RESUMEN
Combined morphological, immunocytochemical, biochemical and molecular genetic studies were performed on skeletal muscle, heart muscle and liver tissue of a 16-months boy with fatal liver failure. The pathological characterization of the tissues revealed a severe depletion of mtDNA (mitochondrial DNA) that was most pronounced in liver, followed by a less severe, but still significant depletion in skeletal muscle and the heart. The primary cause of the disease was linked to compound heterozygous mutations in the polymerase γ (POLG) gene (DNA polymerase γ; A467T, K1191N). We present evidence, that compound heterozygous POLG mutations lead to tissue selective impairment of mtDNA replication and thus to a mosaic defect pattern even in the severely affected liver. A variable defect pattern was found in liver, muscle and heart tissue as revealed by biochemical, cytochemical, immunocytochemical and in situ hybridization analysis. Functionally, a severe deficiency of cytochrome-c-oxidase (cox) activity was seen in the liver. Although mtDNA depletion was detected in heart and skeletal muscle, there was no cox deficiency in these tissues. Depletion of mtDNA and microdissection of cox-positive or negative areas correlated with the histological pattern in the liver. Interestingly, the mosaic pattern detected for cox-activity and mtDNA copy number fully aligned with the immunohistologically revealed defect pattern using Pol γ, mtSSB- and mtTFA-antibodies, thus substantiating the hypothesis that nuclear encoded proteins located within mitochondria become unstable and are degraded when they are not actively bound to mtDNA. Their disappearance could also aggravate the mtDNA depletion and contribute to the non-homogenous defect pattern.
Asunto(s)
ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Fallo Hepático , ADN Polimerasa gamma , Replicación del ADN , Resultado Fatal , Humanos , Lactante , Hígado/metabolismo , Hígado/ultraestructura , Fallo Hepático/genética , Fallo Hepático/metabolismo , Fallo Hepático/patología , Masculino , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Mutación , Miocardio/metabolismo , Miocardio/ultraestructuraRESUMEN
Renal cell carcinoma (RCC) is a rare tumor in the pediatric population. Recently, a phenotypically and genetically distinct kidney carcinoma, mainly prevalent in children and associated with an Xp11.2 translocation or TFE3 gene fusion, has been described. It has been advanced that in this subtype of RCC, there is an accumulation of cyclin D1, cyclin D3, and p21 ((wafl/cip1)). The aim of the present study was to figure out in two pediatric RCC recently diagnosed in our department (one clear cell-type RCC and one TFE3-positive RCC) whether those features are indeed specific of the latter tumor or occur in pediatric RCC irrespective of the tumor type. The following immunostains were performed in both cases: Ki67, p16(ink4a), p21 ((wafl/cip1)), p27(kip1), p53, p63, mdm2, cyclin D1, cyclin D3, TFE3, CD10, vimentin, E-cadherin, and RCC-antigen. We observed in the TFE3-positive carcinoma an intense immunoreaction for p21 ((wafl/cip1)), cyclin D1, and cyclin D3, without expression for p53, p16, p27(kip1), and mdm2, whereas the immunoexpression profile observed in the classic RCC was similar to that of clear cell, adult-type RCC. Our study confirms that TFE3-positive RCC exhibits a deregulation of the cell cycle apparently unrelated to the young age of the patients.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/química , Proteínas de Ciclo Celular/análisis , Cromosomas Humanos X , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/química , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Niño , Ciclina D1/análisis , Ciclina D3 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/análisis , Ciclinas/análisis , Femenino , Genotipo , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Nefrectomía , Fenotipo , Resultado del TratamientoRESUMEN
We report the case of a 13-year-old boy with a longstanding history of unspecific hepatomegaly. The morphological investigations were diagnostic of a cholesterol ester storage disease (CESD), a rare autosomal recessive inherited disease with deficient activity of lysosomal acid lipase (LAL). The combination of hepatomegaly with accumulation of macrophages and ultrastructural evidence of lysosomal lipid storage are groundbreaking for the diagnosis. The probability of a underdiagnosis or false disease classification, for example as nonalcoholic steatohepatitis (NASH), is high, particularly with regard to genetic data which indicate a higher incidence of the disease.
Asunto(s)
Enfermedad de Acumulación de Colesterol Éster/patología , Adolescente , Enfermedad de Acumulación de Colesterol Éster/complicaciones , Enfermedad de Acumulación de Colesterol Éster/genética , Diagnóstico Diferencial , Hepatomegalia/complicaciones , Hepatomegalia/patología , Humanos , Masculino , Esterol Esterasa/deficiencia , Esterol Esterasa/genéticaRESUMEN
Kidney biopsies in 2 females with nephrotic syndrome were suggestive of membranous nephropathy at routine light microscopy and immunohistochemistry. Electron microscopy on re-embedded paraffin tissue, however, revealed that the light microscopic pattern was due to a fibrillary glomerulonephritis with a dominant membranous manifestation. These findings suggest that (a) fibrillary glomerulonephritis may be mis-/under-diagnosed at light microscopy; and (b) in reality, a subset of therapy refractory membranous nephropathies might represent fibrillary glomerulopathies. Therefore, electron microscopy is mandatory in any case of membranous nephropathy with therapy refractory nephrotic syndrome or an unusual immunohistological staining pattern, e.g. with mesangial immunoreactivity.
