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 Case presentation We describe a novel proband presenting MCMD due to unpublished CHKB mutations.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.
Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. Aim of our study is to assess if: 1) burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; 2) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); 3) specific clinical features may help identify ALS subtypes which remain localized to site of onset for a prolonged time (regionally entrenching ALS, re-ALS). A single-center, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC scale for muscle strength and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (p = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (p < 0.001) and with reduced survival (p < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (p = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuo-spatial ECAS domains. Individuals with re-ALS were more frequently women (45.6% vs 36.9%; p = 0.028) and had higher frequencies of symmetric disease onset (40.3% vs 19.7%; p < 0.001) and bulbar phenotype (38.5% vs 16.4%; p < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, re-ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.