RESUMEN
Pompe disease is an autosomal recessive disorder characterized by deficiency of alpha-glucosidase, a lysosomal enzyme, which can lead to glycogen accumulation in skeletal muscle, heart, and nervous system. Clinical presentation is highly variable, with infantile and late-onset (LOPED) forms. Although muscle biopsy findings are rather stereotyped, atypical features have been described. A 52-year-old man without a family history of muscle disorders presented with slowly progressing upper and lower limb girdle weakness and hyperCKemia. At needle EMG, a diffuse neurogenic pattern was detected. Muscle biopsy showed a selective type 1 fiber atrophy with vacuoles of various sizes, filled with PAS and acid phosphatase positive material, confirmed to be glycogen by electron microscopy (EM). Many atrophic fibers contained foci of myofibrillar material recognized as nemaline bodies (NBs) at EM. Low level of alpha-glucosidase activity in blood and molecular genetic testing confirmed the diagnosis of late-onset Pompe disease (LOPED). Major causes of hereditary and acquired NB myopathy were ruled out. In conclusion, NBs represent a novel histological finding in LOPED and characterize the atypical presentation of our case.
RESUMEN
In spinocerebellar ataxia type 2 (SCA-2), a difference of three CAG repeats distinguishes normal alleles (14 to 31 repeats) from pathogenic alleles (34 to 57 repeats). All sequenced pathogenic alleles have a pure CAG repeat structure, whereas interrupted repeats have been seen exclusively in normal alleles. The authors present two patients with sporadic SCA with an interrupted 34-CAG repeat allele, (CAG)24(CAA)(CAG)9, who showed a phenotype compatible with SCA-2. The interrupted allele coding for a 34 pure polyglutamine tract may cause the SCA phenotype.
Asunto(s)
Proteínas/genética , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos , Anciano , Alelos , Ataxinas , Atrofia , Corteza Cerebelosa/patología , Análisis Mutacional de ADN , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas del Tejido Nervioso , Penetrancia , Fenotipo , Ataxias Espinocerebelosas/patologíaAsunto(s)
Furosemida/envenenamiento , Glucosa/efectos adversos , Glycyrrhiza/envenenamiento , Hipopotasemia/inducido químicamente , Enfermedad Iatrogénica , Parálisis/inducido químicamente , Plantas Medicinales , Adulto , Diuréticos/envenenamiento , Femenino , Estudios de Seguimiento , Glucosa/uso terapéutico , Humanos , Hipopotasemia/tratamiento farmacológico , Infusiones Intravenosas , Hipotonía Muscular/inducido químicamente , Hipotonía Muscular/tratamiento farmacológico , Parálisis/tratamiento farmacológico , Potasio/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Myotonic dystrophy is a systemic genetic disorder, with dominant transmittance. It is characterized by generalized progressive muscular abnormality. Although frontoparietal alopecia is one of the most common symptoms in myotonic dystrophy, it has not received much attention. METHODS: We examined 25 subjects from two families: 10 patients were affected by Steinert disease and 15 were not. The various morphologic and biochemical hair alterations are reported. RESULTS: All investigated subjects (affected or not) presented the same type of morphologic and biochemical hair alterations. CONCLUSIONS: These findings could be used to construct a hypothesis to explain the cause of the disease.
Asunto(s)
Enfermedades del Cabello/patología , Cabello/ultraestructura , Distrofia Miotónica/patología , Adulto , Anciano , Aminoácidos/análisis , Cabello/química , Enfermedades del Cabello/complicaciones , Enfermedades del Cabello/genética , Humanos , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , Distrofia Miotónica/complicaciones , Distrofia Miotónica/genéticaRESUMEN
The molecular analysis of the survival motor neuron (SMN) gene and several closely flanking polymorphic markers in an atypical pedigree with four patients suffering from spinal muscular atrophy (SMA) over two generations has raised new aspects concerning the etiology and the molecular spectrum of autosomal recessive SMA. Three patients in two generations show homozygous deletions of exons 7 and 8 of the telomeric copy of SMN (telSMN), thus confirming the presence of autosomal recessive SMA, with localisation on chromosome 5q12. The fourth SMA patient with mild neurogenic atrophy (confirmed by muscle biopsy and electromyography) shows no homozygous deletion of telSMN but carries a heterozygous deletion of telSMN, as can be deduced from her two affected homozygously deleted children. No intragenic mutation has been identified in the remaining telSMN. In addition, she shares only one SMA chromosome with her affected brother, is haploidentical with two healthy brothers, and has a 31-year-old healthy son, who has inherited an SMN-deleted paternal chromosome and the SMN non-deleted maternal chromosome. These results suggest that this patient either has a neurogenic atrophy of a different origin or exhibits an unusual heterozygous manifestation of SMA 5q12. Interestingly, the two haploidentical telSMN-deleted affected sibs in the second generation show a strikingly discordant clinical picture indicating that, in addition to telSMN mutations, other factors influence the phenotype of SMA in the reported pedigree.
