Megaconial Congenital Muscular Dystrophy Research Articles

Megaconial congenital muscular dystrophy due to CHKB gene variants, the first report of thirteen Iranian patients

Megaconial congenital muscular dystrophy (OMIM: 602,541) related to CHKB gene mutation is a newly defined rare autosomal recessive disorder, with multisystem involvement presenting from the neonatal period to adolescence. Choline kinase beta, lipid transport enzyme, catalyzes the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, two major components of the mitochondrial membrane, on which respiratory enzyme activities are dependent. CHKB gene variants lead to loss-of-function of choline kinase b and lipid metabolism defects and mitochondrial structural changes. To date, many megaconial congenital muscular dystrophy cases due to CHKB gene variants have been reported worldwide. We describe thirteen Iranian megaconial congenital muscular dystrophy cases related to CHKB gene variants, including clinical presentations, laboratory and muscle biopsy findings, and novel CHKB gene variants. The most common symptoms and signs included intellectual disability, delayed gross-motor developmental milestones, language skills problems, muscle weakness, as well as autistic features, and behavioral problems. Muscle biopsy examination showed the striking finding of peripheral arrangements of large mitochondria in muscle fibers and central sarcoplasmic areas devoid of mitochondria. Eleven different CHKB gene variants including six novel variants were found in our patients. Despite the rarity of this disorder, recognition of the multisystem clinical presentations combined with characteristic findings of muscle histology can properly guide to genetic evaluation of CHKB gene.

Large heterozygous deletion and uniparental disomy masquerading as homozygosity in CHKB gene.

CHKB mutations have been described in 49 patients with megaconial congenital muscular dystrophy, which is a rare autosomal recessive disorder, of which 40 patients showed homozygosity. Peripheral blood genomic DNA samples were extracted from patients and their parents and were tested by whole exome sequencing. Quantitative PCR was performed to detect deletion. Single nucleotide polymorphism analysis was performed to identify uniparental disomy. Quantitative PCR and western blot were used to measure the expression level of CHKB in patient 1-derived immortalized lymphocytes. Mitochondria were observed in lymphocytes by electron microscopy. Two unrelated cases born to non-consanguineous parents were diagnosed with megaconial congenital muscular dystrophy due to apparently homozygous mutations (patient 1: c.225-2A>T; patient 2: c.701C>T) in the CHKB gene using whole exome sequencing. Quantitative PCR revealed that patient 1 had a large deletion encompassing the CHKB gene, inherited from the mother. Single nucleotide polymorphism analysis revealed patient 2 had paternal uniparental isodisomy containing the CHKB gene. In the immortalized lymphocytes from patient 1, decreased expression of CHKB was revealed by quantitative PCR and western blot, and giant mitochondria were observed using electron microscopy. We provide a possibility to detect giant mitochondria in other cells when muscle was not available. Moreover, clinicians should be aware that homozygous variants can be masqueraded by uniparental disomy or large deletions in offspring of non-consanguineous parents, and excessive homozygosity may be misdiagnosed.

Editorial introductions.

