Muscular dystrophy with large mitochondria associated with mutations in the CHKB gene in three British patients: Extending the clinical and pathological phenotype

Quinlivan, R.; Mitsuahashi, S.; Sewry, Caroline A.; Çırak, Sebahattin; Aoyama, Chieko; Mooore, David; Abbs, Stephen; Robb, Stephanie; Newton, Tina; Moss, Celia; Birchall, Daniel; Sugimoto, Hiroyuki; Bushby, Kate; Guglieri, Michela; Muntoni, Francesco; Nishino, Ichizo; Straub, Volker

doi:10.1016/j.nmd.2013.04.002

Cited by 35 publications

(24 citation statements)

References 11 publications

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“…A recent study has established that the forelimb deformity in CHKB-deficient mice is due to altered growth plate physiology in the embryo, implicating a role for CHKB in endochondral bone formation (42). Homozygous and compound heterozygous mutations in CHKB have been identified in patients with congenital muscular dystrophy (17)(18)(19)43).…”

Section: Discussionmentioning

confidence: 99%

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Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass

Kular¹,

Tickner²,

Pavlos

et al. 2015

Journal of Biological Chemistry

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Background: Bone homeostasis requires constant remodeling by bone-resorbing osteoclasts and bone-forming osteoblasts. Results: Choline kinase ␤ (CHKB)-deficient mice have reduced bone mass, increased osteoclast number, and impaired osteoblast function. Conclusion: CHKB activity controls bone homeostasis via regulation of osteoclasts and osteoblasts. Significance: This is the first report implicating a role for CHKB in bone homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…Deletion of Chka is embryonically lethal in mice attesting to its fundamental role in embryonic development (15), whereas loss of Chkb results in severe rostrocaudal muscular dystrophy in skeletal muscle and bone deformity at the forelimb (16). Recent studies have identified a subset of human muscular dystrophy patients with CHKB mutations (17)(18)(19).…”

mentioning

confidence: 99%

Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass

Kular¹,

Tickner²,

Pavlos

et al. 2015

Journal of Biological Chemistry

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“…A recent report described loss of ambulation in 1 patient after an episode of acute pancreatitis and another patient who had transient loss of leg movement after vaccination, frequent falls after an episode of chicken pox, and severe deterioration of cardiac function after undergoing general anesthesia, resulting in death. 5 The investigators considered that intercurrent infections, vaccination, or anesthesia may deteriorate muscle and cardiac function, but that more data were needed to confirm the association. Our patient experienced transient episodes of generalized worsening of muscle weakness during intercurrent illnesses, which confirms the suggested association.…”

Section: Discussionmentioning

confidence: 99%

“…The characteristic enlarged mitochondria at the periphery of the muscle fibers have given rise to the name megaconial myopathy . Only 4 other cases of CHKB muscular dystrophy have been reported, after the description of the causative gene in 2011 …”

mentioning

confidence: 99%

Novel CHKB mutation expands the megaconial muscular dystrophy phenotype

et al. 2014

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“…It is also possible, as demonstrated by the presence of mitochondrial alteration in the mouse model and in the muscle of a patient with PKAN, that mitochondria play a relevant role or could be a concurrent cause in the pathogenic mechanism of the disease. Interestingly, the presence of giant mitochondria in muscle, although with slight morphological differences, resembles the picture present in another human disorder caused by mutations in the CHKB gene and mainly characterized by muscular dystrophy and mental retardation (Quinlivan et al , 2013). CHKB encodes an enzyme catalysing the first step in de novo phosphatidylcholine synthesis (Mitsuhashi et al , 2013).…”

Section: Discussionmentioning

confidence: 57%

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

Brunetti¹,

Dusi²,

Giordano

et al. 2013

Brain

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Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/−) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2−/− mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.

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Muscular dystrophy with large mitochondria associated with mutations in the CHKB gene in three British patients: Extending the clinical and pathological phenotype

Cited by 35 publications

References 11 publications

Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass

Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass

Novel CHKB mutation expands the megaconial muscular dystrophy phenotype

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

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