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Neoplasias Encefálicas/complicaciones , Glioblastoma/complicaciones , Cefalea/diagnóstico , Cefalea/etiología , Niño , Progresión de la Enfermedad , Cefalea/virología , Humanos , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/complicaciones , Masculino , Enfermedades del Sistema Nervioso/complicacionesRESUMEN
BACKGROUND AND PURPOSE: Leptomeningeal artery abnormalities in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry. METHODS: Frontal and temporal cortex of 6 genetically proven CADASIL brains (average age, 66 years), 6 controls without symptoms of cerebrovascular disease, and 6 very old brains (average age, 89 years) were examined for leptomeningeal artery intimal, medial, and adventitial thickness; inner diameter; and sclerotic index and for smooth muscle markers. RESULTS: The intima of CADASIL arteries was thickened 5-fold compared with controls and the very aged (P<0.0001). Medial thickness was lower in CADASIL compared with controls and the very old (P<0.01). The adventitia was not significantly increased in CADASIL compared with age-matched controls. Arterial diameters were not smaller in CADASIL compared with controls. Sclerotic index was significantly increased in CADASIL compared with other groups (P<0.00001). Intimal cells in CADASIL expressed smooth muscle actin, S100A4, and vimentin but not desmin. CONCLUSIONS: Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle-like cells participate in neointimal thickening of CADASIL arteries.
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Arterias/patología , Encéfalo/patología , CADASIL/patología , Túnica Íntima/patología , Anciano , Anciano de 80 o más Años , Humanos , Hiperplasia/patología , Meninges/irrigación sanguínea , Persona de Mediana EdadRESUMEN
Cerebral endothelial cells participate in the blood-brain barrier and regulate activity-dependent changes in brain blood flow. It has been assumed that all cerebral endothelial cells are similar, but genetic studies in mice suggest that there are heterogeneous populations of endothelial cells in rodent brain. In this study, we tested for molecular heterogeneity of endothelial cells in the human brain. Human brains (five A and five O blood type patients) from autopsies were analyzed by immunohistochemistry and immunofluorescence using antibodies against von Willebrand factor (vWF) and A and H blood group antigens. vWF and ABO antigens were confined to the endothelium. Although all endothelial cells expressed vWF, capillary endothelial cells from A blood type brains showed a heterogeneous expression of A and H antigens, with individual cells expressing either one or both antigens. There were no differences between the gray and the white matter in the percentage of A-reactive or H-reactive capillaries. We conclude that ABO antigen expression in the human brain is modulated at the level of the individual endothelial cell. Future studies are warranted to determine whether differences in capillary permeability and cerebral autoregulation vary over short distances within the brain.
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Sistema del Grupo Sanguíneo ABO/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células Endoteliales/metabolismo , Factor de von Willebrand/metabolismo , Sistema del Grupo Sanguíneo ABO/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos/inmunología , Antígenos/metabolismo , Barrera Hematoencefálica/inmunología , Encéfalo/citología , Encéfalo/inmunología , Capilares/inmunología , Capilares/metabolismo , Células Endoteliales/citología , Células Endoteliales/inmunología , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Humanos , Persona de Mediana Edad , Factor de von Willebrand/inmunologíaRESUMEN
BACKGROUND AND PURPOSE: CADASIL (cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy) is a genetic disorder hallmarked by ischemic stroke and vascular dementia. Characteristic pathological changes in the vasculature include thickening of small arteries and accumulation of heterogeneous material within the vessel wall. We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression. METHODS: Brain sections obtained at autopsy from six North American CADASIL patients were examined using immunohistochemistry for vWF and IgG. Rat aortic smooth muscle cells (A7R5 cells) were tested for binding to infrared-tag labeled vWF. Finally, A7R5 cells were exposed to vWF, and expression of mature smooth muscle marker genes was analyzed by quantitative reverse transcriptase PCR. RESULTS: vWF is expressed in the penetrating arterial walls in all CADASIL samples. IgG, a marker of serum extravasation, was present only in a minority of arterial walls. vWF binds to smooth muscle cells in vitro, and low concentrations of vWF rapidly activate c-fos, EGR, TSP1, and c-myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22. CONCLUSIONS: These data demonstrate that vWF, likely produced by the endothelium, permeates the vessel wall of CADASIL brains. Exposure of smooth muscle cells to vWF results in reduction of specific RNAs required for normal vascular homeostasis. This is the first report of accumulation of a protein within CADASIL vessels that inhibits vascular gene expression and implicates a role for vWF beyond hemostasis.
