Ieke Ginjaar - Academia.edu (original) (raw)

Papers by Ieke Ginjaar

Movement Disorders, Jan 30, 2012

Hyperekplexia (HPX) or startle disease is a rare neurological disease characterized by excessive ... more Hyperekplexia (HPX) or startle disease is a rare neurological disease characterized by excessive startle reactions to unexpected stimuli, followed by short periods of generalized stiffness. At examination, a positive head retraction reflex (HRR) is considered a hallmark of HPX. 1 Clonazepam is the treatment of choice. 2 The alpha1 subunit of the glycine receptor (GLRA1) is the main gene for HPX. 2 We present a HPX family with a new autosomal recessive mutation in the GLRA1 gene and intrafamilial heterogeneity of symptoms. Case Legends to the Video Video 1. The video shows, in subsequent order, the head retraction reflex of the index patient, the twin sisters, the oldest sister, and the mother.

Journal of Aapos, Oct 1, 2009

To the Editor: Nondystrophic myotonia (NDM) is a group of skeletal muscle disorders characterized... more To the Editor: Nondystrophic myotonia (NDM) is a group of skeletal muscle disorders characterized by persistent muscle contraction after voluntary contraction. These disorders are caused by mutations in the genes encoding the sodium (SCN4A) and chloride (CLCN1) ion channels involved in the action potential of the T-tubules of skeletal muscle. Before the advent of DNA sequencing, NDMs were differentiated based on clinical phenotypes that had been loosely matched to a specific ion channel. NDM caused by mutations in the CLCN1 gene cause both Thomsen (autosomal-dominant) and Becker (autosomal-recessive) myotonia congenita. These chloride ion channelopathies present with myotonia associated with muscle hypertrophy and display a characteristic ‘‘warm-up phenomenon.’’ This description refers to diminishing myotonia with repetitive muscle use and can be demonstrated electromyographically with a characteristic ‘‘dive-bomb’’ drop in myotonic activity on audible EMG. This feature has been considered to be a unique diagnostic feature of chloride channel myotonia. Mutations in the SCN4A gene cause a wide range of phenotypes: some characterized by periodic paralysis with or without myotonia, others associated with pure myotonia or paradoxic myotonia (myotonia after a warm-up period). Sodium channel myotonias are generally subdivided into three clinical categories: paramyotonia congenita, potassium aggravated myotonia, and hyperkalemic periodic paralysis. We previously reported extraocular muscle hypertrophy and myotonia, in addition to eyelid myotonia, in a father and son with the clinical diagnosis of Thomsen myotonia congenita. The diagnosis was based on the following: the typical phenotype of congenital myotonia, skeletal muscle hypertrophy, warm-up phenomenon demonstrated both clinically and electromyographically, and a dominant pattern of inheritance in the family. Sequencing of the 23 exons of the CLCN1 gene in the son (proband) did not reveal any pathological mutation. The lack of a mutation in the CLCN1 gene has been reported to occur in 40%70% of individuals with clinically diagnosed myotonia congenita (CLCN1). Undiscovered intron or promoter region mutations have been postulated as the cause of chloride channel dysfunction in these patients. More recently, however, genotype-phenotype mismatches between sodium and chloride ion channelopathies have been reported, and some SCN4A mutations have been shown to display a warm-up effect. In one study, published while ours was in press, patients with a clinical diagnosis of Thomsen or Becker myotonia were screened for mutations in both CLCN1 and SCN4A. Approximately 20% of cases were found to have no CLCN1 mutation. These patients were subsequently screened and 100% were instead found to have a SCN4A mutation, proving that sodium channelopathies can mimic the warm-up phenomenon seen with chloride channelopathies. In light of these new developments, the proband in our original report was reinvestigated and confirmed to have a missense mutation in the SCN4A gene (V445 M) known to cause myotonia. While the clinical diagnosis in our family was appropriately based on the criteria at the time, these new findings indicate that they do not in fact have Thomsen myotonia and perhaps the title should have read, more accurately, ‘‘Extraocular muscle hypertrophy in a patient with myotonia and a mutation in the SCN4A gene (V445 M).’’ Studies have been undertaken to better define the clinical phenotypes of NMDs based on channel and specific genotype. Eyelid myotonia is recognized in NMDs and has recently been shown to be more common and more severe in sodium channel myotonia than chloride channel myotonia (as seen in our patients) and may be an important differentiating feature to guide clinicians in determining which gene to sequence. To date, no studies link extraocular muscle involvement or strabismus to any specific genotype or ion channel. Further studies that determine the frequency and severity of extraocular muscle involvement in these patients, and correlate these findings with specific genotypes, may assist clinicians in investigating these conditions with molecular genetic techniques.