Asunto(s)
Glomerulonefritis Membranosa/patología , Glomerulonefritis/patología , Adulto , Diagnóstico Diferencial , Femenino , Glomerulonefritis/metabolismo , Glomerulonefritis Membranosa/metabolismo , Humanos , Inmunohistoquímica , Microscopía Electrónica de TransmisiónRESUMEN
Renal carcinomas harboring the TFE-3 translocation are rare and occur predominately in children and adolescents. Here, we report a case of infantile renal carcinoma with TFE3 translocation and show that the cell cycle is deregulated in this type of carcinoma. It is characterized by nuclear accumulation of cyclin D1 and D3 in combination with high levels of cyclin-dependent kinase inhibitor p21Cip1/Waf1 but without accumulation of p53, p16INK4a, or mdm2. The combined overexpression of p21, cyclin D1, and cyclin D3 was found exclusively in this type but not in other, more common types of renal carcinoma/oncocytoma (n=27). These results further underscore that renal carcinomas with Xp11. 2 translocations/TFE3-gene fusion represent a special type of renal neoplasm showing deregulation of specific cell cycle components. The analysis of further cases has to prove whether the derangement of the cell cycle is uniform and correlates with the specific type of molecular genetic derangement.
Asunto(s)
Adenoma Oxifílico , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales , Proteínas de Ciclo Celular/análisis , Cromosomas Humanos X , Fusión Génica , Neoplasias Renales , Proteínas de Neoplasias/genética , Adenoma Oxifílico/química , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Carcinoma de Células Renales/química , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Ciclo Celular , Proteínas de Ciclo Celular/genética , Ciclina D , Ciclina D3 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/análisis , Ciclinas/análisis , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Lactante , Neoplasias Renales/química , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Translocación Genética , Regulación hacia ArribaRESUMEN
ES-cell-based cardiovascular repair requires an in-depth understanding of the molecular mechanisms underlying the differentiation of cardiovascular ES cells. A candidate cardiovascular-fate inducer is the bHLH transcription factor MesP1. As one of the earliest markers, it is expressed specifically in almost all cardiovascular precursors and is required for cardiac morphogenesis. Here we show that MesP1 is a key factor sufficient to induce the formation of ectopic heart tissue in vertebrates and increase cardiovasculogenesis by ES cells. Electrophysiological analysis showed all subtypes of cardiac ES-cell differentiation. MesP1 overexpression and knockdown experiments revealed a prominent function of MesP1 in a gene regulatory cascade, causing Dkk-1-mediated blockade of canonical Wnt-signalling. Independent evidence from ChIP and in vitro DNA-binding studies, expression analysis in wild-type and MesP knockout mice, and reporter assays confirm that Dkk-1 is a direct target of MesP1. Further analysis of the regulatory networks involving MesP1 will be required to preprogramme ES cells towards a cardiovascular fate for cell therapy and cardiovascular tissue engineering. This may also provide a tool to elicit cardiac transdifferentiation in native human adult stem cells.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/fisiología , Transducción de Señal , Proteínas Wnt/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Inmunoprecipitación de Cromatina , Células Madre Embrionarias/citología , Endotelio Vascular/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , Xenopus laevis/metabolismoRESUMEN
The need for clinical awareness and diagnostic precision of glycogen storage disease type 2 (GSD2) has increased, as enzyme replacement therapy has become available. So far, only small series have reported the muscle pathology of late-onset GSD2. We reassessed 43 muscle biopsies of 38 GSD2 patients. In all patients the diagnosis of GSD2 has been established by biochemistry and/or mutational analysis of the GAA gene. Additionally to the expected morphological features, ultrastructural analysis revealed a high incidence of autophagic vacuoles, lipofuscin debris, structural Z-line disorganization and histological neurogenic-like pattern that were not thoroughly appreciated, previously. Comparing age at onset and morphology, excessive vacuolar and autophagic myopathy and mitochondrial disorganization of virtually all fibres is common in infants. At juvenile onset, a more moderate vacuolization without significant differences in overall morphology is notable. At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe. Here pronounced secondary alterations are observed that include lipofuscin debris, autophagic vacuoles with residual lysosomal bodies and granular inclusions, structural mitochondrial and Z-line texture alterations. Moreover, there is a high incidence of subtle neurogenic-like alteration in all subtypes. Nineteen patients were genetically tested; in 15 patients the common leaky splicing mutation c.-45T>G (or IVS1-13T>G) in intron1 of the GAA gene was found on at least one allele, facilitating genetic screening. In our patients, GAA genotype appears not to be associated with secondary alterations such as autophagic vacuoles, structural alterations or neurogenic-like changes. These findings may have implications for our understanding of the pathogenesis of GSD2 and for assessing therapeutic success of enzyme replacement therapy.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Músculo Esquelético/ultraestructura , alfa-Glucosidasas/genética , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Biopsia , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo II/metabolismo , Humanos , Inmunohistoquímica , Lactante , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Mutación , FenotipoRESUMEN
Benign symmetric lipomatosis, also called Madelung's disease, is characterized by lipomata and fatty infiltrations. Involvement of the nervous system has occasionally been described, mitochondrial dysfunctions have been suggested. We report a 55 year old male suffering from benign symmetric lipomatosis with associated axonal neuropathy and hyperlipoproteinemia. He showed a remarkable phenotype of neuropathy i.e. no sensory disturbance, ubiquitous fasciculations and muscle cramps, furthermore reduced COX activity and abnormalities in specific mitochondrial tRNA regions.
