RESUMEN
BACKGROUND: Late-onset Pompe disease (LOPD) is a rare, hereditary, progressive disorder that is usually characterized by limb-girdle muscle weakness and/or respiratory insufficiency. LOPD is caused by mutations in the acid alpha-glucosidase (GAA) gene and treated with enzyme replacement therapy (ERT). METHODS: We studied the clinical, brain imaging, and genetic features of the Belgian cohort of late-onset Pompe disease patients (N = 52), and explored the sensitivity of different outcome measures, during a longitudinal period of 7 years (2010-2017), including the activity limitations ActivLim score, 6 min walking distance (6MWD), 10 m walk test (10MWT), MRC sum score, and forced vital capacity (FVC) sitting/supine. RESULTS: In Belgium, we calculated an LOPD prevalence of 3.9 per million. Mean age at onset of 52 LOPD patients was 28.9 years (SD: 15.8 y), ranging from 7 months to 68 years. Seventy-five percent (N = 39) of the patients initially presented with limb-girdle weakness, whereas in 13% (N = 7) respiratory symptoms were the only initial symptom. Non-invasive ventilation (NIV) was started in 37% (N = 19), at a mean age of 49.5 years (SD: 11.9 y), with a mean duration of 15 years (SD: 10.2 y) after symptom onset. Brain imaging revealed abnormalities in 25% (N = 8) of the patients, with the presence of small cerebral aneurysm(s) in two patients and a vertebrobasilar dolichoectasia in another two. Mean diagnostic delay was 12.9 years. All patients were compound heterozygotes with the most prevalent mutation being c.-32-13 T > G in 96%. We identified two novel mutations in GAA: c.1610_1611delA and c.186dup11. For the 6MWD, MRC sum score, FVC sitting and FVC supine, we measured a significant decrease over time (p = 0.0002, p = 0.0001, p = 0.0077, p = 0.0151), which was not revealed with the ActivLim score and 10MWT (p > 0.05). CONCLUSIONS: Awareness on LOPD should even be further increased because of the long diagnostic delay. The 6MWD, but not the ActivLim score, is a sensitive outcome measure to follow up LOPD patients.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Bélgica/epidemiología , Diagnóstico Tardío , Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , alfa-Glucosidasas/uso terapéuticoRESUMEN
OBJECTIVE: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases. METHODS: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible. RESULTS: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants. CONCLUSIONS: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.
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Hipertermia Maligna/genética , Hipertermia Maligna/patología , Músculos/patología , Rabdomiólisis/genética , Rabdomiólisis/patología , Canal Liberador de Calcio Receptor de Rianodina/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.
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Predisposición Genética a la Enfermedad , Heterocigoto , Hipertermia Maligna/genética , Miopatía del Núcleo Central/genética , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina/genética , Adulto , Niño , Preescolar , Familia , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Pierna/patología , Masculino , Hipertermia Maligna/metabolismo , Hipertermia Maligna/patología , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miopatía del Núcleo Central/metabolismo , Miopatía del Núcleo Central/patología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Población Blanca/genéticaRESUMEN
OBJECTIVE: In this study, we investigated the detailed clinical findings and underlying genetic defect in 3 presumably related Bulgarian families displaying dominantly transmitted adult onset distal myopathy with upper limb predominance. METHODS: We performed neurologic, electrophysiologic, radiologic, and histopathologic analyses of 13 patients and 13 at-risk but asymptomatic individuals from 3 generations. Genome-wide parametric linkage analysis was followed by bidirectional sequencing of the filamin C (FLNC) gene. We characterized the identified nonsense mutation at cDNA and protein level. RESULTS: Based on clinical findings, no known myopathy subtype was implicated in our distal myopathy patients. Light microscopic analysis of affected muscle tissue showed no specific hallmarks; however, the electron microscopy revealed changes compatible with myofibrillar myopathy. Linkage studies delineated a 9.76 Mb region on chromosome 7q22.1-q35 containing filamin C (FLNC), a gene previously associated with myofibrillar myopathy. Mutation analysis revealed a novel c.5160delC frameshift deletion in all patients of the 3 families. The mutation results in a premature stop codon (p.Phe1720LeufsX63) that triggers nonsense-mediated mRNA decay. FLNC transcript levels were reduced in muscle and lymphoblast cells from affected subjects and partial loss of FLNC in muscle tissue was confirmed by protein analysis. CONCLUSIONS: The FLNC mutation that we identified is distinct in terms of the associated phenotype, muscle morphology, and underlying molecular mechanism, thus extending the currently recognized clinical and genetic spectrum of filaminopathies. We conclude that filamin C is a dosage-sensitive gene and that FLNC haploinsufficiency can cause a specific type of myopathy in humans.
