Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review
Abstract Background Choline kinase beta (CHKB) catalyzes the first step in the de novo biosynthesis of phosphatidyl choline and phosphatidylethanolamine via the Kennedy pathway. Derangement of this pathway might also influence the homeostasis of mitochondrial membranes. Autosomal recessive CHKB muta...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-09-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13395-022-00306-8 |
| _version_ | 1828167358058856448 |
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| author | Francesca Magri Sara Antognozzi Michela Ripolone Simona Zanotti Laura Napoli Patrizia Ciscato Daniele Velardo Giulietta Scuvera Valeria Nicotra Antonella Giacobbe Donatella Milani Francesco Fortunato Manuela Garbellini Monica Sciacco Stefania Corti Giacomo Pietro Comi Dario Ronchi |
| author_facet | Francesca Magri Sara Antognozzi Michela Ripolone Simona Zanotti Laura Napoli Patrizia Ciscato Daniele Velardo Giulietta Scuvera Valeria Nicotra Antonella Giacobbe Donatella Milani Francesco Fortunato Manuela Garbellini Monica Sciacco Stefania Corti Giacomo Pietro Comi Dario Ronchi |
| author_sort | Francesca Magri |
| collection | DOAJ |
| description | Abstract Background Choline kinase beta (CHKB) catalyzes the first step in the de novo biosynthesis of phosphatidyl choline and phosphatidylethanolamine via the Kennedy pathway. Derangement of this pathway might also influence the homeostasis of mitochondrial membranes. Autosomal recessive CHKB mutations cause a rare form of congenital muscular dystrophy known as megaconial congenital muscular dystrophy (MCMD). Case presentation We describe a novel proband presenting MCMD due to unpublished CHKB mutations. The patient is a 6-year-old boy who came to our attention for cognitive impairment and slowly progressive muscular weakness. He was the first son of non-consanguineous healthy parents from Sri Lanka. Neurological examination showed proximal weakness at four limbs, weak osteotendinous reflexes, Gowers’ maneuver, and waddling gate. Creatine kinase levels were mildly increased. EMG and brain MRI were normal. Left quadriceps skeletal muscle biopsy showed a myopathic pattern with nuclear centralizations and connective tissue increase. Histological and histochemical staining suggested subsarcolemmal localization and dimensional increase of mitochondria. Ultrastructural analysis confirmed the presence of enlarged (“megaconial”) mitochondria. Direct sequencing of CHKB identified two novel defects: the c.1060G > C (p.Gly354Arg) substitution and the c.448-56_29del intronic deletion, segregating from father and mother, respectively. Subcloning of RT-PCR amplicons from patient’s muscle RNA showed that c.448-56_29del results in the partial retention (14 nucleotides) of intron 3, altering physiological splicing and transcript stability. Biochemical studies showed reduced levels of the mitochondrial fission factor DRP1 and the severe impairment of mitochondrial respiratory chain activity in patient’s muscle compared to controls. Conclusions This report expands the molecular findings associated with MCMD and confirms the importance of considering CHKB variants in the differential diagnosis of patients presenting with muscular dystrophy and mental retardation. The clinical outcome of MCMD patients seems to be influenced by CHKB molecular defects. Histological and ultrastructural examination of muscle biopsy directed molecular studies and allowed the identification and characterization of an intronic mutation, usually escaping standard molecular testing. |
| first_indexed | 2024-04-12T02:16:21Z |
| format | Article |
| id | doaj.art-09db868ddfdf4d55970f761e53d08dd4 |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-04-12T02:16:21Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-09db868ddfdf4d55970f761e53d08dd42022-12-22T03:52:15ZengBMCSkeletal Muscle2044-50402022-09-011211910.1186/s13395-022-00306-8Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature reviewFrancesca Magri0Sara Antognozzi1Michela Ripolone2Simona Zanotti3Laura Napoli4Patrizia Ciscato5Daniele Velardo6Giulietta Scuvera7Valeria Nicotra8Antonella Giacobbe9Donatella Milani10Francesco Fortunato11Manuela Garbellini12Monica Sciacco13Stefania Corti14Giacomo Pietro Comi15Dario Ronchi16IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neurology UnitDino Ferrari Center, Department of Pathophysiology and Transplantation, University of MilanIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Medical Genetics Unit, Woman-Child-Newborn DepartmentIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Medical Genetics Unit, Woman-Child-Newborn DepartmentIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neonatal Intensive Care UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neonatal Intensive Care UnitDino Ferrari Center, Department of Pathophysiology and Transplantation, University of MilanIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neurology UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neurology UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neurology UnitIRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Neurology UnitAbstract Background Choline kinase beta (CHKB) catalyzes the first step in the de novo biosynthesis of phosphatidyl choline and phosphatidylethanolamine via the Kennedy pathway. Derangement of this pathway might also influence the homeostasis of mitochondrial membranes. Autosomal recessive CHKB mutations cause a rare form of congenital muscular dystrophy known as megaconial congenital muscular dystrophy (MCMD). Case presentation We describe a novel proband presenting MCMD due to unpublished CHKB mutations. The patient is a 6-year-old boy who came to our attention for cognitive impairment and slowly progressive muscular weakness. He was the first son of non-consanguineous healthy parents from Sri Lanka. Neurological examination showed proximal weakness at four limbs, weak osteotendinous reflexes, Gowers’ maneuver, and waddling gate. Creatine kinase levels were mildly increased. EMG and brain MRI were normal. Left quadriceps skeletal muscle biopsy showed a myopathic pattern with nuclear centralizations and connective tissue increase. Histological and histochemical staining suggested subsarcolemmal localization and dimensional increase of mitochondria. Ultrastructural analysis confirmed the presence of enlarged (“megaconial”) mitochondria. Direct sequencing of CHKB identified two novel defects: the c.1060G > C (p.Gly354Arg) substitution and the c.448-56_29del intronic deletion, segregating from father and mother, respectively. Subcloning of RT-PCR amplicons from patient’s muscle RNA showed that c.448-56_29del results in the partial retention (14 nucleotides) of intron 3, altering physiological splicing and transcript stability. Biochemical studies showed reduced levels of the mitochondrial fission factor DRP1 and the severe impairment of mitochondrial respiratory chain activity in patient’s muscle compared to controls. Conclusions This report expands the molecular findings associated with MCMD and confirms the importance of considering CHKB variants in the differential diagnosis of patients presenting with muscular dystrophy and mental retardation. The clinical outcome of MCMD patients seems to be influenced by CHKB molecular defects. Histological and ultrastructural examination of muscle biopsy directed molecular studies and allowed the identification and characterization of an intronic mutation, usually escaping standard molecular testing.https://doi.org/10.1186/s13395-022-00306-8Choline kinase beta (CHKB)Megaconial congenital muscular dystrophyEnlarged mitochondriaMitochondrial dynamics |
| spellingShingle | Francesca Magri Sara Antognozzi Michela Ripolone Simona Zanotti Laura Napoli Patrizia Ciscato Daniele Velardo Giulietta Scuvera Valeria Nicotra Antonella Giacobbe Donatella Milani Francesco Fortunato Manuela Garbellini Monica Sciacco Stefania Corti Giacomo Pietro Comi Dario Ronchi Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review Skeletal Muscle Choline kinase beta (CHKB) Megaconial congenital muscular dystrophy Enlarged mitochondria Mitochondrial dynamics |
| title | Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review |
| title_full | Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review |
| title_fullStr | Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review |
| title_full_unstemmed | Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review |
| title_short | Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review |
| title_sort | megaconial congenital muscular dystrophy due to novel chkb variants a case report and literature review |
| topic | Choline kinase beta (CHKB) Megaconial congenital muscular dystrophy Enlarged mitochondria Mitochondrial dynamics |
| url | https://doi.org/10.1186/s13395-022-00306-8 |
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