Asunto(s)
Axones/fisiología , Hiperlipoproteinemias/genética , Lipomatosis Simétrica Múltiple/genética , Enfermedades del Sistema Nervioso Periférico/genética , ARN de Transferencia/genética , ARN/genética , Humanos , Hiperlipoproteinemias/complicaciones , Lipomatosis Simétrica Múltiple/complicaciones , Masculino , Persona de Mediana Edad , Mutación , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/fisiopatología , ARN MitocondrialRESUMEN
Chondroblastoma is a benign bone tumor, accounting for approximately one percent of all benign bone tumors. It mostly occurs in typical locations such as long bones. Malignant transformation including metastasis has been described in only a few cases. Therefore, we report a unique case of chondroblastoma with tumor manifestation in the 7th decade of life, location of the tumor in the scapula and occurrence of metastasis in the soft tissue of the mandible branch. Due to aggravation of the clinical course, a scapula en bloc resection was performed. The differential diagnosis is discussed and the current literature concerning malignant transformation of chondroblastoma is reviewed.
Asunto(s)
Neoplasias Óseas , Condroblastoma/secundario , Anciano , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Condroblastoma/diagnóstico , Condroblastoma/patología , Humanos , Masculino , Neoplasias Mandibulares/secundario , EscápulaRESUMEN
Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.
Asunto(s)
Errores Innatos del Metabolismo/complicaciones , Músculo Esquelético/enzimología , Enfermedades Musculares/etiología , Ubiquinona/análogos & derivados , Adulto , Coenzimas , Creatina Quinasa/sangre , Parto Obstétrico , Progresión de la Enfermedad , Complejo I de Transporte de Electrón/deficiencia , Complejo III de Transporte de Electrones/deficiencia , Femenino , Humanos , Ácido Láctico/sangre , Metabolismo de los Lípidos , Masculino , Debilidad Muscular/etiología , Músculo Esquelético/metabolismo , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/patología , Enfermedades Musculares/fisiopatología , Embarazo , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/fisiopatología , Ubiquinona/deficiencia , Ubiquinona/uso terapéuticoRESUMEN
We report on clinical, histological and genetic findings in two patients carrying novel heteroplasmic mutations in the mitochondrial cytochrome c oxidase subunit genes COII and COIII. The first patient, a 35 year-old man had a multisystemic disease, with clinical symptoms of bilateral cataract, sensori-neural hearing loss, myopathy, ataxia, cardiac arrhythmia, depression and short stature and carried a 7970 G>T (E129X) nonsense mutation in COII. A sudden episode of metabolic encephalopathy caused by extremely high blood lactate lead to coma. The second patient developed exercise intolerance and rhabdomyolysis at age 22 years. A heteroplasmic missense mutation 9789 T>C (S195P) was found in skeletal muscle, but not in blood and myoblasts pointing to a sporadic mutation. Our report of two patients with isolated COX deficiency and new mutations in COX subunit genes may help to draw more attention to this type of mtDNA defects and provide new aspects for counselling affected families.