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Proteínas Contráctiles/genética , Miopatías Distales/genética , Haploinsuficiencia/genética , Proteínas de Microfilamentos/genética , Adulto , Bulgaria , Análisis Mutacional de ADN , Femenino , Filaminas , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
OBJECTIVE: Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. METHODS: We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. RESULTS: In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. CONCLUSIONS: With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.
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Enfermedad de Charcot-Marie-Tooth/genética , Proteínas del Tejido Nervioso/genética , Animales , Axones/patología , Células COS , Chlorocebus aethiops , Estudios de Cohortes , Análisis Mutacional de ADN , Exones/genética , Genes Dominantes , Haplotipos , Células HeLa , Humanos , Intrones/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Mutación , Paternidad , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVES: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. CONCLUSION: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.
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Técnicas de Diagnóstico Molecular , Enfermedad de la Neurona Motora/diagnóstico , Enfermedades Musculares/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Humanos , Enfermedad de la Neurona Motora/genética , Enfermedades Musculares/genética , Enfermedades del Sistema Nervioso Periférico/genéticaRESUMEN
BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a complex neurodegenerative disorder caused by mutations in SACS. The phenotype consists of a childhood-onset triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. OBJECTIVE: To provide more insight into the prevalence of SACS mutations and the variability of the associated phenotype. METHODS: Mutation screening of SACS by direct sequencing and multiplex amplicon quantification for detection of intragenic copy number variations in a cohort of 85 index patients with phenotypes suggestive for ARSACS. Additional short tandem repeat (STR) marker analysis was performed for haplotype sharing. RESULTS: In 11 families,18 new SACS mutations were found (12.9% of total cohort). Five patients displayed onset ages in adulthood, a feature not known to be associated with ARSACS. The remaining index patients displayed a classic early onset phenotype. Initial phenotypic presentation was atypical in several patients, obscuring the clinical diagnosis. A founder mutation in SACS was identified in 3 Belgian families. In one isolated patient, an intragenic SACS deletion of exons 3-5 was detected. Partial SACS deletions were not previously described. CONCLUSIONS: In this study, we enlarge the ARSACS phenotype and the underlying genetic spectrum of SACS mutations. Patients with ARSACS are more common than previously known and risk underdiagnosis due to late onset age and unusual presentation.
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Proteínas de Choque Térmico/genética , Mutación/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Niño , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Fenotipo , Paraplejía Espástica Hereditaria/patología , Adulto JovenRESUMEN
BACKGROUND: Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or Seipin. AIM: To report the first Serbian family with a BSCL2 mutation showing variable expression within the family. PATIENTS AND METHODS: A 55-year-old woman presented with weakness of both hands at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in her legs. Physical examination revealed atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs. There was generalized hyperreflexia with the exception of ankle reflexes which were diminished. Her 25year-old son had only stiffness of both legs at the age of 22. Physical examination revealed only generalized hyporeflexia. The third affected member in this family was her 55year-old cousin who showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract features. RESULTS: In all three patients sensory nerve conduction velocities (NCV) were normal in all extremities. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients. Concentric needle EMG showed evidence of chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients. CONCLUSION: This report is further confirmation of phenotypic heterogenity due to the N88S mutation of BSCL2 gene in the same family.
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Subunidades gamma de la Proteína de Unión al GTP/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Potenciales de Acción , Adulto , ADN/genética , Electrodiagnóstico , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Mutación/genética , Mutación/fisiología , Mutación Missense/fisiología , Conducción Nerviosa/fisiología , Linaje , Células Receptoras Sensoriales/fisiologíaRESUMEN
OBJECTIVES: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. CONCLUSION: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.