Algorithms for Molecular Biology, 2013

Background Proteins are known to be dynamic in nature, changing from one conformation to another ... more Background Proteins are known to be dynamic in nature, changing from one conformation to another while performing vital cellular tasks. It is important to understand these movements in order to better understand protein function. At the same time, experimental techniques provide us with only single snapshots of the whole ensemble of available conformations. Computational protein morphing provides a visualization of a protein structure transitioning from one conformation to another by producing a series of intermediate conformations. Results We present a novel, efficient morphing algorithm, Morph-Pro based on linear interpolation. We also show that apart from visualization, morphing can be used to provide plausible intermediate structures. We test this by using the intermediate structures of a c-Jun N-terminal kinase (JNK1) conformational change in a virtual docking experiment. The structures are shown to dock with higher score to known JNK1-binding ligands than structures solved usi...

Human Molecular Genetics, Jul 1, 2001

Due to frame-shifting mutations in the DMD gene that cause dystrophin deficiency, Duchenne muscul... more Due to frame-shifting mutations in the DMD gene that cause dystrophin deficiency, Duchenne muscular dystrophy (DMD) patients suffer from lethal muscle degeneration. In contrast, mutations in the allelic Becker muscular dystrophy (BMD) do not disrupt the translational reading frame, resulting in a less severe phenotype. In this study, we explored a genetic therapy aimed at restoring the reading frame in muscle cells from DMD patients through targeted modulation of dystrophin pre-mRNA splicing. Considering that exon 45 is the single most frequently deleted exon in DMD, whereas exon (45+46) deletions cause only a mild form of BMD, we set up an antisense-based system to induce exon 46 skipping from the transcript in cultured myotubes of both mouse and human origin. In myotube cultures from two unrelated DMD patients carrying an exon 45 deletion, the induced skipping of exon 46 in only ∼15% of the mRNA led to normal amounts of properly localized dystrophin in at least 75% of myotubes. Our results provide first evidence of highly effective restoration of dystrophin expression from the endogenous gene in DMD patient-derived muscle cells. This strategy may be applicable to not only >65% of DMD mutations, but also many other genetic diseases.

Neuromuscular Disorders, Oct 1, 2008

Neuromuscular Disorders, Oct 1, 2016

Neurology, Apr 22, 2012

Objective: To perform Anoctamin 5 (ANO) mutation analysis, neurological and cardiological examina... more Objective: To perform Anoctamin 5 (ANO) mutation analysis, neurological and cardiological examination in the genetically undiagnosed remainder of the Dutch limb girdle muscular dystrophy (LGMD) cohort encompassing 105 patients from 68 families and in a proportion of a cohort of 22 patients from 16 families with a Miyoshi-type muscular dystrophy (MMD) in which no dysferlin mutations were found. Background ANO 5 mutations have recently been found to cause LGMD2L, MMD3 and asymptomatic hyperCKemia. Design/Methods: Neurological examination, cardiological investigations (i.e. electrocardiography, Holter monitoring, echocardiography), serum creatine kinase (sCK) activity assessments and ANO 5 mutation analysis were performed in LGMD and MMD patients. Results: 32 LGMD index patients and 12 MMD3 patients from 8 kindreds were examined. ANO 5 mutations were found in 13 sporadic LGMD cases (8 males). Age at onset ranged from 21-57 years, age at examination from 26-69. Symmetrical proximal leg muscle weakness had been the first manifestation. Rhabdomyolysis attacks were mentioned in one patient, and three had cardiological abnormalities, including intraventricular septum thickening (2) and hypertrophic cardiomyopathy (1). SCK was 10-25 times the upper limit of normal (ULN). In 8 patients (all male) from 6 MMD families mutations were identified. Age at onset ranged from 18-51 years and age at examination from 30-67. Uni- or bilateral calf muscle weakness had been the presenting symptom in 7 patients and one had been asymptomatic at time of diagnosis. SCK was 20-40 times ULN. None had associated symptoms and cardiological examination was normal. Exon 5 c.191dupA was the most frequently observed mutation and in addition novel mutations were identified. Conclusions: 1. LGMD 2L is found in 16% of the Dutch LGMD families and MMD3 in 40% of the MMD families.2. In three LGMD2L patients heart involvement was found and in none of the MMD3 patients. Disclosure: Dr. De Visser has received research support from Biogen Idec. Dr. van der Kooi has received research support from Biogen Idec. Dr. Linssen has nothing to disclose. Dr. Ginjaar has nothing to disclose. Dr. Wokke has received research support from Genzyme Corporation. Dr. van Doorn has received personal compensation for activities with Talecris, ZLB, Baxter, and Octapharma. Dr. van Doorn has received research support from Baxter.