Current Opinion in Neurology was launched in 1988. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of neurology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Luis QuerolLuis QuerolLuis Querol (Valencia, 1980) graduated in Medicine at the University of Oviedo, Spain, and completed his residency in Neurology at the Santa Creu i Sant Pau Hospital in Barcelona. In 2009, he joined the group of Prof. Isabel Illa where he developed his doctoral thesis on the role of autoantibodies in immune-mediated neuropathies. In 2012, he worked as an associate researcher in the group of Dr Kevin O’Connor, Department of Neurology, Yale University (USA), where he developed projects related to autoantibodies in multiple sclerosis and myasthenia gravis. He completed his PhD in Medicine at the Universidad Autónoma de Barcelona, Spain, in 2013 thanks to studies that identified anti-contactin antibodies in a specific subgroup of patients with CIDP, in what is the first clinically useful marker detected in CIDP. Since then, he has led the auoimmune neurology clinics at Hospital Sant Pau in Barcelona and has continued a fruitful scientific production in the field of autoantibodies and biomarkers in autoimmune neurological disorders. Ichizo NishinoIchizo NishinoDr Ichizo Nishino, FAAN, FANA, is Director of Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP). He obtained his M.D. in 1989 and Ph.D. in 1998 from Kyoto University, Japan. After five years of training in clinical neurology and six years of research fellowship, including two years at Columbia University, he was appointed to his current position in 2001. By now, he has published more than 600 PubMed-listed papers in the field, including the reports of gene discoveries for MNGIE and Danon disease, and the report of a new muscle disease – megaconial congenital muscular dystrophy (OMIM: 602541) whose causative was also later identified by his own group. His laboratory functions as a nationwide referral center for muscle disease, providing diagnostic analyses for muscle pathology and genetic diagnosis. His lab receives around 80% of muscle biopsies performed in Japan (1103 cases in 2021) and he signs out all cases. As a result, more than 22,000 frozen muscle biopsy samples have been accumulated in his muscle repository, which is one of the largest collections of the patient's muscles. Currently, Dr Nishino is a Visiting Professor at six universities: University of Yamanashi (Japan), Shinshu University (Japan), Kaohsiung Medical University (Taiwan), Fu Jen Catholic University (Taiwan), Peking University First Hospital (China), and Siriraj Hospital Mahidol University (Thailand). He is also serving as President of Asian-Oceanian Myology Center and Executive Board member in several societies including World Muscle Society. Albert LudolphAlbert LudolphAlbert Ludolph is currently Professor of Neurology, Chair and Director of the Department of Neurology, University of Ulm, Ulm, Germany and Speaker of the Site Ulm of the German Center for Neurodegenerative diseses (DZNE, Helmholtz Society). He obtained his M.D. from the University of Mainz, Germany, in 1981 and is a boarded neurologist and psychiatrist (education from University of Münster, Germany). His research focusses on translational work in neurodegenerative diseases; his work is mirrored by more than 600 PubMed-listed papers. His specific focus of interests are motor neuron diseases, Huntington's disease and frontotemporal dementias. The Department of Neurology in Ulm is an international referral center in particular for patients with ALS/MND. In the past his research focused on neurotoxicological and neuropharmacological research in humans, but also non-human primates. He was involved and initiated studies of neurogenetics of ALS, of the epidemiology of the disease (established registers in Southern Germany, Egypt and Mongolia), of the definition of the neuroanatomical sequence of events describing ALS and FTD, the development of biomarkers in ALS and FTD and beyond, and several drug trials, including investigator-initiated interventions. In recent years he tried to define the preclinical period of ALS including the role of the hypothalamus and its metabolic consequences.

Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review

BackgroundCholine 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 presentationWe 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.ConclusionsThis 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.

Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy

Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

The Common miRNA Signatures Associated with Mitochondrial Dysfunction in Different Muscular Dystrophies

Secondary mitochondrial damage in skeletal muscles is a common feature of different neuromuscular disorders, which fall outside the mitochondrial cytopathies. The common cause of mitochondrial dysfunction and structural changes in skeletal muscle tissue remains to be discovered. Although they are associated with different clinical, genetic, and pathologic backgrounds, the pathomechanisms underlying neuromuscular disorders might be attributed to the complex interaction and cross talk between mitochondria and the associated miRNAs. This study aimed to identify the common miRNA signatures that are associated with mitochondrial damage in different muscular dystrophies (MDs; Duchenne muscular dystrophy, megaconial congenital muscular dystrophy, Ullrich congenital muscular dystrophy, and α-dystroglycanopathy). The miRNome profiles of skeletal muscle biopsies acquired from four different MD groups and control individuals were analyzed by miRNA microarray. We identified 17 common up-regulated miRNAs in all of the tested MD groups. A specific bioinformatics approach identified 10 of these miRNAs to be specifically related to the mitochondrial pathways. Six miRNAs, miR-134-5p, miR-199a-5p, miR-382-5p, miR-409-3p, miR-497-5p, and miR-708-5p, were associated with the top four mitochondrial pathways and were thus selected as priority candidates for further validation by quantitative real-time PCR analysis. We demonstrate, for the first time, common up-regulated miRNAs that are associated with mitochondrial damage in different MD groups, therefore contributing to the pathophysiology. Our findings may open a new gate toward therapeutics.

