RESUMO
TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.
Assuntos
Senescência Celular/fisiologia , Desenvolvimento Muscular/fisiologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mioblastos/patologia , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Mioblastos/metabolismo , Linhagem , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. METHODS: Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. KEY RESULTS: We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort. CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.
Assuntos
Actinas/genética , Predisposição Genética para Doença/genética , Pseudo-Obstrução Intestinal/genética , Adolescente , Adulto , Australásia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Adulto JovemRESUMO
An MYH2 mutation p.(Glu706Lys) was originally described in a family with autosomal dominant inheritance, where the affected family members presented with multiple congenital contractures and ophthalmoplegia, progressing to a proximal myopathy in adulthood. Another patient with a dominant mutation p.(Leu1870Pro) was described, presenting as a congenital myopathy with ophthalmoplegia. Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia. Initially, clinically classified as oculopharyngodistal myopathy, the patient was found to carry a novel, de novo MYH2 mutation c.5630T>C p.(Leu1877Pro). This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum.
Assuntos
Predisposição Genética para Doença/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Oftalmoplegia/genética , Sequência de Aminoácidos , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Adulto JovemRESUMO
The last few years have seen major changes in the delivery of vascular services in the UK. An increasingly elderly population with greater expectations from their medical services has challenged established methods. It also became apparent that outcomes for low volume, high risk index vascular interventions such as abdominal aortic aneurysm repair were poor in the UK compared to the rest of Europe. Other ongoing challenges were the introduction of a national aortic aneurysm screening programme and the development of vascular surgery as a separate speciality. This article details the approach taken to modernise vascular services in the UK, using a quality framework agreed by vascular specialists, which drove the structural change to move vascular interventions into fewer, higher volume centres. The introduction of modern networks is designed to maintain services in surrounding hospitals without on site vascular inpatient services. The initial effects of this service remodelling are positive, with elective aortic aneurysm mortality rates falling nationally from 7.5 to 2.4 per cent.
Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/cirurgia , Prestação Integrada de Cuidados de Saúde/organização & administração , Procedimentos Endovasculares , Acessibilidade aos Serviços de Saúde/organização & administração , Programas de Rastreamento/organização & administração , Medicina Estatal/organização & administração , Procedimentos Cirúrgicos Vasculares/organização & administração , Aneurisma da Aorta Abdominal/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Humanos , Modelos Organizacionais , Seleção de Pacientes , Valor Preditivo dos Testes , Indicadores de Qualidade em Assistência à Saúde/organização & administração , Medição de Risco , Fatores de Risco , Especialidades Cirúrgicas/organização & administração , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidadeRESUMO
Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the "core myopathies") have been mainly associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the selenoprotein N (SEPN1) gene. A proportion of cases remain unresolved. Mutations in MYH7 encoding the beta myosin heavy chain protein have been implicated in cardiac and, less frequently, skeletal muscle disorders. Here we report four patients from two families with a histopathological diagnosis of MmD, presenting in childhood with slowly progressive muscle weakness, more proximal in Family 1 and more distal in Family 2, and variable degrees of cardiorespiratory impairment evolving later in life. There was also a strong family history of sudden death in the first family. Muscle biopsies obtained in early childhood showed multiple minicores as the most prominent feature. Sequencing of the MYH7 gene revealed heterozygous missense mutations, c.4399C>G; p.Leu1467Val (exon 32) in Family 1 and c.4763G>C; p.Arg1588Pro (exon 34) in Family 2. These findings suggest MYH7 mutations as another cause of a myopathy with multiple cores, in particular if associated with dominant inheritance and cardiac involvement. However, clinical features previously associated with this genetic background, namely a more distal distribution of weakness and an associated cardiomyopathy, may only evolve over time.
Assuntos
Miosinas Cardíacas/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Mutação/genética , Miopatia da Parte Central/genética , Cadeias Pesadas de Miosina/genética , Adulto , Criança , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Doenças Musculares/patologia , Miopatia da Parte Central/diagnóstico , Miopatia da Parte Central/patologia , Linhagem , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
OBJECTIVES: There is evidence that the improvement following supervised exercise for claudication results from skeletal muscle adaptation. The myosin heavy chain (MHC) determines muscle fibre type and therefore efficiency. Immunohistochemical analysis has failed to take account of hybrid MHC expression within myofibres. This study sought evidence of differential MHC protein expression following supervised exercise for claudication. DESIGN: 38 claudicants were recruited. Subjects undertook a three-month supervised exercise programme. Controls were patients awaiting angioplasty for claudication. MATERIALS AND METHODS: Subjects underwent paired gastrocnemius biopsy. Relative expression of MHC proteins was determined by SDS-PAGE electrophoresis. Non-parametric data is presented as median with the inter-quartile range and parametric as the mean ± standard deviation. RESULTS: Upon completion of the exercise programme there was a 94% increase (124 (106-145) to 241 (193-265) metres, p = 0.002) in maximum walking distance, which was not evident in the control group. An 11.1% (p = 0.02) increase in MHC I expression was observed in the exercise but not the control group (34.3% ± 6.8 to 45.4% ± 4.4). There was a positive correlation between the change in MHC I expression and the improvement in claudication distance (r = 0.69, p < 0.05). CONCLUSIONS: Supervised exercise training for claudication results in an increase in the proportion of MHC type I expression within the symptomatic gastrocnemius muscle.