Neuromuscular Disorders, Jun 1, 1999

X-linked Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the emerin gene. Since... more X-linked Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the emerin gene. Since the emerin gene is ubiquitously expressed and since all EMD mutations published so far should be detectable by an RNA-based mutation assay, we have designed a protein truncation test for emerin. To facilitate the detection of mutations in the translation initiation site, reported for several EMD-cases, the standard tailed forward PTT-primer had to be modified. The effectiveness of the assay was established by a mutation scan in four EMD-patients. Two patients could be shown to carry emerin mutations, one affecting the ATG translation initiation codon. The PTT-assay did not detect a mutation in the two other patients. Since an immunohistochemical analysis of patient-derived cells revealed normal emerin levels, these patients are thus affected by another muscular dystrophy, most likely autosomal dominant EMD.

Humana Press eBooks, Feb 17, 2004

The aim of this study was to determine the response to an oral glucose tolerance test (OGTT) in a... more The aim of this study was to determine the response to an oral glucose tolerance test (OGTT) in adult males with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD), and to investigate whether body composition contributes to any variance in the glucose response. Twenty-eight adult males with dystrophinopathy (BMD, n = 13; DMD, n = 15) and 12 non-dystrophic controls, ingested 75 g oral anhydrous glucose solution. Fingertip capillary samples were assessed for glucose at 30-min intervals over 2-h post glucose ingestion. Fat free mass relative to body mass (FFM/BM) and body fat (BF%) was assessed using bioelectrical impedance. Vastus lateralis muscle anatomical cross sectional area (VL ACSA) was measured using B-mode ultrasonography. Blood glucose was higher in MD groups than control at 60, 90 and 120 min post ingestion of glucose. Compared to controls, FFM/BM and VL ACSA were lower in MD groups compared to controls (p < 0.001). Glucose tolerance values at 120 min were correlated with FFM/BM and BF% in the BMD group only. Our results suggest that glucose tolerance is impaired following OGTT in adult males with BMD and DMD. It is recommended that adults with BMD and DMD undertake routine glucose tolerance assessments to allow early detection of impaired glucose tolerance.

Clinical Genetics, May 6, 2019

Limb girdle muscular dystrophies ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor ... more Limb girdle muscular dystrophies ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 23 oktober 2020, te 13.00 uur door Leroy ten Dam geboren te Dordrecht

Neuromuscular Disorders, Jun 1, 2013

LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in AN... more LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies. Limb-girdle muscular dystrophies (LGMD) form a group of inherited myopathies showing progressive limb-girdle weakness with sparing of the facial and distal muscles. According to the inheritance mode, LGMD is classified into two general categories: autosomal dominant (LGMD1) and autosomal recessive (LGMD2) forms. So far, 33 genes have been associated with the disease, nine dominant and 26 recessive 1-3. Molecular pathophysiology and therefore clinical phenotypes of the LGMDs are highly heterogeneous as the mechanisms of disease include defects in numerous proteins 1,4. The observation that mutations within the same gene could be associated with variable phenotypes was made for numerous LGMD associated genes, including desmin and dysferlin 1,4-8. It is noteworthy that variable symptoms are often observed even within a family with the same causative mutation, indicating that a primary pathogenic variant combined with potentially modifying variants may exacerbate or mitigate the phenotype (for example 9). The LGMD2L subtype is associated with mutations in the anoctamin-5 gene (ANO5). ANO5 is localized to chr11p14.3, spans 90,192 bp and contains 22 exons. The gene encodes anoctamin-5 (ANO5), a ~100-kDa protein composed of 913 amino acids, containing eight transmembrane domains 10,11. The protein belongs to a family of

