Clinical characteristics of megaconial congenital muscular dystrophy due to choline kinase beta gene defects in a series of 15 patients

Abstract

A new form of congenital muscular dystrophy (CMD) with multisystem involvement and characteristic mitochondrial structural changes, due to choline kinase beta (CHKB) gene defects has been characterized by intellectual disability, autistic features, ichthyosis-like skin changes, and dilated cardiomyopathy. We define the clinical characteristics in 15 patients, from 14 unrelated families with so-called 'megaconial CMD', all having mutations in CHKB. Core clinical phenotype included global developmental delay prominent in gross-motor and language domains, severe intellectual disability (ID), and/or muscle weakness in all cases. Muscle biopsies were equivocally 'megaconial' in all. Other peculiarities were: ichthyosis-like skin changes (n = 11), increased serum CK levels (n = 12), microcephaly (n = 6), dysmorphic facial features (n = 7), neonatal hypotonia (n = 3), seizures (n = 3), epileptiform activity without clinically overt seizures (n = 2), dilated cardiomyopathy (n = 2), decreased left ventricular systolic function (n = 2), congenital heart defects (n = 3), sensorineural (n = 1), and conductive hearing loss (n = 1). Ten patients had cranial neuroimaging (MRI-MRS) study, which was notably normal in all, other than one patient having a decreased choline: creatine peak. Intra-familial variability in clinical expression of the disease is noted in four families. Two siblings from the same family, one presenting with global developmental delay and dilated cardiomyopathy, and the other with ichthyosis, ID and proximal weakness without cardiomyopathy died at the ages of 2 years 1 month, and 7 years 4 months respectively. Evolution was progressive (n = 13) and static (n = 2).

Heart Disease in Disorders of Muscle, Neuromuscular Transmission, and the Nerves

“…CI has been reported in various types of CMD. Cardiac involvement, in particular, appears to occur in patients carrying mutations in the LMNA (arrhythmias, dCMP), 72) COL6A (dCMP, systolic dysfunction requiring HTX), 73) 74) POMT1 (aortic root ectasia, systolic dysfunction), 75) CHKB (dCMP, systolic dysfunction, congenital heart defects), 76) and LAMA2 (dCMP) 77) 78) genes. Additionally, CI has been reported in patients with Fukuyama congenital muscular dystrophy (dCMP, systolic dysfunction) due to FKTN mutations, 79) congenital muscular dystrophy with alpha-dystroglycan deficiency (dCMP, CCDs, mitral regurgitation), 80) and in merosin-positive congenital muscular dystrophy (systolic and diastolic dysfunction).…”

Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

“…In those cases, ichthyosis in proximal areas with fine scaling was suggested as an important clue to the diagnosis. The largest megaconial CMD patient series by Haliloglu et al demonstrated that ichthyosis-like changes was the most frequent (11/15) skin change in megaconial CMD [ 8 ]. Nummular eczema, which is shown in the elder sister of our patients, has not been described before and the symptoms improved after topical corticosteroid therapy.…”

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

“…Differential expression patterns [116,117], mitochondrial activity [118], and neuromuscular junctions [119] are all effects of ChoKβ deficiency in mice. Inactivating mutations in the CHKB gene have been linked to human muscular dystrophy and myopathy in several recent studies [11,[120][121][122][123][124][125][126][127][128]. Since a lack of ChoKβ activity causes muscular dystrophy, any intervention that restores ChoKβ activity can help to restore normal muscle development in this pathological situation.…”