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Rinsho Shinkeigaku = Clinical Neurology Dec 2023A 19-year-old female, normal at birth, grew up without neck movement when getting up. She needed a handrail to climb stairs since the age of 10 years old, and walked...
A 19-year-old female, normal at birth, grew up without neck movement when getting up. She needed a handrail to climb stairs since the age of 10 years old, and walked slowly since the age of 16 years old. Neurological examination revealed loss of deep tendon reflexes, decreased vibratory sensation, weakness of distal muscles of the lower extremities, and weakness of mainly cervical trunk muscles suspected to be due to myopathy. Nerve conduction studies suggested axonal polyneuropathy, and needle EMG showed short duration MUP, myotonic discharge, and rimmed vacuoles on muscle biopsy. Genetic analysis revealed a previously reported pathological mutation (p.P209L, heterozygous) in Bcl2-Associated Athanogene 3 (BAG3), and a diagnosis of MFM6 was made. P209L is a poor prognosis myopathy that develops in childhood and is associated with cardiomyopathy. P209L is a solitary myopathy associated with axonal neuropathy and characterized by apex foot contracture and weak neck to trunk flexion. This disease is suspected in young-onset neuromyopathy.
Topics: Female; Infant, Newborn; Humans; Child; Adolescent; Young Adult; Adult; Apoptosis Regulatory Proteins; Muscular Diseases; Muscle, Skeletal; Mutation; Peripheral Nervous System Diseases; Adaptor Proteins, Signal Transducing
PubMed: 37989284
DOI: 10.5692/clinicalneurol.cn-001915 -
Journal of Neurology Feb 2024To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.
OBJECTIVE
To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.
METHODS
This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3.
RESULTS
Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members.
CONCLUSIONS
We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.
Topics: Adult; Humans; Female; Middle Aged; Aged; Pedigree; Charcot-Marie-Tooth Disease; Phenotype; Muscle, Skeletal; Muscular Atrophy, Spinal; Mutation; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins
PubMed: 37907725
DOI: 10.1007/s00415-023-12039-9 -
Human Molecular Genetics Dec 2023
PubMed: 37788121
DOI: 10.1093/hmg/ddad168 -
European Journal of Neurology Jan 2024Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time,...
BACKGROUND AND PURPOSE
Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB.
METHODS
Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features.
RESULTS
The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination.
DISCUSSION
In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.
Topics: Humans; Charcot-Marie-Tooth Disease; Mutation; Genetic Testing; Phenotype; Crystallins; Cataract; Pedigree
PubMed: 37772343
DOI: 10.1111/ene.16063 -
Stem Cell Research Oct 2023Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a...
Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a myofibrillar myopathy, carrying a heterozygous c.4984C > T [p.Q1662X] mutation in the filamin C (FLNC)-gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi001-A displays typical embryonic stem cell-like morphology, carries the c.4984C > T FLNC gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY) and holds the potential to differentiate in all three germ layers. We postulate that HIMRi001-A can be used for the elucidation of FLNC-associated pathomechanisms and for developing new therapeutic options.
Topics: Male; Humans; Middle Aged; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Pluripotent Stem Cells; Fibroblasts; Mutation; Cell Differentiation
PubMed: 37748332
DOI: 10.1016/j.scr.2023.103210 -
Clinical Genetics Dec 2023Missense mutations in MYOT encoding the sarcomeric Z-disk protein myotilin cause three main myopathic phenotypes including proximal limb-girdle muscular dystrophy,...
Missense mutations in MYOT encoding the sarcomeric Z-disk protein myotilin cause three main myopathic phenotypes including proximal limb-girdle muscular dystrophy, spheroid body myopathy, and late-onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early-adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full-length myotilin protein revealed that the 4-YERPKH-9 amino acids are involved in local interactions within the N-terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I-band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early-onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers.
Topics: Adult; Animals; Humans; Connectin; Distal Myopathies; Microfilament Proteins; Muscle Proteins; Muscle, Skeletal; Mutation; Zebrafish
PubMed: 37553249
DOI: 10.1111/cge.14413 -
International Journal of Molecular... Jul 2023Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk...
Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk disintegration, and the accumulation of degradation products into protein aggregates. They are caused by mutations in several genes that encode either structural proteins or molecular chaperones. Nevertheless, the mechanisms by which mutated genes result in protein aggregation are still unknown. To unveil the role of myotilin and αB-crystallin in the pathogenesis of MFM, we injected zebrafish fertilized eggs at the one-cell stage with expression plasmids harboring cDNA sequences of human wildtype or mutated (p.Ser95Ile) and human wildtype or mutated (p.Gly154Ser). We evaluated the effects on fish survival, motor behavior, muscle structure and development. We found that transgenic zebrafish showed morphological defects that were more severe in those overexpressing mutant genes. which developed a myopathic phenotype consistent with that of human myofibrillar myopathy, including the formation of protein aggregates. Results indicate that pathogenic mutations in myotilin and αB-crystallin genes associated with MFM cause a structural and functional impairment of the skeletal muscle in zebrafish, thereby making this non-mammalian organism a powerful model to dissect disease pathogenesis and find possible druggable targets.
Topics: Animals; Humans; alpha-Crystallin B Chain; Crystallins; Muscle, Skeletal; Mutation; Myofibrils; Myopathies, Structural, Congenital; Protein Aggregates; Zebrafish
PubMed: 37511242
DOI: 10.3390/ijms241411483 -
International Journal of Molecular... Jul 2023Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene...
Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene () result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.
Topics: Humans; Desmin; Greece; Cardiomyopathies; Myopathies, Structural, Congenital; Muscle, Skeletal; Mutation; Muscular Diseases
PubMed: 37446359
DOI: 10.3390/ijms241311181 -
Human Molecular Genetics Aug 2023The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle...
The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Filamins; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Protein Isoforms; Zebrafish; Zebrafish Proteins
PubMed: 37427997
DOI: 10.1093/hmg/ddad113 -
Neurological Research and Practice Jun 2023Here we report on a patient with Parkinson's Disease and camptocormia due to Myofibrillar Myopathy Type 3. By leading the reader through the clinical reasoning process...
Here we report on a patient with Parkinson's Disease and camptocormia due to Myofibrillar Myopathy Type 3. By leading the reader through the clinical reasoning process and highlighting the respective red flags we aim to increase the readers' awareness for the differential diagnosis of camptocormia.
PubMed: 37287054
DOI: 10.1186/s42466-023-00250-y