Journal of Medical Genetics, Sep 1, 1993

This report is the second part of a trilogy from a multidisciplinary study which was undertaken t... more This report is the second part of a trilogy from a multidisciplinary study which was undertaken to record the relationships between clinical severity and dystrophin gene and protein expression. The aim in part 2 was to correlate the effect of gene deletions on protein expression in individual patients with well defined clinical phenotypes. Among the DMD patients, most of the deletions/duplications disrupted the open reading frame, but three patients had in frame deletions. Some of the intermediate D/BMD patients had mutations which were

Journal of Medical Genetics, Sep 1, 1993

This multidisciplinary study was undertaken to record the variation in gene and protein expressio... more This multidisciplinary study was undertaken to record the variation in gene and protein expression in a large cohort of patients with well defined clinical phenotypes. The patients, whose ages ranged from 4 years to 66 years, spanned a wide range of disease severity. They represented the first 100 patients who had been examined in Newcastle, had undergone a muscle biopsy, and provided a blood sample for DNA analysis. The study had three aims: to observe any trends in the analyses across the clinical groups, to correlate gene and protein expression in individual patients, and to use the data collected to assess the relative usefulness of different techniques in the diagnosis and prognosis of patients with Duchenne and Becker dystrophy (DMD/BMD). In on February 22, 2022 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmg.30.9.728 on 1 September 1993. Downloaded from * = Predicted dystrophin sizes for patients with frameshifting deletions are calculated so [A] = size to premature stop codon, and [B] = size if reading frame immediately restored (see part 2).-= data not available. ? or parentheses = data not certain. dup = exons duplicated rather than deleted. J = junctional fragment. ICC = immunocytochemistry. V,P, = verbal IQ, performance IQ. ESN = classified as educationally subnormal. Patients F58 and F59, and patients F67 and F94 are related.

Neuromuscular Disorders, Oct 1, 2008

Journal of Medical Genetics, Oct 1, 1997

Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystroph... more Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% ofpatients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a non-quantitative test method. Detection of microlesions in Duchenne and Becker muscular dystrophy is currently under way. Single strand conformational analysis, heteroduplex analysis, and the protein truncation test are mostly used for this purpose. In this paper we review the available methods for detection of large and small mutations in patients and in carriers and propose a systematic approach for genetic analysis and genetic counselling of DMD and BMD families, including prenatal and preimplantation diagnosis.

Journal of neuromuscular diseases, Mar 2, 2021

Background:A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patient... more Background:A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patients from 68 families has been subject to genetic testing over the last 20 years. After subsequent targeted gene analysis around two thirds (45/68) of the families had received a genetic diagnosis in 2013.Objective:To describe the results of further genetic testing in the remaining undiagnosed limb girdle muscular dystrophy families in this cohort.Methods:In the families of the cohort for whom no genetic diagnosis was established (n = 23) further testing using Sanger sequencing, next generation sequencing with gene panel analysis or whole-exome sequencing was performed. In one case DNA analysis for facioscapulohumeral dystrophy type 1 was carried out.Results:In eight families no additional genetic tests could be performed. In 12 of the remaining 15 families in which additional testing could be performed a genetic diagnosis was established: two LGMDR1 calpain3-related families with CAPN3 mutations, one LGMDR2 dysferlin-related family with DYSF mutations, three sarcoglycanopathy families (LGMDR3-5 α-, β- and γ-sarcoglycan-related) with SGCA/SGCB/SGCG mutations, one LGMDR8 TRIM 32-related family with TRIM32 mutations, two LGMDR19 GMPPB-related families with GMPPB mutations, one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1. At this moment a genetic diagnosis has been made in 57 of the 60 families of which DNA was available (95%).Conclusion:A genetic diagnosis is obtained in 95% of the families of the original Dutch LGMD cohort of which DNA was available.

Annals of Neurology, 2014

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD g... more Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative magnetic resonance (MR) imaging to study brain microstructure in DMD. T1-weighted and diffusion tensor images were obtained on a 3T MR scanner from 30 patients and 22 age-matched controls (age = 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and diffusion tensor imaging parameters were made between DMD patients and controls, and between 2 DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140(+) and DMD_Dp140(-) ). DMD patients had smaller total brain volume, smaller gray matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140(-) subjects contributed most to the gray matter volume differences and performed worse on information processing. Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.

