , Doença de Huntington/patologia , Córtex Motor/fisiopatologia , Adulto , Estudos de Casos e Controles , Eletroencefalografia , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Tratos Piramidais/fisiopatologia , Estimulação Magnética TranscranianaRESUMO
Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.
Assuntos
Caveolina 3/genética , Tolerância ao Exercício , Mialgia/genética , Rabdomiólise/genética , Adolescente , Adulto , Idoso de 80 Anos ou mais , Caveolina 3/metabolismo , Criança , Distroglicanas/metabolismo , Exercício Físico/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Músculo Esquelético/patologia , Mutação , Mialgia/metabolismo , Mialgia/patologia , Fenótipo , Rabdomiólise/metabolismo , Rabdomiólise/patologiaRESUMO
BACKGROUND: Alternating hemiplegia of childhood is a very rare and serious neurodevelopmental syndrome; its genetic basis has recently been established. Its characteristic features include typically-unprovoked episodes of hemiplegia and other transient or more persistent neurological abnormalities. METHODS: We used transcranial magnetic stimulation to assess the effect of the condition on motor cortex neurophysiology both during and between attacks of hemiplegia. Nine people with alternating hemiplegia of childhood were recruited; eight were successfully tested using transcranial magnetic stimulation to study motor cortex excitability, using single and paired pulse paradigms. For comparison, data from ten people with epilepsy but not alternating hemiplegia, and ten healthy controls, were used. RESULTS: One person with alternating hemiplegia tested during the onset of a hemiplegic attack showed progressively diminishing motor cortex excitability until no response could be evoked; a second person tested during a prolonged bilateral hemiplegic attack showed unusually low excitability. Three people tested between attacks showed asymptomatic variation in cortical excitability, not seen in controls. Paired pulse paradigms, which probe intracortical inhibitory and excitatory circuits, gave results similar to controls. CONCLUSIONS: We report symptomatic and asymptomatic fluctuations in motor cortex excitability in people with alternating hemiplegia of childhood, not seen in controls. We propose that such fluctuations underlie hemiplegic attacks, and speculate that the asymptomatic fluctuation we detected may be useful as a biomarker for disease activity.
Assuntos
Hemiplegia/fisiopatologia , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana , Adolescente , Adulto , Estudos de Casos e Controles , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Mutação/genética , Adulto JovemRESUMO
The major link between the visual and motor systems is via the dorsal stream pathways from visual to parietal and frontal areas of the cortex. Although the pathway appears to be indirect, there is evidence that visual input can reach the motor cortex at relatively short latency. To shed some light on its neural basis, we studied the visuomotor interaction using paired transcranial magnetic stimulation (TMS). Motor-evoked potentials (MEPs) were recorded from the right first dorsal interosseous in sixteen healthy volunteers. A conditioning stimulus (CS) was applied over the phosphene hotspot of the visual cortex, followed by a test stimulus over the left primary motor cortex (M1) with a random interstimulus interval (ISI) in range 12-40 ms. The effects of paired stimulation were retested during visual and auditory reaction-time tasks (RT). Finally, we measured the effects of a CS on short-interval intracortical inhibition (SICI). At rest, a CS over the occiput significantly (P < 0.001) suppressed test MEPs with an ISI in the range 18-40 ms. In the visual RT, inhibition with an ISI of 40 ms (but not 18 ms) was replaced by a time-specific facilitation (P < 0.001), whereas, in the auditory RT, the CS no longer had any effect on MEPs. Finally, an occipital CS facilitated SICI with an ISI of 40 ms (P < 0.01). We conclude that it is possible to study separate functional connections from visual to motor cortices using paired-TMS with an ISI in the range 18-40 ms. The connections are inhibitory at rest and possibly mediated by inhibitory interneurones in the motor cortex. The effect with an ISI of 40 ms reverses into facilitation during a visuomotor RT but not an audiomotor RT. This suggests that it plays a role in visuomotor integration.
Assuntos
Córtex Motor/fisiologia , Estimulação Magnética Transcraniana , Córtex Visual/fisiologia , Adulto , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação/fisiologiaRESUMO
Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3-8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9-13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.