Artikel
A new early-onset myopathy associated with deficiency in kyphoscoliosis peptidase (KY)
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Autoren
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Carola Hedberg-Oldfors
- University of Gothenburg, Dept. of Pathology and Genetics, Gothenburg, Sweden
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Niklas Darin
- University of Gothenburg, Department of Pediatrics, Gothenburg, Sweden
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Mia Olsson Engman
- Blekinge Hospital, Pediatric Clinic, Karlskrona, Sweden
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Zacharias Orfanos
- University of Bonn, Department of Molecular Cell Biology, Bonn, Germany
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Peter F.M. van der Ven
- University of Bonn, Department of Molecular Cell Biology, Bonn, Germany
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Anders Oldfors
- University of Gothenburg, Dept. of Pathology and Genetics, Gothenburg, Sweden
| Veröffentlicht: | 14. September 2016 |
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Gliederung
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Introduction: A neuromuscular disorder caused by a homozygous variant in the kyphoscoliosis peptidase gene (Ky) was first described in a mouse model (ky/ky). In this model, kyphoscoliosis develops due to atrophy of postural muscles during postnatal growth. The muscle phenotype of the ky/ky was morphologically characterized by muscle fiber regeneration, necrosis and internally located nuclei.
Objectivs: To define a new early-onset myopathy due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase (KY) in a child.
Patients & Methods: We investigated a 7.5-year-old girl with walking difficulties from two years of age who presented with generalized muscle weakness; mild contractures in the shoulders, hips, and feet; cavus feet; and lordosis but no scoliosis. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Muscle pathology and whole-exome sequencing were performed to identify the pathogenic mutation. Further immunofluorescence microscopy and RT-PCR were performed to investigate the role of possible KY deficiency in or patient.
Results: Muscle biopsy showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and occasional small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel revealed that KY is predominantly expressed in skeletal muscle in humans. Immunofluorescence microscopy demonstrated abnormal distribution of Xin and the Ky-binding partner filamin C in the muscle fibers of our patient.
Conclusion: We describe the first human case of a disease associated with KY inactivation. As in the mouse model, the affected child showed myopathy and muscle weakness – but in contrast, no kyphoscoliosis at age 7.5 years. The abnormal distribution of Xin and filamin C in the muscle fibers was highly similar to their altered localization in the ky/ky mouse muscle fibers. Finding of other individuals affected by KY inactivation and following them for a longer period will help to clarify the natural course of the disease and the phenotypic variability.