Journal of Medical Genetics, Dec 1, 1992

Among 85 patients with Duchenne and Becker muscular dystrophy, 29 were found to have mutations wh... more Among 85 patients with Duchenne and Becker muscular dystrophy, 29 were found to have mutations which disrupted the open reading frame for dystrophin. Thus any dystrophin detected in this group of patients should consist of the severely truncated polypeptides that represent prematurely terminated translation products. Dystrophin was detected in blots from 17/29 biopsies and the observed sizes of the polypeptides were compared with predicted sizes calculated in two ways: if translation was terminated at the stop codon generated by each frameshifting deletion, and if the reading frame was restored and translation proceeded. In every case the observed size matched the size predicted on the basis of a restored reading frame. This was in accord with immunocytochemical labelling of scattered dystrophin positive fibres which were found on serial sections labelled with antibodies to both the rod and C-terminal domains. Thus analysis at the protein level supports genetic evidence of exon skipping as a mechanism which restores frameshifting mutations in some fibres.

Movement Disorders, Jan 30, 2012

Hyperekplexia (HPX) or startle disease is a rare neurological disease characterized by excessive ... more Hyperekplexia (HPX) or startle disease is a rare neurological disease characterized by excessive startle reactions to unexpected stimuli, followed by short periods of generalized stiffness. At examination, a positive head retraction reflex (HRR) is considered a hallmark of HPX. 1 Clonazepam is the treatment of choice. 2 The alpha1 subunit of the glycine receptor (GLRA1) is the main gene for HPX. 2 We present a HPX family with a new autosomal recessive mutation in the GLRA1 gene and intrafamilial heterogeneity of symptoms. Case Legends to the Video Video 1. The video shows, in subsequent order, the head retraction reflex of the index patient, the twin sisters, the oldest sister, and the mother.

Journal of Aapos, Oct 1, 2009

To the Editor: Nondystrophic myotonia (NDM) is a group of skeletal muscle disorders characterized... more To the Editor: Nondystrophic myotonia (NDM) is a group of skeletal muscle disorders characterized by persistent muscle contraction after voluntary contraction. These disorders are caused by mutations in the genes encoding the sodium (SCN4A) and chloride (CLCN1) ion channels involved in the action potential of the T-tubules of skeletal muscle. Before the advent of DNA sequencing, NDMs were differentiated based on clinical phenotypes that had been loosely matched to a specific ion channel. NDM caused by mutations in the CLCN1 gene cause both Thomsen (autosomal-dominant) and Becker (autosomal-recessive) myotonia congenita. These chloride ion channelopathies present with myotonia associated with muscle hypertrophy and display a characteristic ‘‘warm-up phenomenon.’’ This description refers to diminishing myotonia with repetitive muscle use and can be demonstrated electromyographically with a characteristic ‘‘dive-bomb’’ drop in myotonic activity on audible EMG. This feature has been considered to be a unique diagnostic feature of chloride channel myotonia. Mutations in the SCN4A gene cause a wide range of phenotypes: some characterized by periodic paralysis with or without myotonia, others associated with pure myotonia or paradoxic myotonia (myotonia after a warm-up period). Sodium channel myotonias are generally subdivided into three clinical categories: paramyotonia congenita, potassium aggravated myotonia, and hyperkalemic periodic paralysis. We previously reported extraocular muscle hypertrophy and myotonia, in addition to eyelid myotonia, in a father and son with the clinical diagnosis of Thomsen myotonia congenita. The diagnosis was based on the following: the typical phenotype of congenital myotonia, skeletal muscle hypertrophy, warm-up phenomenon demonstrated both clinically and electromyographically, and a dominant pattern of inheritance in the family. Sequencing of the 23 exons of the CLCN1 gene in the son (proband) did not reveal any pathological mutation. The lack of a mutation in the CLCN1 gene has been reported to occur in 40%70% of individuals with clinically diagnosed myotonia congenita (CLCN1). Undiscovered intron or promoter region mutations have been postulated as the cause of chloride channel dysfunction in these patients. More recently, however, genotype-phenotype mismatches between sodium and chloride ion channelopathies have been reported, and some SCN4A mutations have been shown to display a warm-up effect. In one study, published while ours was in press, patients with a clinical diagnosis of Thomsen or Becker myotonia were screened for mutations in both CLCN1 and SCN4A. Approximately 20% of cases were found to have no CLCN1 mutation. These patients were subsequently screened and 100% were instead found to have a SCN4A mutation, proving that sodium channelopathies can mimic the warm-up phenomenon seen with chloride channelopathies. In light of these new developments, the proband in our original report was reinvestigated and confirmed to have a missense mutation in the SCN4A gene (V445 M) known to cause myotonia. While the clinical diagnosis in our family was appropriately based on the criteria at the time, these new findings indicate that they do not in fact have Thomsen myotonia and perhaps the title should have read, more accurately, ‘‘Extraocular muscle hypertrophy in a patient with myotonia and a mutation in the SCN4A gene (V445 M).’’ Studies have been undertaken to better define the clinical phenotypes of NMDs based on channel and specific genotype. Eyelid myotonia is recognized in NMDs and has recently been shown to be more common and more severe in sodium channel myotonia than chloride channel myotonia (as seen in our patients) and may be an important differentiating feature to guide clinicians in determining which gene to sequence. To date, no studies link extraocular muscle involvement or strabismus to any specific genotype or ion channel. Further studies that determine the frequency and severity of extraocular muscle involvement in these patients, and correlate these findings with specific genotypes, may assist clinicians in investigating these conditions with molecular genetic techniques.