Evidence of involvement of a novel VUS variant in the CHKB gene to congenital muscular dystrophy affection

BackgroundCongenital muscular dystrophies (CMDs) are a group of clinical and genetic heterogeneous neuromuscular disorders with the onset of affection at birth or during infancy. Megaconial congenital muscular dystrophy (MDCMC) is a form of CMDs with the recessive inheritance. The CHKB gene on chromosome 22q13 is the responsible gene for this form of CMDs affection. Methods and resultsIn this study, a pedigree consisted of one affected member with clinical features involving mental retardation, myopathy, paresis and lack of speech was screened. The proband was showing abnormal myopathic and mental symptoms. By using the whole-exome sequencing method for genetic screening for the proband, we detected a homozygous variant in the CHKB gene, at position c.1129C > T (p.Arg377Trp); Chr22(GRCh37):g.51017669G > A. This is the first report of this variant in the scientific literature. This novel variant is classified as a variant with uncertain significance (class 3) according to the recommendations of ACMG. ConclusionThe mentioned variant in the CHKB gene is the candidate for the affected member's medical condition. The previously reported variations in the CHKB gene are also potentially related to the proband's medical condition. Moreover, In-silico analysis of the identified variant by MutationTaster, SIFT, PolyPhen-2, and PROVEAN software predicted that this variant is pathogenic and has damaging effects on the relevant protein function.

Alteration of mitochondrial membrane inner potential in three Italian patients with megaconial congenital muscular dystrophy carrying new mutations in CHKB gene

Congenital Muscular Dystrophies (CMDs) are a heterogeneous group of autosomal recessive disorders presenting at birth with psychomotor delay, cognitive impairment, muscle weakness and hypotonia. Here we described an alteration of mitochondrial inner membrane potential and mitochondrial network in cells derived from Italian patients carrying three novel mutations in CHKB gene, recently associated with “megaconial CMD”. On the bases of our findings, we hypothesize that the mitochondrial membrane potential alteration, presumably as a consequence of the altered biosynthesis of phosphatidylcholine, could be responsible for the peculiar morphological aspect of mitochondria in this disease and might be involved in the disease pathogenesis.

Late-onset megaconial myopathy in mice lacking group I Paks

BackgroundGroup I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase β (Chk β) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKβ are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria.MethodsWe analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase β (Chk β) were analyzed for Pak1/2 phosphorylation.ResultsdKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkβ and are a model for human diseases associated with CHKβ deficiency. Pak1/2 and Chkβ activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis.ConclusionsConditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKβ deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes.

Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses

Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.

G.P.67 - Expanding the pathological phenotype in megaconial congenital muscular dystrophy

G.P.67 - Expanding the pathological phenotype in megaconial congenital muscular dystrophy

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

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).

Exome sequencing identifies a CHKB mutation in Spanish patient with Megaconial Congenital Muscular Dystrophy and mtDNA depletion

BackgroundCholine kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, but never in patients with an additional combined deficiency of complexes I, III and IV and mitochondrial DNA (mtDNA) depletion. AimsTo report mutations in carry genes for MDCMC with respiratory chain defects and mtDNA depletion. MethodsWhole-exome sequencing (WES) was used to identify the carry genes in a Spanish child with muscle weakness, mild hypotonia at lower limb muscles, mildly elevated creatine kinase (CK), enlarged mitochondria in the periphery of the fibers, combined deficiency of complex I, III and IV and depletion of mtDNA. ResultsWith WES data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The first filter of WES data with the nuclear-encoded mitochondrial genes (MitoCarta) did not get any candidate. However, the analysis of whole exome uncovered a homozygous nonsense pathogenic mutation in CHKB gene (NM_005198.4:c.810T>A, p.Tyr270*). ConclusionsOur data confirm the role of CHKB in MDCMC and point to this gene as unique candidate for the combined deficiency of respiratory chain and mtDNA depletion observed in this patient.

