RESUMO
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Assuntos
Distonia , Distúrbios Distônicos , Malformações do Sistema Nervoso , Masculino , Humanos , Estudos Transversais , Mutação/genética , Fenótipo , Distonia/genética , Distúrbios Distônicos/genética , Chaperonas Moleculares/genéticaRESUMO
OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.
Assuntos
Apirase , Deficiência Intelectual , Paraplegia Espástica Hereditária , Substância Branca , Apirase/genética , Disartria , Humanos , Deficiência Intelectual/genética , Mutação/genética , Paraplegia/genética , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/genética , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.
Assuntos
Anormalidades Múltiplas/etiologia , Doenças do Desenvolvimento Ósseo/etiologia , Ectromelia/etiologia , Quadril/anormalidades , Homozigoto , Ísquio/anormalidades , Mutação com Perda de Função , Pneumopatias/etiologia , Pulmão/anormalidades , Patela/anormalidades , Pelve/anormalidades , Proteínas com Domínio T/genética , Anormalidades Múltiplas/patologia , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Criança , Ectromelia/patologia , Feminino , Quadril/patologia , Humanos , Ísquio/patologia , Pulmão/patologia , Pneumopatias/patologia , Masculino , Patela/patologia , Linhagem , Pelve/patologia , PrognósticoRESUMO
Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.
RESUMO
Myosin storage myopathy is a protein aggregate myopathy associated with the characteristic subsarcolemmal accumulation of myosin heavy chain in muscle fibers. Despite similar histological findings, the clinical severity and age of onset are highly variable, ranging from no weakness to severe impairment of ambulation, and usually childhood-onset to onset later in life. Mutations located in the distal end of the tail of slow/ß-cardiac myosin heavy chain are associated with myosin storage myopathy. Four missense mutations (L1793P, R1845W, E1883K and H1901L), two of which have been reported in several unrelated families, are located within or closed to the assembly competence domain. This location is critical for the proper assembly of sarcomeric myosin rod filaments. To assess the mechanisms leading to protein aggregation in myosin storage myopathy and to evaluate the impact of these mutations on myosin assembly and muscle function, we expressed mutated myosin proteins in cultured human muscle cells and in the nematode Caenorhabditis elegans. While L1793P mutant myosin protein efficiently incorporated into the sarcomeric thick filaments, R1845W and H1901L mutants were prone to formation of myosin aggregates without assembly into striated sarcomeric thick filaments in cultured muscle cells. In C. elegans, mutant alleles of the myosin heavy chain gene unc-54 corresponding to R1845W, E1883K and H1901L, were as effective as the wild-type myosin gene in rescuing the null mutant worms, indicating that they retain functionality. Taken together, our results suggest that the basis for the pathogenic effect of the R1845W and H1901L mutations are primarily structural rather than functional. Further analyses are needed to identify the primary trigger for the histological changes seen in muscle biopsies of patients with L1793P and E1883K mutations.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Doenças Musculares/congênito , Cadeias Pesadas de Miosina/genética , Miosinas/genética , Agregação Patológica de Proteínas/genética , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/biossíntese , Humanos , Células Musculares/metabolismo , Células Musculares/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Doenças Musculares/genética , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mutação , Cadeias Pesadas de Miosina/biossíntese , Miosinas/biossíntese , Sarcômeros/genética , Sarcômeros/metabolismoRESUMO
BACKGROUND: In humans, muscle-specific nicotinergic acetylcholine receptor (AChR) is a transmembrane protein with five different subunits, coded by CHRNA1, CHRNB, CHRND and CHRNG/CHRNE. The gamma subunit of AChR encoded by CHRNG is expressed during early foetal development, whereas in the adult, the γ subunit is replaced by a ε subunit. Mutations in the CHRNG encoding the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome. The MPS is a condition characterised by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. RESULTS: Our whole exome sequencing studies have identified one novel and two previously reported homozygous mutations in CHRNG in three families affected by non-lethal EVMPS. The mutations consist of deletion of two nucleotides, cause a frameshift predicted to result in premature termination of the foetally expressed gamma subunit of the AChR. CONCLUSIONS: Our data suggest that severity of the phenotype varies significantly both within and between families with MPS and that there is no apparent correlation between mutation position and clinical phenotype. Although individuals with CHRNG mutations can survive, there is an increased frequency of abortions and stillbirth in their families. Furthermore, genetic background and environmental modifiers might be of significance for decisiveness of the lethal spectrum, rather than the state of the mutation per se. Detailed clinical examination of our patients further indicates the changing phenotype from infancy to childhood.