Assuntos
Terapia por Exercício , Tolerância ao Exercício , Claudicação Intermitente/terapia , Músculo Esquelético/fisiopatologia , Adaptação Fisiológica , Idoso , Biópsia , Eletroforese em Gel de Poliacrilamida , Inglaterra , Teste de Esforço , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Isoformas de Proteínas , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , CaminhadaRESUMO
Exercise advice is a well established component of the conservative management of intermittent claudication. Supervised programmes of exercise remain relatively uncommon and are provided mainly in secondary care. This review outlines the evidence for the effectiveness of different exercise regimens and the relative benefits of exercise therapy, where comparisons have been made with medical therapy, angioplasty and surgery.
Assuntos
Exercício Físico , Claudicação Intermitente/terapia , Humanos , Resultado do TratamentoRESUMO
The aim of this study was to examine the impact of Friedreich ataxia (FRDA) on quality of life (QOL) using a generic tool to explore factors potentially associated with health status. Sixty-three individuals with genetically confirmed FRDA, self completed the Medical Outcomes Study 36 item Short Form Health Survey Version 2 (SF-36V2) and were assessed using the FRDA Rating Scale. Disease-specific, demographic, and social characteristics were also recorded. SF-36V2 results were compared with Australian population norms. Sample subgroups of disease severity and age at disease onset were reviewed. Physical and mental component summaries were examined in relation to clinical and social characteristics using multiple linear regression. QOL is significantly worse in individuals with FRDA compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, whilst, increased disease duration was positively associated with mental QOL. There were limitations associated with the use of SF-36V2 in the FRDA population. Further exploration of health-related QOL and FRDA may benefit from the use of a more appropriate generic tool.
Assuntos
Demografia , Ataxia de Friedreich/psicologia , Relações Interpessoais , Qualidade de Vida , Adulto , Idade de Início , Austrália , Feminino , Ataxia de Friedreich/fisiopatologia , Nível de Saúde , Indicadores Básicos de Saúde , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Spontaneous resolution of carotid stenosis has not been previously reported in the context of preoperative duplex ultrasound scanning, although it has been described as a recognizable phenomenon in the past. We report a case in whom significant carotid stenosis was noted at the time of listing for surgery on both duplex ultrasound and MRA. On preoperative imaging there was resolution of the lesion and surgery was avoided. This case emphasises that spontaneous resolution of carotid stenosis can occur and that preoperative duplex is useful as a prelude to surgery and can prevent unwarranted intervention.
Assuntos
Estenose das Carótidas/diagnóstico por imagem , Ultrassonografia Doppler Dupla , Idoso , Artéria Carótida Interna/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Humanos , Angiografia por Ressonância Magnética , Masculino , Remissão EspontâneaRESUMO
BACKGROUND: Laing early onset distal myopathy (MPD1) is an autosomal dominant myopathy caused by mutations within the slow skeletal muscle fibre myosin heavy chain gene, MYH7. It is allelic with myosin storage myopathy, with the commonest form of familial hypertrophic cardiomyopathy, and with one form of dilated cardiomyopathy. However, the clinical picture of MPD1 is distinct from these three conditions. OBJECTIVE: To collate and discuss the histological features reported in the muscle biopsies of MPD1 patients and to outline the clinical features. RESULTS: The phenotype of MPD1 was consistent, with initial weakness of great toe/ankle dorsiflexion, and later development of weakness of finger extension and neck flexion. Age of onset was the only variable, being from birth up to the 20 s, but progression was always very slow. The pathological features were variable. In this retrospective series, there were no pathognomonic diagnostic features, although atrophic type I fibres were found in half the families. Rimmed vacuoles are consistently seen in all other distal myopathies with the exception of Myoshi distal myopathy. However, they were found in a minority of patients with MPD1, and were not prominent when present. Immunohistochemical staining for slow and fast myosin showed co-expression of slow and fast myosin in some type I fibres, possibly indicating a switch to type II status. This may be a useful aid to diagnosis. CONCLUSIONS: The pathological findings in MPD1 are variable and appear to be affected by factors such as the specific muscle biopsied, the age of the patient at biopsy, and the duration of disease manifestations.