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Canalopatías/diagnóstico , Demencia/diagnóstico , Epilepsia/diagnóstico , Trastornos Migrañosos/diagnóstico , Biología Molecular/normas , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Accidente Cerebrovascular/diagnóstico , Canalopatías/epidemiología , Canalopatías/genética , Demencia/epidemiología , Demencia/genética , Epilepsia/epidemiología , Epilepsia/genética , Europa (Continente)/epidemiología , Medicina Basada en la Evidencia , Humanos , Recién Nacido , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/genética , Biología Molecular/métodos , Biología Molecular/tendencias , Técnicas de Diagnóstico Molecular/tendencias , Sociedades Médicas/normas , Sociedades Médicas/tendencias , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genéticaRESUMEN
BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.
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Ataxia/diagnóstico , Ataxia/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Ataxia/metabolismo , Humanos , Paraplejía/diagnóstico , Paraplejía/genética , Paraplejía/metabolismo , Paraplejía Espástica Hereditaria/metabolismoRESUMEN
OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.
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Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Biología Molecular/métodos , HumanosRESUMEN
BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.
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Distonía/diagnóstico , Guías como Asunto/normas , Enfermedad de Huntington/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Enfermedad de Parkinson/diagnóstico , Bases de Datos Bibliográficas/estadística & datos numéricos , Distonía/genética , Asesoramiento Genético/métodos , Humanos , Enfermedad de Huntington/genética , Enfermedad de Parkinson/genéticaRESUMEN
A spinal epidural abscess (SEA) is an uncommon condition, appearing in 0.2-2 cases per 10,000 hospital admissions. Urgent surgical decompression in combination with long term antibiotics is the common treatment of choice for SEA. However, in some cases, a non-surgical treatment can also be considered. In this case report, a patient is presented with SEA extending from C2 to L3 which was successfully treated with antibiotic therapy without surgical intervention.
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Antibacterianos/uso terapéutico , Absceso Epidural/tratamiento farmacológico , Floxacilina/uso terapéutico , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/uso terapéutico , Antibacterianos/efectos adversos , Vértebras Cervicales/patología , Absceso Epidural/diagnóstico , Gastroplastia , Humanos , Vértebras Lumbares/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/tratamiento farmacológico , Radiculopatía/diagnóstico , Radiculopatía/tratamiento farmacológico , Reoperación , Médula Espinal/patología , Infecciones Estafilocócicas/diagnóstico , Teicoplanina/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
Opsoclonus-myoclonus syndrome (OMS), a movement disorder characterised by chaotic eye movements and myoclonus, is a rare clinical entity. We present two cases of opsoclonus-myoclonus syndrome of paraneoplastic origin. In the first patient the syndrome was associated with a breast carcinoma and in the second patient with a non small cell lung carcinoma. However none of the commonly associated antibodies were found in these cases. From the neuropathological findings from the first patient we find arguments that support the current hypothesis on the pathophysiology of OMS namely a dysfunction in brainstem and cerebellum. We conclude that in adults with OMS one has to be very suspicious of a possible neoplastic origin of the syndrome. The antibodies associated with some cases of OMS are thought to play a role in the pathophysiology of the syndrome although the exact immunologic mechanism remains unknown. Research into the neuropathological substrate of OMS yields a broad range of abnormalities in brain stem and cerebellum. However none of these findings seem to be pathognomonic. As for the possible therapy of OMS, several immunomodulating strategies can be used with varying success. At present there is no established standard therapy.
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Encéfalo/patología , Síndrome de Opsoclonía-Mioclonía/etiología , Síndrome de Opsoclonía-Mioclonía/fisiopatología , Encéfalo/metabolismo , Neoplasias de la Mama/complicaciones , Carcinoma de Células Pequeñas/complicaciones , Depresión/complicaciones , Diagnóstico Diferencial , Femenino , Humanos , Hipertensión/complicaciones , Inmunohistoquímica , Neoplasias Pulmonares/complicaciones , Persona de Mediana Edad , Síndrome de Opsoclonía-Mioclonía/sangre , Fumar , Neuronitis Vestibular/patologíaRESUMEN
Although orthodontic repositioning of impacted teeth is widely used, the treatment has its limitations. Autotransplantation or intra-alveolar surgical repositioning of teeth is an alternative therapy that may be used in selected cases of desperate impactions, when orthodontic extrusion is unsuccessful or when orthodontic treatment is rejected by the patient. A case report is presented to stress both the indications and limitations of a modified technique of intra-alveolar surgical uprighting of impacted teeth.