Asunto(s)
Complejo IV de Transporte de Electrones/genética , Encefalomiopatías Mitocondriales/genética , Enfermedades Musculares/genética , Mutación , Adulto , Análisis Mutacional de ADN/métodos , Ácido Glutámico/genética , Humanos , Inmunohistoquímica/métodos , Masculino , Encefalomiopatías Mitocondriales/enzimología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Enfermedades Musculares/enzimología , Prolina/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Rabdomiólisis/genética , Rabdomiólisis/patología , Serina/genéticaRESUMEN
Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
Asunto(s)
Catarata/congénito , Cobre/metabolismo , Discapacidades del Desarrollo/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Hipotonía Muscular/patología , Adenosina Trifosfatasas/metabolismo , Southern Blotting , Encéfalo/metabolismo , Proteínas de Transporte de Catión/metabolismo , ATPasas Transportadoras de Cobre , Deficiencia de Citocromo-c Oxidasa/diagnóstico , Análisis Mutacional de ADN , Electrofisiología , Exones , Fibroblastos/metabolismo , Histidina/metabolismo , Humanos , Immunoblotting , Inmunohistoquímica , Lactante , Imagen por Resonancia Magnética , Masculino , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Músculos/metabolismo , Mutación , Mioblastos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
This case report deals with an, in our regions, unusual diagnosis of coincidence of a genital schistosomiasis of a 30-year-old woman, coming from Africa. The female patient presented herself by a specialist because of longer lasting hypermenorrhoe. After clinical examination the patient underwent an operation because of an uterus myomatosus. The histopathological evaluation showed beside a leimyoma an expanded infestation with schistosomiasis haematobium. After pathological diagnosis the patient underwent the standard therapy with a single injection of praziquantel. We report about the clinic, epidemiology, morphology and diagnostic.
Asunto(s)
Leiomioma/patología , Esquistosomiasis mansoni/patología , Neoplasias Uterinas/patología , Adulto , Animales , Femenino , Alemania , Humanos , Schistosoma mansoni/aislamiento & purificación , Sierra Leona/etnologíaAsunto(s)
Actinas/genética , Predisposición Genética a la Enfermedad , Mutación Missense , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miopatías Estructurales Congénitas/patología , LinajeAsunto(s)
Codón sin Sentido , ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Miopatías Mitocondriales/genética , Adenosina Trifosfatasas/metabolismo , Adolescente , Adulto , Edad de Inicio , Complejo IV de Transporte de Electrones/metabolismo , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Miopatías Mitocondriales/enzimología , Miopatías Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Polimorfismo de Longitud del Fragmento de Restricción , Recuperación de la Función , Remisión EspontáneaAsunto(s)
Predisposición Genética a la Enfermedad , Miopatías Mitocondriales/genética , Mutación , ARN de Transferencia de Alanina/genética , Adulto , Apoptosis , Línea Celular , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/ultraestructura , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/patología , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Mioblastos Esqueléticos/citología , Distrofia Miotónica/diagnósticoRESUMEN
We describe a hitherto unknown lesion of gastric chief cell proliferation mimicking structurally mucosal gastric cancer. The unremarkable cytology of the cells, their very low Ki-67 index, the inclusion of occasional parietal cells and especially ultrastructural evidence of chief cell differentiation proved helpful in the differentiation from early gastric cancer. The exact classification of the alteration remains unresolved. The presence of microcysts suggests that the lesion is a variant of fundic gland polyp formation.
Asunto(s)
División Celular , Células Principales Gástricas/patología , Mucosa Gástrica/patología , Neoplasias Gástricas , Anciano , Células Principales Gástricas/química , Diagnóstico Diferencial , Mucosa Gástrica/química , Humanos , Antígeno Ki-67/análisis , Masculino , Microscopía Electrónica , Pólipos/patologíaRESUMEN
A 46-year-old female patient with Sjögren's syndrome, hypertension, and stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL) had a progressive worsening of renal function (CR, 5.0 mg/dL) after 11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g). Light microscopy revealed nonspecific angionephrosclerosis. Electron microscopy showed accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells. In the tubular system, mainly protein droplets were stored. Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg), ruling out Fabry's disease. Clinical, morphological, and biochemical findings were consistent with chloroquine-associated deterioration of renal function that improved considerably after discontinuation of chloroquine treatment. Adverse effects of chloroquine may aggravate preexisting renal disease. Electron microscopy is a worthwhile tool for establishing the correct diagnosis.
Asunto(s)
Cloroquina/efectos adversos , Enfermedad de Fabry , Enfermedades Renales/inducido químicamente , Fosfolípidos/metabolismo , Síndrome de Sjögren/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Humanos , Hipertensión/complicaciones , Riñón/ultraestructura , Enfermedades Renales/patología , Fallo Renal Crónico/complicaciones , Glomérulos Renales/ultraestructura , Leucocitos/enzimología , Microscopía Electrónica , Persona de Mediana Edad , Nefroesclerosis , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , alfa-Galactosidasa/metabolismoRESUMEN
We describe an atypical case of nemaline myopathy with an unusual distribution of muscle weakness who presented at 14 years of age with kyphoscoliosis. In this patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3). This is the first mutation identified in a constitutively expressed exon of TPM3 in a nemaline myopathy patient, but is similar to recently described mutations in beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.