Asunto(s)
Atrofia Muscular Espinal/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia/genética , Adulto , Cromosomas Humanos Par 5/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Exones/genética , Femenino , Genes Recesivos/genética , Ligamiento Genético , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Atrofia Muscular Espinal/patología , Linaje , Proteínas de Unión al ARN , Proteínas del Complejo SMN , TelómeroRESUMEN
Myotonic dystrophy (DM) is associated with an expansion of an unstable (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. We studied six patients from two families who showed no expansions of the repeat, in spite of their clinical diagnosis of DM. These patients had multi-systemic manifestations that were distinguishable from those seen in other myotonic disorders, including proximal myotonic myopathy (PROMM). In one additional family, two symptomatic members showed no expanded (CTG)n repeats, while their affected relatives had the expanded repeats. DM haplotype analysis failed to exclude the DMPK locus as a possible site of mutation in each family; however, DMPK mRNA levels were normal. We conclude that a mutation(s) other than the expanded (CTG)n repeat can cause the DM phenotype. The mutation(s) in these families remain(s) to be mapped and characterized.
Asunto(s)
Mutación , Distrofia Miotónica/genética , Proteínas Serina-Treonina Quinasas/genética , Adolescente , Adulto , Anciano , Cromosomas Humanos Par 19 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Quinasa de Distrofia Miotónica , LinajeRESUMEN
The L-malate NAD(P)+ oxidoreductase (decarboxylating) E.C.1.1.1.39 was purified from human skeletal muscle; the specific activity estimated in the presence of NAPD+ as coenzyme was approximately 15 mumol/min/mg. The apparent Vmax values for NAD+ (approximately 8 mumol/min/mg) and NADP+ (approximately 16 mumol/min/mg) show that the enzyme (in this tissue) is more active in the presence of NAPD+. This observation was confirmed by the estimation of enzymatic activity in competition experiments where both NAD+ and NADP+ were used together as coenzymes. The absence of pyruvate carboxylation and of oxalacetate decarboxylation activities demonstrates that the enzyme studied is E.C.1.1.1.39. In addition, the apparent Km values for NAD+ and NADP+ were calculated (15 and 0.05 mM, respectively). This paper provides the first demonstration of a NADP+ preferring activity of the enzyme in human skeletal muscle.
Asunto(s)
Malato Deshidrogenasa/metabolismo , Músculo Esquelético/enzimología , NADP/metabolismo , NAD/metabolismo , Carboxiliasas/metabolismo , Cromatografía de Afinidad , Cromatografía por Intercambio Iónico , Electroforesis en Gel de Poliacrilamida , Humanos , Concentración de Iones de Hidrógeno , Cinética , Malato Deshidrogenasa/aislamiento & purificación , Piruvato Carboxilasa/metabolismoRESUMEN
The myotonic dystrophy (DM) mutation has been identified as an unstable, expanded (CTG)n repeat in the 3' untranslated region of a gene designated DM protein kinase (DMPK). Both decreased and increased levels of mutant DMPK mRNA as well as decreased levels of protein have been variously reported and invoked to explain disparate molecular bases of this dominantly inherited disease. Most recently, increased nucleosome binding to such expanded repeats has been interpreted as support for transcriptional repression. A quantitative allele-specific RT-PCR procedure was developed and applied to a spectrum of patient tissue samples and cell lines. Equal levels of unprocessed pre-mRNA were produced by the wildtype (+) and disease (DM) alleles in skeletal muscle and cell lines of heterozygous DM patients. Thus, any increased nucleosome binding had no effect at the level of transcriptional initiation and transcription of the mutant DMPK locus. In contrast, processed mRNA levels from the DM allele were reduced relative to the+allele as the size of the expansion increased. The unstable repeat, therefore, impairs post-transcriptional processing of DM allele transcripts. This phenomenon has profound effects on overall DMPK locus steady-state transcript levels in cells missing a wildtype allele and does not appear to be mediated by imprinting, decreased mRNA stability, generation of aberrant splice forms, or absence of polyadenylation of the mutant allele.
Asunto(s)
Cromosomas Humanos Par 19 , Distrofia Miotónica/genética , Proteínas Serina-Treonina Quinasas/genética , Transcripción Genética , Adolescente , Adulto , Anciano , Alelos , Animales , Secuencia de Bases , Células CHO , Niño , Preescolar , Cricetinae , Femenino , Fibroblastos/enzimología , Humanos , Células Híbridas , Recién Nacido , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Distrofia Miotónica/enzimología , Proteína Quinasa de Distrofia Miotónica , Polimorfismo Genético , ARN Mensajero/genética , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
A genotype-phenotype study based on the primary clinical features of adult myotonic dystrophy (DM) included 116 patients from 62 Italian pedigrees. A significant correlation between clinical severity and the number of repeats at the 3' untranslated region of the myotonin-protein kinase gene (MT-PK) was found. These results suggest that the CTG amplification is directly related to the myotonic dystrophy phenotype and provide important information on morbidity and prognosis in this disease.