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Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.
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Arterias/patología , CADASIL/patología , Capilares/patología , Colágeno/análisis , Túnica Media/patología , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , Humanos , Persona de Mediana Edad , Isoformas de Proteínas/análisisRESUMEN
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best characterized genetic cause of vascular dementia and stroke and has been extensively reported in European and Asian populations. OBJECTIVE: To report the pathological and genetic analysis of CADASIL in an African American man with a 15-base pair NOTCH3 duplication. DESIGN: Case report. SETTING: University hospital. PATIENT: A 78-year-old man with dementia, recurrent strokes, a family history of similar neurological disease, and white matter abnormalities seen on brain magnetic resonance imaging. MAIN OUTCOME MEASURES: Brain pathology and genetic analysis of NOTCH3. RESULTS: The patient's brain showed widespread arteriopathy in large and small arteries. Using electron microscopy, granular osmiophilic material typical of CADASIL was identified abutting the plasma membrane of smooth muscle cells. Brain extracts contained elevated NOTCH3 protein levels. Sequencing of the NOTCH3 gene revealed a novel 15-base pair heterozygous duplication in exon 7, which is predicted to direct expression of a protein that contains 5 extra amino acids, including a cysteine residue. CONCLUSIONS: To our knowledge, this is the first reported pathological and genetic analysis of an African American patient with CADASIL. The mutation in NOTCH3 is the longest duplication within this gene yet reported.
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CADASIL/genética , CADASIL/patología , Duplicación de Gen , Receptores Notch/genética , Negro o Afroamericano/genética , Anciano , Demencia/genética , Demencia/patología , Genes Dominantes , Humanos , Enfermedades Arteriales Intracraneales/genética , Masculino , Mutación/genética , Receptor Notch3 , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patologíaRESUMEN
Ossifying fibromyxoid tumors (OFT), first described in 1989 by Enzinger et al., are rare lesions; malignant OFT (MOFT) are even rarer. We report a large recurrent paraspinal MOFT invading the spine and causing epidural compression in a 70-year-old male, despite prior debulking and radiotherapy. Paraspinal involvement of these tumors has been reported only twice before. We describe its imaging, pathology, and also review the pertinent literature.
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Fibroma Osificante/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de la Médula Espinal/patología , Anciano , Fibroma Osificante/complicaciones , Fibroma Osificante/cirugía , Humanos , Masculino , Recurrencia Local de Neoplasia/complicaciones , Recurrencia Local de Neoplasia/cirugía , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/cirugía , Neoplasias de la Médula Espinal/complicaciones , Neoplasias de la Médula Espinal/cirugíaRESUMEN
BACKGROUND: Primary meningeal osteosarcomas and radiation-induced extraosseous tumors are extremely rare. We encountered a patient with a radiation-induced meningeal osteosarcoma with metastatic spread. CASE DESCRIPTION: A 54-year-old man presented with a 2-week history of nausea, vomiting, and ataxia. CT and MRI studies revealed an extra-axial, dural-based mass in the posterior fossa arising from the tentorium cerebelli. The patient underwent complete resection of the tumor with adjuvant chemotherapy. Histopathologic analysis revealed chondroblastic osteosarcoma. Tumor recurrence was observed 9 months after initial diagnosis, and adjuvant radiation therapy was administered. The intracranial disease stabilized; however, multiple cervico-thoracic spinal metastases were discovered 15 months after initial diagnosis. The patient expired 16 months after initial diagnosis. CONCLUSION: Meningeal osteosarcomas are rare lesions that can metastasize and should be considered in the differential diagnosis for dural-based lesions, especially in the case of previous radiation therapy.