Assuntos
Anormalidades Múltiplas/genética , Hipertermia Maligna/genética , Mutação , Linhagem , Receptores Nicotínicos/genética , Anormalidades da Pele/genética , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Lactente , Masculino , GravidezRESUMO
BACKGROUND: Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses. METHODS AND RESULTS: Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis. CONCLUSIONS: RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Morte Fetal , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Mutação/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/genética , Feminino , Feto/patologia , HumanosRESUMO
OBJECTIVE: An essential role for embryonic MyHC in foetal development has been found from its association with distal arthrogryposis syndromes, a heterogeneous group of disorders characterised by congenital contractions. The latter probably result from severe myopathy during foetal development. Lack of embryonic muscle biopsy material and suitable animal models has hindered study of the pathomechanisms linking mutations in MYH3 to prenatal myopathy. METHODS AND RESULTS: We determined the pathomechanisms of developmental myopathy caused by recurrent p.Thr178Ile MYH3 heterozygosity, using patient-derived skeletal muscle cells in culture as an experimental disease model to emulate early embryonic development. These cultured cells were processed for discrimination and quantitative analysis of mutant and wild-type MYH3 alleles and MyHC transcripts, real-time RT-qPCR, sequence analysis, immunofluorescence microscopy, immunoblot, and proteomic assessments. Involvement of the ubiquitin proteasome system was investigated in patients with p.Thr178Ile mutations in MYH3 and MYH2. We found equal overall expression of mutant and wild-type MyHC mRNAs and proteins. Compared to the controls, however, expression of embryonic MyHC transcripts and proteins was reduced whereas expression of myosin-specific E3 ubiquitin ligase (MuRF1) was increased. We also found delayed myofibrillogenesis and atrophic myotubes but structured sarcomeres. CONCLUSION: In conclusion, this study suggests that developmental p.Thr178Ile MYH3 myopathy is associated with a combined pathomechanism of insufficient dosage of functional embryonic MyHC and production of mutant protein.
Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Doenças Musculares/embriologia , Doenças Musculares/genética , Proteínas Mutantes/genética , Cadeias Pesadas de Miosina/genética , Diferenciação Celular/genética , Humanos , Lactente , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Isoformas de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sarcômeros/metabolismo , Transcrição Gênica , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.
Assuntos
Predisposição Genética para Doença/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Oftalmoplegia/genética , Adulto , Biópsia , Criança , Códon sem Sentido , Análise Mutacional de DNA , Saúde da Família , Feminino , Expressão Gênica , Genes Recessivos , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Musculares de Contração Rápida/patologia , Debilidade Muscular/patologia , Doenças Musculares/patologia , Oftalmoplegia/patologia , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation. METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed. RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection. CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.
Assuntos
Artrogripose , Proteínas do Citoesqueleto/genética , Tropomiosina/genética , Troponina I/genética , Adolescente , Adulto , Idoso , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Artrogripose/genética , Artrogripose/patologia , Artrogripose/fisiopatologia , Biópsia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Destreza Motora , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Dor Musculoesquelética/etiologia , Polimorfismo de Fragmento de Restrição , Suécia , Adulto JovemRESUMO
Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. It is a major determinant of the physiological properties of each of the three muscle fibre types that make up the skeletal muscles. Heterozygous dominant missense mutations in myosin heavy chain genes cause various types of cardiomyopathy and skeletal myopathy, but the effects of myosin heavy chain null mutations in humans have not previously been reported. We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2. Five adult patients, two males and three females, from three unrelated families in UK and Finland were clinically assessed and muscle biopsy was performed in one patient from each family. MYH2 was sequenced and the expression of the corresponding transcripts and protein was analysed in muscle tissue. The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis. Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue. No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced. All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations. Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function. The relatively mild phenotype is interesting in relation to the more severe phenotypes generally seen in relation to recessive null mutations in sarcomeric proteins.
Assuntos
Genes Recessivos , Doenças Musculares/genética , Mutação , Cadeias Pesadas de Miosina/deficiência , Adulto , Idade de Início , Sequência de Aminoácidos , Feminino , Haplótipos , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fibras Musculares de Contração Rápida/patologia , Debilidade Muscular/genética , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Doenças Musculares/fisiopatologia , Músculos Oculomotores/fisiopatologia , Oftalmoplegia/diagnóstico , Oftalmoplegia/genética , Linhagem , Fenótipo , RNA Mensageiro/metabolismo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied. OBJECTIVES: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations. DESIGN: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels. RESULTS: We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient. CONCLUSIONS: Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.
