Reducing bodies in distal myopathy with rimmed vacuole formation

Kiyomoto, Beatriz Hitomi; Murakami, Nobuyuki; J, Kishibayashi; Sunohara, Nobuhiko; Nonaka, Ikuya

doi:10.1007/bf00294268

Cited by 10 publications

(3 citation statements)

References 7 publications

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“…Patient 1 and patient 2 have fatal infantile form, 2,3 and patient 3 has adult-onset form. 4 Patients 4 (son) and 5 (his mother) had familial cases. 5 We directly sequenced all exons and their flanking intronic regions of FHL1 in the five RBM patients and 250 Japanese controls.…”

Section: Methodsmentioning

confidence: 98%

NOVEL FHL1 MUTATIONS IN FATAL AND BENIGN REDUCING BODY MYOPATHY

Shalaby¹,

Hayashi²,

Nonaka³

et al. 2009

Neurology

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NOVEL FHL1 MUTATIONS IN FATAL AND BE-NIGN REDUCING BODY MYOPATHYReducing body myopathy (RBM) is a rare disorder characterized pathologically by the presence of intracytoplasmic inclusions strongly stained by menadione-NBT (nitroblue tetrazolium) staining in the absence of the substrate ␣-glycerophosphate. The causative gene for RBM was recently identified as FHL1 on chromosome Xq27 encoding four and a half LIM domains 1. 1 FHL1 is a 32 kDa protein, composed of four LIM domains preceded by a single N-terminal zinc finger. FHL1 is highly expressed in skeletal muscle and heart. Here, we searched for FHL1 mutations in three sporadic cases 2-4 and one familial case 5 of RBM we previously reported. Methods.All clinical materials used in this study were obtained for diagnostic purpose with informed consent. Patient 1 and patient 2 have fatal infantile form, 2,3 and patient 3 has adult-onset form. 4 Patients 4 (son) and 5 (his mother) had familial cases. 5 We directly sequenced all exons and their flanking intronic regions of FHL1 in the five RBM patients and 250 Japanese controls. Frozen muscle specimens were examined by immunohistochemistry and immunoblotting using standard technique. Results.We identified four novel mutations in FHL1: a heterozygous missense mutation of c.449GϾA (p.C150Y) in patient 1 and c.302GϾT (p.C101F) in patient 2, an in-frame 9 bp deletion at c.304-312delAAGGGGTGC (p.102-104delKFC) in patient 3, and a hemizygous mutation c.310TϾC (p.C104R) in patient 4. The mother (patient 5) had the same mutation in heterozygous mode. All mutations we identified are located in the second LIM domain of FHL1 (figure e-1 on the Neurology ® Web site at www.neurology.org).Immunohistochemical analysis of patients' muscles showed strong immunoreactive depositions of FHL1, ␣5-integrin, myosin heavy chain-slow (MyHC-slow), ribosomal proteins, and nucleolar protein coilin (figure). Protein amount of FHL1 was significantly reduced in patients 2 and 4 with less reduction in patient 5 after normalization to actin level. In contrast, patient 3 showed mild increase in FHL1 (figure).Discussion. All our RBM patients, with a wide range of clinical phenotypes, fatal infantile (patient 1 and 2), benign childhood (patient 4), and adultonset (patients 3 and 5), had novel FHL1 mutations, confirming the recent report that FHL1 is the causative gene for RBM. 1 All the mutations identified in RBM patients affects the cysteine or histidine residues located within the second LIM domain of FHL1, indicating their irreplaceable role in stabilizing FHL1 (figure e-1). Phenotypic severity may depend on how the altered residue affects the zinc binding sites and resulting disruption of the structure and function of the LIM domain.In this study, clinical severity is correlated with the amount of the FHL1 protein. Nevertheless, previously reported fatal RBM patients show increased FHL1 amount. 1 Since RBM shows asymmetric muscle involvement and focal pathologic changes in the same muscle specimen (figure), the decrease or increase of FHL1 amount m...