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A novel H1N1 influenza A virus emerged in April 2009, and rapidly reached pandemic proportions. We report a retrospective observational case study of pathologic findings in 8 patients with fatal novel H1N1 infection at the University of Michigan Health Systems (Ann Arbor) compared with 8 age-, sex-, body mass index-, and treatment-matched control subjects. Diffuse alveolar damage (DAD) in acute and organizing phases affected all patients with influenza and was accompanied by acute bronchopneumonia in 6 patients. Organizing DAD with established fibrosis was present in 1 patient with preexisting granulomatous lung disease. Only 50% of control subjects had DAD. Peripheral pulmonary vascular thrombosis occurred in 5 of 8 patients with influenza and 3 of 8 control subjects. Cytophagocytosis was seen in all influenza-related cases. The autopsy findings in our patients with novel H1N1 influenza resemble other influenza virus infections with the exception of prominent thrombosis and hemophagocytosis. The possibility of hemophagocytic syndrome should be investigated in severely ill patients with H1N1 infection.
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Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/patología , Pulmón/patología , Adulto , Bronconeumonía/patología , Bronconeumonía/virología , ADN Viral/análisis , Resultado Fatal , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Gripe Humana/virología , Pulmón/virología , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/virología , Masculino , Persona de Mediana Edad , Alveolos Pulmonares/patología , Alveolos Pulmonares/virología , Embolia Pulmonar/patología , Embolia Pulmonar/virología , Estudios Retrospectivos , Adulto JovenRESUMEN
Corpora amylacea (CA) have long been described in aging brains and in patients with neurodegenerative conditions, but their origins have been debated. It has been proposed that CA represent collections of nervous system breakdown products that accumulate within astrocytic cytoplasm. In support of this, studies have shown that CA include glycosylated material, ubiquitin, and an assortment of proteins derived from neuronal cytoplasm. On the other hand, many of these proteins are not specifically localized to neurons or astrocytes; some components of CA, such as complement proteins, are most abundantly expressed outside the central nervous system. The characteristic predilection for CA to accumulate near vessels and ependyma suggests that proteins extravasated from blood or transudated from CSF may form a component of these structures. In this study, we report the immunohistochemical localization of blood and platelet proteins thrombospondin1 and ADAMTS13 in CA from aged individuals and patients with vascular dementia. Thrombospondin1 localized to neurons, but was most prominently localized to CA. An independent serum and platelet expressed protein, ADAMTS13, was found in CA in the same brain regions. In vitro analysis shows that thrombospondin1 and ADAMTS13 form complexes together in cells and in direct protein binding assays. We speculate that CA could result from a conglomeration of interacting proteins from degenerating neurons and from extravasated blood elements released after transient breakdown of the blood-brain barrier.
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Proteínas ADAM/metabolismo , Encéfalo/metabolismo , Demencia Vascular/metabolismo , Trombospondina 1/metabolismo , Proteína ADAMTS13 , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Envejecimiento/patología , Astrocitos/metabolismo , Encéfalo/patología , Demencia Vascular/patología , Femenino , Humanos , Inmunohistoquímica , Inmunoprecipitación , Cuerpos de Inclusión/metabolismo , Masculino , Persona de Mediana Edad , Neuronas/metabolismoRESUMEN
A 24-year-old man presented with long-term headache and progressive visual loss. Neuro-ophthalmic manifestations included finger counting acuity in both eyes, weakly reactive pupils, pale optic discs, and increased deep tendon reflexes. Brain MRI showed meningeal thickening that involved the optic nerves and chiasm and enveloped and displaced the brainstem as far caudally as the foramen magnum. The diffuse extensive nature of the lesion suggested an inflammatory process such as idiopathic hypertrophic pachymeningitis (IHP), but anterior temporal brain biopsy disclosed a relatively high proportion of meningothelial cells with islands of polyclonal inflammatory reaction consistent with a diagnosis of lymphoplasmacyte-rich meningioma (LRM), a rare variant. Among the 19 reported cases of LRM, none has shown as extensive a mass as seen in our patient. Distinguishing between LRM and IHP is important because these entities are treated differently.