Assuntos
Miopatias Distais/genética , Cadeias Pesadas de Miosina/genética , Adolescente , Adulto , Alelos , Biópsia , Miosinas Cardíacas , Criança , Pré-Escolar , Progressão da Doença , Miopatias Distais/diagnóstico , Miopatias Distais/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Fenótipo , Nervo Sural/patologiaRESUMO
Although hemophilia A, a congenital disorder caused by defective or deficient factor VIII:C (FVIII), is cured by liver transplantation, the exact site of hepatic FVIII production is unknown. Further, while intracellular co-localization of FVIII and von Willebrand factor (VWF) is required for in vitro FVIII secretion, whether it is required for in vivo FVIII secretion is not known. An ideal setting to study this problem is in individuals with hemophilia A following liver transplantation, as their FVIII is synthesized primarily in hepatic, but not extrahepatic endothelial cells, while VWF is synthesized primarily in extrahepatic vascular endothelium. Following liver transplantation for end-stage liver disease, three hemophilic men showed VWF, but no FVIII response to (DDAVP) infusion. By contrast, both VWF and FVIII increased in a non-hemophilic transplant recipient after DDAVP. These findings support a model in which intracellular co-localization of FVIII and VWF is necessary for in vivo FVIII secretion after DDAVP.
Assuntos
Desamino Arginina Vasopressina/farmacologia , Fator VIII/biossíntese , Hemofilia A/tratamento farmacológico , Transplante de Fígado , Adulto , Desamino Arginina Vasopressina/administração & dosagem , Fator VIII/efeitos dos fármacos , Fator VIII/metabolismo , Hemofilia A/terapia , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Fator de von Willebrand/efeitos dos fármacos , Fator de von Willebrand/metabolismoRESUMO
Political initiatives and European health and safety working time regulations have combined to reduce the time available for surgical training in the United Kingdom in the future by a third. For the safety of patient care, surgeons must evolve strategies to cope with these reduced training times so that they preserve the current high level of competence exhibited by UK trainees when they attain the right to independent surgical practice recognized by appointment as a Consultant Surgeon. Such strategies include a focus on dedicated training time, the use of simulators, and a move towards progression based on satisfactory completion of a defined curriculum and competency assessment rather than the amount of time served. With insufficient time to train in every aspect of general surgery, a move towards fragmentation into its sub-specialty components seems unavoidable. Such a move offers an opportunity to re-evaluate conventional surgical training and to consider the evolution of a system-specific vascular specialist with patient-focused expertise in vascular surgery, endovascular radiology, and vascular medicine.
Assuntos
Competência Clínica , Currículo , Cirurgia Geral/educação , Internato e Residência/tendências , Procedimentos Cirúrgicos Vasculares/educação , Educação de Pós-Graduação em Medicina , Feminino , Previsões , Humanos , Masculino , Fatores de Tempo , Reino UnidoRESUMO
OBJECTIVES: To determine the effect of acute normovolaemic haemodilution (ANH) on the inflammatory response and clinical outcome in elective open abdominal aortic aneurysm (AAA) repair. DESIGN: Randomised controlled clinical trial. METHODS: Thirty-six patients were randomised to undergo ANH or act as controls. Cell salvage was permitted in both groups. Heterologous blood was transfused according to pre-determined triggers. Outcome measures were markers of the systemic inflammatory response in serum and urine observed at multiple time points, and clinical recovery. RESULTS: Median 890 (range 670-1620) ml of blood was removed at ANH in 16 patients. There were no differences in peri-operative changes in neutrophil count ( P = 0.13), serum C-reactive protein ( P = 0.38), interleukin-6 ( P = 0.50), total antioxidant capacity ( P = 0.73), urinary secretion of albumin ( P = 0.97) or retinol binding protein ( P = 0.41). There were no differences in the mortality and morbidity rates, systemic inflammatory response syndrome, ITU or hospital stay. CONCLUSIONS: ANH, when used in combination with cell salvage, made no impact on systemic inflammatory response and clinical outcome when compared to cell salvage alone after AAA repair. ANH cannot be recommended for routine use in patients undergoing abdominal aortic aneurysm surgery when cell salvage is available.
Assuntos
Albuminúria/metabolismo , Aneurisma da Aorta Abdominal/terapia , Implante de Prótese Vascular , Proteína C-Reativa/metabolismo , Hemodiluição/métodos , Proteínas de Ligação ao Retinol/urina , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/fisiopatologia , Biomarcadores/sangue , Biomarcadores/urina , Creatinina/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/urina , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória/métodos , Projetos Piloto , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Three infants are described who had nemaline rods on muscle biopsy and isolated deficiency of complex I of the respiratory chain on biochemical analysis. They all manifested failure to thrive from birth, and hypotonia and muscle weakness within the first three months of life. Different genetic defects leading to isolated complex I deficiency have been described associated with a variety of morphological changes on muscle biopsy, but rods have not been described. Nemaline rods have been secondary phenomena in a number of conditions, as well as being the primary abnormality in nemaline myopathy. However, the combination of nemaline rods and complex I deficiency is an association not previously reported.