Megaconial congenital muscular dystrophy due to loss-of-function mutations in choline kinase β

Recessive mutations in CHKB cause a megaconial congenital muscular dystrophy whose most characteristic feature is mitochondrial enlargement at the periphery of muscle fibers and loss of mitochondria in the center of muscle fibers. This review will summarize clinicopathological features, genetic cause, and biochemical abnormalities of the disease, trying to decipher the mechanism of this complex disorder. Since our report of CHKB mutations found in 15 cases with megaconial congenital muscular dystrophy from Japanese, Turkish, and British populations, we have further identified two British and one French patients. One African-American patient has also been reported by another group. All patients have relatively homogenous phenotype although severity varies to some extent. The peculiar distribution pattern of enlarged mitochondria on muscle section seems to be due to a compensatory mechanism after the elimination of functionally defective mitochondria by mitophagy. CHKB encodes choline kinase β, an enzyme that catalyzes the first de-novo biosynthetic step of phosphatidylcholine, the most abundant phospholipid in the eukaryotic membrane. The identification of a new muscle disease caused by the defect in phospholipid metabolism will pave the way for a novel biological pathway that connects phospholipid metabolism, mitochondria biology, and muscular dystrophy.

Mitochondrial Dysfunction in Neuromuscular Disorders

This review deciphers aspects of mitochondrial (mt) dysfunction among nosologically, pathologically, and genetically diverse diseases of the skeletal muscle, lower motor neuron, and peripheral nerve, which fall outside the traditional realm of mt cytopathies. Special emphasis is given to well-characterized mt abnormalities in collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy), megaconial congenital muscular dystrophy, limb-girdle muscular dystrophy type 2 (calpainopathy), centronuclear myopathies, core myopathies, inflammatory myopathies, spinal muscular atrophy, Charcot-Marie-Tooth neuropathy type 2, and drug-induced peripheral neuropathies. Among inflammatory myopathies, mt abnormalities are more prominent in inclusion body myositis and a subset of polymyositis with mt pathology, both of which are refractory to corticosteroid treatment. Awareness is raised about instances of phenotypic mimicry between cases harboring primary mtDNA depletion, in the context of mtDNA depletion syndrome, and established neuromuscular disorders such as spinal muscular atrophy. A substantial body of experimental work, derived from animal models, attests to a major role of mitochondria (mt) in the early process of muscle degeneration. Common mechanisms of mt-related cell injury include dysregulation of the mt permeability transition pore opening and defective autophagy. The therapeutic use of mt permeability transition pore modifiers holds promise in various neuromuscular disorders, including muscular dystrophies.

P.15.11 Megaconial congenital muscular dystrophy in two children with mutations in the CHKB Gene

Congenital Muscular Dystrophy (CMD) is a clinically and genetically heterogenous group of muscle disorders. Mutations in the gene encoding the beta subunit of choline kinase (CHKB) are associated with a recently described form of CMD characterised by the presence of large and abnormal mitochondria in muscle fibres. Choline kinase is a key enzyme in the synthesis of phosphatidyl choline and phosphatidylethanolamine, two phospholipids that are essential components of biological membranes. We present two children, 9 and 5 years old, with congenital hypotonia, joint hyperlaxity,proximal weakness and cognitive impairment without microcephaly or brain structural changes. Autonomous ambulation started at 2 and 3 years respectively Both patients showed mildly elevated creatine kinase levels (250–400 UI/L). Muscle pathology of both patients was similar showing dystrophic changes, oxidative enzymes staining defects and very large mitochondria distributed at the periphery of the fibre. Electron microscopy performed in one patient confirmed the presence of large mitochondrial with structurally abnormal cristae and inclusions. One patient was homozygous for a frameshift mutation (p.Gln198fs, exon 5) whereas the other patient was heterozygous for a mutation in intron 3 (c.447 + 2t > c) and a missense mutation in exon 9 (p.Arg344Gln). These mutations have not been reported before. This form of CMD must be taken into account in the differential diagnosis of children presenting in the first year of life with muscle weakness, elevated creatine kinase levels and mental retardation and with a characteristic muscle biopsy which shows dystrophic changes in combination with mitochondrial abnormalities.