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Duramadre/patología , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Meningitis/diagnóstico , Células Plasmáticas/patología , Adulto , Diagnóstico Diferencial , Humanos , Hipertrofia , Imagen por Resonancia Magnética , MasculinoRESUMEN
OBJECTIVE: Craniopharyngiomas (CPs) are benign tumors that almost always occur in a suprasellar location, making complete resection difficult and often necessitating radiotherapy. A case of CP presenting in an unusual location in an 8-year-old boy highlights the goals of CP treatment. CLINICAL PRESENTATION: An 8-year-old boy sought treatment for symptoms of nasal obstruction and snoring. He also had a history of mild developmental delay, and his father had a thyroglossal duct cyst resected in his own youth. After tonsillectomy and adenoidectomy failed to improve the patient's symptoms, nasal endoscopy and biopsy revealed an intranasal CP. After this treatment, he experienced chronic thin brown nasal discharge. Magnetic resonance imaging further revealed tumor invading the sphenoid body and the clivus and that the tumor had no intracranial extension. INTERVENTION: The child underwent surgical resection via a Le Fort I osteotomy approach. Complete resection was accomplished based on intraoperative frozen section pathological examination and postoperative magnetic resonance imaging results. CONCLUSION: CP with no intracranial extension is a very rare but benign tumor. We recommend vigorous attempts to resect such tumors completely to minimize the chance of recurrence and the possible need for radiotherapy. Although radiotherapy controls CP growth quite well, it has its own risks that should be avoided if possible. Cranial base techniques may facilitate total resection.
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Craneofaringioma/diagnóstico , Craneofaringioma/cirugía , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/cirugía , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/cirugía , Niño , Humanos , Masculino , Resultado del TratamientoRESUMEN
A 10-year-old girl presented with increasing lower back pain without gait or sphincter disturbances. MRI demonstrated a large, intramedullary tumor at the level of the conus. The imaging findings were unlike those of a classic ependymoma or astrocytoma. Histopathologic examination demonstrated clear-cell ependymoma, which is a distinct entity. We found three cases of clear-cell ependymoma of the spinal cord reported in the literature. Clear-cell ependymoma of the spinal cord can be resected completely and needs to be recognized for its imaging features, benign course and favorable prognosis.
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Ependimoma/diagnóstico , Neoplasias de la Médula Espinal/diagnóstico , Niño , Medios de Contraste , Ependimoma/patología , Femenino , Estudios de Seguimiento , Humanos , Vértebras Lumbares/patología , Imagen por Resonancia Magnética , Canal Medular/patología , Neoplasias de la Médula Espinal/patologíaRESUMEN
BACKGROUND: Nontuberculous mycobacterial infections occur in immunocompromised patients but so rarely involve the central nervous system (CNS) that they may not be included in a differential diagnosis of CNS lesions in such patients. OBJECTIVE: To illustrate a putative mechanism for nontuberculous mycobacterial infection of the CNS via breakdown of the blood-brain barrier by metastatic neoplasm. RESULTS: A 56-year-old man who had undergone renal transplantation in February 2003 and was taking an immunosuppressive regimen of mycophenolate mofetil and cyclosporine was seen in the emergency department after a syncopal episode. Head computed tomography revealed a single focal occipital lesion with vasogenic edema. Hospital admission and further workup led to diagnosis of metastatic carcinoma infected with nontuberculous mycobacteria in the setting of a disseminated nontuberculous mycobacterial infection. CONCLUSION: This case illustrates that breakdown of the blood-brain barrier by metastatic neoplasm may provide a route of access for a pathogen that is not normally seen in the CNS.
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Adenocarcinoma/secundario , Neoplasias Encefálicas/secundario , Huésped Inmunocomprometido , Infecciones por Mycobacterium no Tuberculosas/inmunología , Metástasis de la Neoplasia , Adenocarcinoma/microbiología , Adenocarcinoma/patología , Neoplasias Encefálicas/microbiología , Neoplasias Encefálicas/patología , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/patología , Tomógrafos Computarizados por Rayos XRESUMEN
PURPOSE: Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. EXPERIMENTAL DESIGN: Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. RESULTS: Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. CONCLUSION: Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.