Assuntos
Complexo I de Transporte de Elétrons/deficiência , Insuficiência de Crescimento/etiologia , Hipotonia Muscular/etiologia , Debilidade Muscular/etiologia , Miopatias da Nemalina/complicações , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
OBJECTIVE: To evaluate the impact of standard fluid management on the effectiveness of ANH as a blood conservation method in elective open AAA repair. DESIGN: Prospective randomised controlled study. METHODS: Thirty-four patients undergoing elective AAA repair were randomised to have ANH (16) or act as controls (18). Intra-operative cell salvage was permitted in both groups. Haemoglobin (Hb) concentrations were determined at variable intervals peri-operatively. Blood loss and the use of heterologous blood were recorded. RESULTS: The pre- and post-operative Hb concentrations, surgical blood loss and the use of cell salvage were similar in both groups. Hb concentration (median, range) decreased significantly from pre-operative to aortic clamping (with blood loss <100 ml) in ANH patients from 8.8 (7.5-10.2) to 5.7 (4.2-6.6)mmol/l following ANH but also in controls from 8.6 (7.5-9.7) to 7.0 (4.5-9.0)mmol/l due to fluid infusion (P<0.01 for every comparison). Bank blood requirements were similar: median 2 units in ANH and 2.5 units in control patients (P=0.68). CONCLUSIONS: Large volumes of fluids infused during AAA repair already conserve blood by the mechanism of hypervolaemic haemodilution. When cell salvage is used with standard fluid management during AAA repair, additional ANH is ineffective in saving blood.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Transfusão de Sangue Autóloga , Volume Sanguíneo , Hemodiluição , Substitutos do Plasma/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica , Transfusão de Sangue , Soluções Cristaloides , Feminino , Hemodiluição/métodos , Hemoglobinas/análise , Humanos , Derivados de Hidroxietil Amido , Soluções Isotônicas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos ProspectivosRESUMO
BACKGROUND: There remains a dilemma whether or not to re-explore the carotid artery when a neurological complication occurs after carotid endarterectomy. This study reviewed the indications for, findings and clinical outcomes following re-exploration. METHODS: Patients who experienced transient or permanent neurological events following carotid endarterectomy were identified from a prospectively compiled computerized database. Case notes were retrieved to determine time to onset of symptoms, use of carotid artery imaging and details about patients who had surgical re-exploration, and outcomes. RESULTS: Some 780 consecutive carotid endarterectomies were performed over 16 years, with an incidence of major stroke or death of 2.3 per cent (18 patients). Fifty-one patients experienced transient or permanent neurological events following surgery, 25 of whom underwent re-exploration. The findings included carotid thrombosis (ten patients), flap or other technical cause (three), haematoma (two) and no abnormality (ten). The neurological outcome after 30 days was similar, whether or not the carotid artery was re-explored. CONCLUSION: Carotid artery re-exploration was undertaken in approximately half of the patients who developed neurological complications following carotid endarterectomy. Although the cause was identified and a secondary procedure was undertaken in 14 of 25 patients, there was no improvement in clinical outcome at 30 days compared with that of patients managed non-operatively.
Assuntos
Doenças das Artérias Carótidas/cirurgia , Endarterectomia das Carótidas/efeitos adversos , Doenças do Sistema Nervoso/etiologia , Idoso , Análise de Variância , Emergências , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/cirurgia , Estudos Prospectivos , Reoperação/estatística & dados numéricos , Resultado do TratamentoRESUMO
Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness and the presence of nemaline rods. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in the ryanodine receptor gene (RYR1) have been associated with core-rod myopathy. Here we report linkage in two unrelated families, with a variant of nemaline myopathy, with associated core-like lesions. The clinical phenotype consists of muscle weakness in addition to a peculiar kind of muscle slowness. A genome-wide scan revealed a locus for nemaline myopathy with core-like lesions on chromosome 15q21-q23 for both families. Combining the two families gave a two-point LOD score of 10.65 for D15S993. The alpha-tropomyosin-1 gene (TPM1) located within this region is the strongest candidate gene. However, no mutations were found in the protein-coding region of TPM1, although small deletions or mutations in an intron cannot be excluded. The critical region contains few other candidate genes coding for muscle proteins and several genes of unknown function, and has not yet been sequenced completely. The novel phenotype of nemaline myopathy in the two presented families corresponds to an also novel, as yet uncharacterized, genotype.