Assuntos
Artrogripose/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Doenças Musculares/genética , Mutação/genética , Cadeias Pesadas de Miosina/genética , Diagnóstico Pré-Natal , Artrogripose/diagnóstico , Sequência de Bases , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Doenças Musculares/congênito , Doenças Musculares/diagnóstico , Cadeias Pesadas de Miosina/fisiologia , Diagnóstico Pré-Natal/métodos , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologiaRESUMO
OBJECTIVES: Hypertrophic cardiomyopathy (HCM) represents an important cause of sudden cardiac death particularly in otherwise healthy young individuals. In some families, HCM is caused by distinct mutations of the cardiac beta myosin heavy chain gene (MYH7). DESIGN: We have analyzed the expression of the malignant MYH7Arg453Cys mutation, in cardiac and skeletal muscle, and related it to morphological alterations. RESULTS: Morphological investigation revealed hypertrophic cardiomyocytes but regularly arranged myofibrils. Skeletal muscle showed no sign of structural alterations. CONCLUSIONS: Our results indicate that cardiomyocyte hypertrophy is secondary, due to impaired function, and that the mutation causes no structural alteration in myofibrillar structure in cardiac or skeletal muscle.
Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Morte Súbita Cardíaca/patologia , Músculo Esquelético/patologia , Miócitos Cardíacos/patologia , Cadeias Pesadas de Miosina/genética , Miosinas Cardíacas/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Criança , Análise Mutacional de DNA , Eletroforese em Gel de Poliacrilamida , Evolução Fatal , Feminino , Humanos , Músculo Esquelético/metabolismo , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/metabolismoRESUMO
OBJECTIVE: To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. PATIENTS: A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. RESULTS: Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the beta-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. CONCLUSIONS: The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.
Assuntos
Mutação de Sentido Incorreto/genética , Miopatias da Nemalina/genética , Tropomiosina/genética , Adulto , Idoso , Blefaroptose/etiologia , Blefaroptose/genética , Assimetria Facial/genética , Feminino , Genótipo , Humanos , Debilidade Muscular/etiologia , Debilidade Muscular/genética , Músculo Esquelético/patologia , Mutação de Sentido Incorreto/fisiologia , Miopatias da Nemalina/patologia , Palato/anormalidadesRESUMO
A novel R133W beta-tropomyosin (beta-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the beta-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the beta-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P<0.05) and ktr (P<0.01), and a faster V0 (P<0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W beta-Tm mutation. It is suggested that the R133W beta-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.
Assuntos
Artrogripose/metabolismo , Contração Muscular , Fibras Musculares de Contração Lenta/metabolismo , Força Muscular , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Mutação , Tropomiosina/metabolismo , Actinas/metabolismo , Adulto , Idoso , Artrogripose/genética , Artrogripose/patologia , Artrogripose/fisiopatologia , Cálcio/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Fibras Musculares de Contração Lenta/patologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Miosinas/metabolismo , Tropomiosina/genéticaRESUMO
We report a sporadic case of congenital muscular dystrophy (CMD) in a 13-year-old girl with early manifestation of muscle weakness and hypotonia, severe contractures, bulbar syndrome, progressive external ophtalmoplegia, and white matter changes on magnetic resonance imaging (MRI) of the brain, but no mental defect. Serum creatine kinase (CK) level was normal. Muscle biopsy revealed a dystrophic picture with a prominent inflammatory infiltrate mimicking inflammatory myopathy-typical histological findings in CMD. Immunostaining showed normal expression of merosin, alpha and beta-dystroglycans. Mutation analyses of calpain3, dysferlin, and SEPN1 genes were negative. An electron microscopy revealed the accumulation of abnormally enlarged mitochondria located under the sarcolemma. Measurement of respiratory chain enzyme activities did not reveal any biochemical defect and mitochondrial genetic studies, including sequencing of the entire mitochondrial genome, were unremarkable. Phenotypic presentation of our patient is very unusual and differs considerably from other CMD variants.
Assuntos
Encéfalo/patologia , Creatina Quinase/sangue , Distrofia Miotônica , Neuroglia/patologia , Oftalmoplegia/etiologia , Adolescente , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Distrofia Miotônica/sangue , Distrofia Miotônica/complicações , Distrofia Miotônica/patologiaRESUMO
Mutations in SEPN1 have been associated with three autosomal recessive congenital myopathies, including rigid spine muscular dystrophy, multiminicore disease and desmin-related myopathy with Mallory body-like inclusions. These disorders constitute the SEPN1 related myopathies (SEPN-RM). On the basis of clinical and laboratory features compatible with SEPN-RM, we performed mutation analysis of SEPN1 in 11 unrelated patients and found one case with pathogenic mutations. He showed early onset axial muscle weakness and developed scoliosis with respiratory insufficiency. Muscle biopsy showed increased variability of fiber size and slight, focal increase of connective tissue. A few fibers showed mini-core changes. SEPN1 mutation analysis revealed that the patient was a compound heterozygote: a previously described insertion (713-714 insA), and a novel nonsense mutation (R439stop).
Assuntos
Proteínas Musculares/genética , Mutação , Miopatias Congênitas Estruturais/genética , Adolescente , Arginina/genética , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Humanos , Lactente , Masculino , Fibras Musculares Esqueléticas/patologia , Miopatias Congênitas Estruturais/classificação , Miopatias Congênitas Estruturais/patologia , SelenoproteínasRESUMO
Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.