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Neoplasias Encefálicas/irrigación sanguínea , Gliosarcoma/irrigación sanguínea , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor D de Crecimiento Endotelial Vascular/metabolismo , Animales , Antineoplásicos Alquilantes/uso terapéutico , Velocidad del Flujo Sanguíneo , Volumen Sanguíneo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Carmustina/uso terapéutico , Gliosarcoma/tratamiento farmacológico , Gliosarcoma/metabolismo , Imagen por Resonancia Magnética , Masculino , Perfusión , Fenotipo , ARN sin Sentido/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor D de Crecimiento Endotelial Vascular/genéticaRESUMEN
We describe a patient with genetically- and biochemically-proven mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who was initially misdiagnosed as having had multiple ischemic strokes in part because the clinical presentation appeared to be acute, the MRI of lesions showed restricted diffusion, and the brain biopsy showed features suggestive of stroke. This report emphasizes the pitfalls in the diagnosis of MELAS and points out the similarities and differences between MELAS and ischemic stroke.
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Acidosis Láctica/diagnóstico , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Encefalomiopatías Mitocondriales/diagnóstico , Accidente Cerebrovascular/diagnóstico , Adulto , Biopsia , Diagnóstico Diferencial , Electroencefalografía , Estudios de Seguimiento , Humanos , Masculino , Encefalomiopatías Mitocondriales/complicacionesAsunto(s)
Dolor Abdominal/diagnóstico , Perforación Intestinal/diagnóstico , Enfermedades Cutáneas Papuloescamosas/diagnóstico , Vasculitis/diagnóstico , Dolor Abdominal/tratamiento farmacológico , Diagnóstico Diferencial , Dipiridamol/administración & dosificación , Esquema de Medicación , Resultado Fatal , Femenino , Humanos , Indometacina/administración & dosificación , Inyecciones Intravenosas , Perforación Intestinal/tratamiento farmacológico , Persona de Mediana Edad , Recurrencia , Enfermedades Cutáneas Papuloescamosas/tratamiento farmacológico , Enfermedades Cutáneas Papuloescamosas/patologíaRESUMEN
BACKGROUND: Distal myopathies (MPDs) are genetically heterogeneous. Genetic causes within this subgroup of muscle disorders remain largely unknown. An MPD linked to chromosome 14q11-q13 (MPD1) is rare, and to our knowledge, only one family with definitive linkage has been described. OBJECTIVE: To describe the results of clinical and genetic analysis of the second kindred with MPD1. PATIENTS AND METHODS: We have identified a family with an MPD segregating in an autosomal dominant fashion. We tested linkage to previously identified genetic loci on chromosomes 2p, 2q, and 14q. The coding sequence of PABP2 (the polyadenylate-binding protein 2 gene) was analyzed. RESULTS: Every affected individual had selective weakness of foot extensors, with the average age of symptom onset at 20 years. Some patients also had proximal weakness, but none had signs of finger or hand extensor muscle involvement, even in advanced stages of the disease. Two typically affected individuals had signs of idiopathic dilated cardiomyopathy. Genetic analysis detected a tight linkage to chromosome 14q11-q13. Recombination at the telomeric end of the 14q11-q13 locus was found in an unaffected individual who was not considered to be at risk, potentially reducing the locus interval by 2 centimorgans. No mutations in the PABP2 gene were identified. CONCLUSIONS: To our knowledge, our described family is only the second known kindred with a chromosome 14-linked MPD in whom the linkage has been unequivocally established. We did not detect signs of involvement of hand or finger extensors and neck muscles, seen in the original family with MPD1. The degree and frequency of proximal weakness seem to be more prominent than in other patients with MPD1. Haplotype analysis suggests that the gene is located between polymorphic microsatellite markers D14S283 and D14S1034 on chromosome 14q11-q13. The presence of cardiomyopathy in some affected individuals may help in the identification of candidate genes.