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Section: Methodsmentioning

confidence: 98%

NOVEL FHL1 MUTATIONS IN FATAL AND BENIGN REDUCING BODY MYOPATHY

Shalaby¹,

Hayashi²,

Nonaka³

et al. 2009

Neurology

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“…Four girls were reported to have later onset between age 9 and 13 years with progression to loss of ambulation between the age of 13 and 27 years (Hubner and Pongratz, 1981;Hubner and Pongratz, 1982;Nomizu et al, 1992;Bertini et al, 1994). Clinical symptoms of the disease in adulthood are reported in six additional female patients, with onset between 22 and 50 years of age (Keith and Brownell, 1990;Kiyomoto et al, 1995a;Figarella-Branger et al, 1999;Goebel et al, 2001;Shinde et al, 2004;Ohsawa et al, 2006). Five of these patients progressed slowly, but one patient had a rapidly progressive course leading to loss of ambulation within 5 years after onset.…”

Section: Clinical Analysismentioning

confidence: 99%

Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1

Scheßl¹,

Taratuto²,

Sewry³

et al. 2008

Brain

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We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.

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“…Based on immunohistochemical preparations, the protein content of reducing bodies is still incompletely known and somewhat controversial in that desmin, vimentin, dystrophin, spectrin, laminin, and a-actin were found absent by one group [24], and dystrophin, a-sarcoglycan, ubiquitin, and vimentin were found present, while a-B crystallin, a-actinin, titin, and nebulin were absent, and desmin was seen in the periphery of some reducing bodies by others [12] ( Table 3). These immunohistochemical differences may be reflected in the different ultrastructural composition of reducing bodies which are described as granular, like nuclear chromatin [21,23,24,30,37] or tubular [4] as in our patients muscle tissue, but are also described as consisting of tubulofilaments and 17-nm thick, apparently similar to those seen in inclusion body myositis/inclusion body myopathy, and perhaps representing a different type or variant of reducing bodies [12].…”

Section: Morphologymentioning

confidence: 99%

Reducing Body Myopathy with Cytoplasmic Bodies and Rigid Spine Syndrome: A Mixed Congenital Myopathy

Goebel¹,

Halbig²,

Goldfarb³

et al. 2001

Neuropediatrics

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At the age of five years a male child started to develop a progressive rigid spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips, and ankles owing to severe proximal and distal muscle weakness. He had three muscle biopsies from three different muscles at ages 7, 11, and 14 years, respectively. Myopathologically, these muscle tissues contained numerous inclusions which, at the ultrastructural level, turned out to be reducing bodies and cytoplasmic bodies, often in close spatial proximity. Similar histological inclusions, although not further identified by histochemistry and electron microscopy, were seen in his maternal grandmother's biopsied muscle tissue who had developed weakness of the legs and hands after the age of 50 years. The patient's parents were healthy, but the mother's quadriceps muscle showed an increased spectrum of muscle fibre diameters. Our patient, thus, had a neuromuscular disorder, perhaps familial, presenting as a mixed congenital myopathy, i.e., reducing body myopathy with cytoplasmic bodies, of which the morphological lesions could be consistently documented over several years in his different limb muscles. While other mixed congenital myopathies had shown cores and rods, both related to sarcomeres and thus possibly morphogenetically related, cytoplasmic bodies thought to be related to Z-bands and reducing bodies dissimilar to any muscle fibre constituent do not share any common denominator. Therefore, we suggest that this neuromuscular disorder may be a unique mixed congenital myopathy, either sporadic or genetic. In the latter case, the transmission pattern suggested X-linked recessive inheritance, but an autosomal-dominant transmission with variable penetrance could not be ruled out.

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Reducing bodies in distal myopathy with rimmed vacuole formation

Cited by 10 publications

References 7 publications

NOVEL FHL1 MUTATIONS IN FATAL AND BENIGN REDUCING BODY MYOPATHY

NOVEL FHL1 MUTATIONS IN FATAL AND BENIGN REDUCING BODY MYOPATHY

Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1

Reducing Body Myopathy with Cytoplasmic Bodies and Rigid Spine Syndrome: A Mixed Congenital Myopathy

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