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Central core disease.

Jungbluth H - Orphanet J Rare Dis (2007)

Bottom Line: Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis.Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment.In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Evelina Children's Hospital, Department of Paediatric Neurology, St. Thomas' Hospital, London, UK. Heinz.Jungbluth@gstt.nhs.uk

ABSTRACT
Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

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* Muscle involvement in the lower limbs in CCD secondary to dominant RYR1 mutations: T1-weighted MR imaging, transverse sections of the proximal thigh (A-C) and the proximal lower leg (D-F) in an eleven (A) and a thirteen year old boy (B,E), and a twelve (C,F) and seventeen year old girl (D). In the thigh (A-C), there is marked increase in abnormal signal within vasti, sartorius and adductor magnus with relative sparing of rectus femoris, adductor longus, gracilis and semitendinosus. In the lower leg, there is increase in abnormal signal in soleus (D-F), and – in more severe cases (E-F) – peroneal group and gastrocnemius medialis. Tibialis anterior and gastrocnemius lateralis are relatively spared. (VL = vastus lateralis, VI = vastus intermedius, VM = vastus medialis, RF = rectus femoris, AL = adductor longus, AM = adductor magnus, S = sartorius, G = gracilis, St = semitendinosus). * Reprinted from Neuromuscul Disord 2004, 14: Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA, Bydder G, Muntoni F. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Pages: 785–790. Copyright Owner Elsevier, Copyright (2004), with permission from Elsevier".
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Figure 2: * Muscle involvement in the lower limbs in CCD secondary to dominant RYR1 mutations: T1-weighted MR imaging, transverse sections of the proximal thigh (A-C) and the proximal lower leg (D-F) in an eleven (A) and a thirteen year old boy (B,E), and a twelve (C,F) and seventeen year old girl (D). In the thigh (A-C), there is marked increase in abnormal signal within vasti, sartorius and adductor magnus with relative sparing of rectus femoris, adductor longus, gracilis and semitendinosus. In the lower leg, there is increase in abnormal signal in soleus (D-F), and – in more severe cases (E-F) – peroneal group and gastrocnemius medialis. Tibialis anterior and gastrocnemius lateralis are relatively spared. (VL = vastus lateralis, VI = vastus intermedius, VM = vastus medialis, RF = rectus femoris, AL = adductor longus, AM = adductor magnus, S = sartorius, G = gracilis, St = semitendinosus). * Reprinted from Neuromuscul Disord 2004, 14: Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA, Bydder G, Muntoni F. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Pages: 785–790. Copyright Owner Elsevier, Copyright (2004), with permission from Elsevier".

Mentions: In cases with equivocal histopathological features, muscle MR imaging may complement clinical assessment and indicate involvement of the RYR1 gene, as RYR1 C-terminal mutations may be associated with a consistent pattern of selective muscle involvement [35] (Figure 2) distinct from that observed in other congenital myopathies such as nemaline myopathy [34].


Central core disease.

Jungbluth H - Orphanet J Rare Dis (2007)

* Muscle involvement in the lower limbs in CCD secondary to dominant RYR1 mutations: T1-weighted MR imaging, transverse sections of the proximal thigh (A-C) and the proximal lower leg (D-F) in an eleven (A) and a thirteen year old boy (B,E), and a twelve (C,F) and seventeen year old girl (D). In the thigh (A-C), there is marked increase in abnormal signal within vasti, sartorius and adductor magnus with relative sparing of rectus femoris, adductor longus, gracilis and semitendinosus. In the lower leg, there is increase in abnormal signal in soleus (D-F), and – in more severe cases (E-F) – peroneal group and gastrocnemius medialis. Tibialis anterior and gastrocnemius lateralis are relatively spared. (VL = vastus lateralis, VI = vastus intermedius, VM = vastus medialis, RF = rectus femoris, AL = adductor longus, AM = adductor magnus, S = sartorius, G = gracilis, St = semitendinosus). * Reprinted from Neuromuscul Disord 2004, 14: Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA, Bydder G, Muntoni F. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Pages: 785–790. Copyright Owner Elsevier, Copyright (2004), with permission from Elsevier".
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1887524&req=5

Figure 2: * Muscle involvement in the lower limbs in CCD secondary to dominant RYR1 mutations: T1-weighted MR imaging, transverse sections of the proximal thigh (A-C) and the proximal lower leg (D-F) in an eleven (A) and a thirteen year old boy (B,E), and a twelve (C,F) and seventeen year old girl (D). In the thigh (A-C), there is marked increase in abnormal signal within vasti, sartorius and adductor magnus with relative sparing of rectus femoris, adductor longus, gracilis and semitendinosus. In the lower leg, there is increase in abnormal signal in soleus (D-F), and – in more severe cases (E-F) – peroneal group and gastrocnemius medialis. Tibialis anterior and gastrocnemius lateralis are relatively spared. (VL = vastus lateralis, VI = vastus intermedius, VM = vastus medialis, RF = rectus femoris, AL = adductor longus, AM = adductor magnus, S = sartorius, G = gracilis, St = semitendinosus). * Reprinted from Neuromuscul Disord 2004, 14: Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA, Bydder G, Muntoni F. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Pages: 785–790. Copyright Owner Elsevier, Copyright (2004), with permission from Elsevier".
Mentions: In cases with equivocal histopathological features, muscle MR imaging may complement clinical assessment and indicate involvement of the RYR1 gene, as RYR1 C-terminal mutations may be associated with a consistent pattern of selective muscle involvement [35] (Figure 2) distinct from that observed in other congenital myopathies such as nemaline myopathy [34].

Bottom Line: Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis.Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment.In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Evelina Children's Hospital, Department of Paediatric Neurology, St. Thomas' Hospital, London, UK. Heinz.Jungbluth@gstt.nhs.uk

ABSTRACT
Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

Show MeSH
Related in: MedlinePlus