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 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 Case presentation We describe a novel proband presenting MCMD due to unpublished CHKB mutations.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.

The congenital muscular dystrophies

“…Muscle biopsy shows a distinct pattern: absence of mitochondria in the center of the fibers, but giant mitochondria (megaconia) around (Figure 7). Observing the pattern of multisystem involvement, pathognomonic features in muscle biopsy, increased serum CK, and finding CHKB gene mutation confirms the diagnosis 3,41,42,69–71 …”

“…The phenotype is variable, and the disease is characterized by mild muscle weakness, microcephaly, ID, seizures, hemivertebra, and torticollis, with a mild increase in CK and dystrophic pattern in muscle biopsy. 12,21,41,42 Integrin α9-deficient CMD The integrin α9 subunit is expressed in different cells. Few publications have described mutations in integrin α9, suggesting that it is rare.…”

“…Observing the pattern of multisystem involvement, pathognomonic features in muscle biopsy, increased serum CK, and finding CHKB gene mutation confirms the diagnosis. 3,41,42,[69][70][71] Marinesco-Sjogren syndrome Marinesco-Sjogren syndrome is a multisystem disorder with autosomal recessive inheritance caused by biallelic mutations in SIL1. The disease is characterized by severe mental retardation, early-onset cataracts, findings of cerebellar involvement (cerebellar atrophy, ataxia, wide gait, nystagmus, dysarthria), and myopathy.…”

“…Integrin α7 deficiency ( ITGA7 gene) CMD has been documented in only a few individuals worldwide, including one neonate. The phenotype is variable, and the disease is characterized by mild muscle weakness, microcephaly, ID, seizures, hemivertebra, and torticollis, with a mild increase in CK and dystrophic pattern in muscle biopsy 12,21,41,42 …”

Defects in integrin complex formation promoteCHKB-mediated muscular dystrophy

“…A thought-provoking form of muscular dystrophy is because of autosomal recessive loss of function of the CHKB gene (#602541; OMIM) ( 8 , 9 , 10 ). CHKB -mediated muscular dystrophy is the only defect in the synthesis of a major membrane lipid known to cause a muscular dystrophy ( 9 , 10 , 11 , 12 , 13 ). CHKB encodes choline kinase β, the first enzymatic step in the synthesis of phosphatidylcholine (PC), the most abundant phospholipid in eukaryotic membranes comprising 40–60% of total phospholipid in most eukaryotic cell types ( 14 , 15 , 16 ).…”