Asunto(s)
Mutación , Distrofia Miotónica/genética , Fenotipo , Proteínas Serina-Treonina Quinasas , Adolescente , Adulto , Alelos , Secuencia de Bases , Niño , ADN/análisis , ADN/metabolismo , Femenino , Amplificación de Genes , Humanos , Italia , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Musculares/genética , Distrofia Miotónica/patología , Proteína Quinasa de Distrofia Miotónica , Proteínas Quinasas/genética , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
DNA was recovered from sections of muscle biopsies of 20 spinal muscular atrophy (SMA) patients fixed on microscopic slides and stored from one to 20 years at room temperature. Microsatellite DNA markers tightly linked to the SMA locus were amplified using the polymerase chain reaction (PCR) to obtain specific amplified products. The procedure was successful in all cases, and allowed prenatal diagnosis in one at-risk pregnancy. In our hands this procedure is quick, sensitive and reproducible.
Asunto(s)
ADN Satélite/análisis , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Reacción en Cadena de la Polimerasa/métodos , Alelos , Secuencia de Bases , Biopsia , Mapeo Cromosómico , ADN Satélite/genética , Femenino , Amplificación de Genes , Humanos , Masculino , Microscopía/instrumentación , Microscopía/métodos , Datos de Secuencia Molecular , Músculos/patología , Atrofia Muscular Espinal/patología , Estudios Retrospectivos , TemperaturaRESUMEN
The NADP(+)-dependent activity of malic enzymes EC 1.1.1.39 and EC 1.1.1.40 was studied in human cardiac and skeletal muscle obtained from living subjects. We used polyacrylamide gel electrophoresis to detect and extract the enzymatic forms and starch gel electrophoresis to confirm their identification. This simple procedure allowed us to provide evidence of a selective NADP(+)-dependent distribution of malic enzyme activities between the two muscular tissues, using a smaller amount of sample than used with previous methods.
Asunto(s)
Malato Deshidrogenasa/metabolismo , Músculos/enzimología , Miocardio/enzimología , Electroforesis en Gel de Poliacrilamida , Electroforesis en Gel de Almidón , Humanos , Distribución TisularRESUMEN
Two unrelated pedigrees, which show recurrence of Emery-Dreifuss muscular dystrophy (EDMD) in three generations, have been studied using 13 X-linked DNA polymorphisms and somatic cell hybrids to establish the phase of the corresponding alleles in some obligate carriers. The reconstruction of cross-over points on the X chromosomes carrying the EDMD gene excludes from mapping most regions of the X chromosome except for the terminal portion of Xq. Pooled linkage data from the two pedigrees confirm the linkage previously reported with locus DXS15. A cross-over in a carrier female suggests that the EDMD gene is probably located distally to DXS15. In addition the recombinant meioses from one of the two pedigrees suggest the following order for some Xq polymorphic loci: DXS1 (DXYS1-DXS178) DXS42 (F9-DXS15).
Asunto(s)
Intercambio Genético , Genes , Distrofias Musculares/genética , Cromosoma X , Mapeo Cromosómico , Femenino , Humanos , Italia , Masculino , Linaje , Polimorfismo GenéticoRESUMEN
A 35-year-old man, who had been ingesting one or two bags of tablets of pure licorice daily (20-40 g/day) for about two years, developed an acute myopathy with high levels of serum muscle enzymes and the typical features of mineralocorticoid excess: serious hypokalemia, hypertension, metabolic alkalosis. Both plasma renin and serum aldosterone were below the normal values. Ultrastructural study of muscle showed only minor, aspecific changes. Glycyrrhizinic acid, a steroid-like glycoside contained in natural licorice, has a well-known mineralocorticoid activity but severe potassium depletion and rhabdomyolysis due to chronic licorice ingestion have rarely been reported. This case further indicates that such a possibility is to be considered in the differential diagnosis of a patient admitted because of acute flaccid tetraparesis and hypokalemia.
Asunto(s)
Glycyrrhiza , Hipopotasemia/etiología , Plantas Medicinales , Rabdomiólisis/etiología , Adulto , Aldosterona/sangre , Humanos , Masculino , Microscopía Electrónica , Mitocondrias Musculares/ultraestructura , Músculos/patología , Renina/sangreRESUMEN
A case of a complete Kearns-Sayre syndrome, of early onset, associated with cerebral and cerebellar leukodystrophy and basal ganglia calcification is reported. The clinical, neurophysiological and morphological findings suggest multisystem involvement.