Algorithms for Molecular Biology, 2013

Background Proteins are known to be dynamic in nature, changing from one conformation to another ... more Background Proteins are known to be dynamic in nature, changing from one conformation to another while performing vital cellular tasks. It is important to understand these movements in order to better understand protein function. At the same time, experimental techniques provide us with only single snapshots of the whole ensemble of available conformations. Computational protein morphing provides a visualization of a protein structure transitioning from one conformation to another by producing a series of intermediate conformations. Results We present a novel, efficient morphing algorithm, Morph-Pro based on linear interpolation. We also show that apart from visualization, morphing can be used to provide plausible intermediate structures. We test this by using the intermediate structures of a c-Jun N-terminal kinase (JNK1) conformational change in a virtual docking experiment. The structures are shown to dock with higher score to known JNK1-binding ligands than structures solved usi...

Human Molecular Genetics, Jul 1, 2001

Due to frame-shifting mutations in the DMD gene that cause dystrophin deficiency, Duchenne muscul... more Due to frame-shifting mutations in the DMD gene that cause dystrophin deficiency, Duchenne muscular dystrophy (DMD) patients suffer from lethal muscle degeneration. In contrast, mutations in the allelic Becker muscular dystrophy (BMD) do not disrupt the translational reading frame, resulting in a less severe phenotype. In this study, we explored a genetic therapy aimed at restoring the reading frame in muscle cells from DMD patients through targeted modulation of dystrophin pre-mRNA splicing. Considering that exon 45 is the single most frequently deleted exon in DMD, whereas exon (45+46) deletions cause only a mild form of BMD, we set up an antisense-based system to induce exon 46 skipping from the transcript in cultured myotubes of both mouse and human origin. In myotube cultures from two unrelated DMD patients carrying an exon 45 deletion, the induced skipping of exon 46 in only ∼15% of the mRNA led to normal amounts of properly localized dystrophin in at least 75% of myotubes. Our results provide first evidence of highly effective restoration of dystrophin expression from the endogenous gene in DMD patient-derived muscle cells. This strategy may be applicable to not only >65% of DMD mutations, but also many other genetic diseases.

Neuromuscular Disorders, Oct 1, 2008

Neuromuscular Disorders, Oct 1, 2016

Neurology, Apr 22, 2012

Objective: To perform Anoctamin 5 (ANO) mutation analysis, neurological and cardiological examina... more Objective: To perform Anoctamin 5 (ANO) mutation analysis, neurological and cardiological examination in the genetically undiagnosed remainder of the Dutch limb girdle muscular dystrophy (LGMD) cohort encompassing 105 patients from 68 families and in a proportion of a cohort of 22 patients from 16 families with a Miyoshi-type muscular dystrophy (MMD) in which no dysferlin mutations were found. Background ANO 5 mutations have recently been found to cause LGMD2L, MMD3 and asymptomatic hyperCKemia. Design/Methods: Neurological examination, cardiological investigations (i.e. electrocardiography, Holter monitoring, echocardiography), serum creatine kinase (sCK) activity assessments and ANO 5 mutation analysis were performed in LGMD and MMD patients. Results: 32 LGMD index patients and 12 MMD3 patients from 8 kindreds were examined. ANO 5 mutations were found in 13 sporadic LGMD cases (8 males). Age at onset ranged from 21-57 years, age at examination from 26-69. Symmetrical proximal leg muscle weakness had been the first manifestation. Rhabdomyolysis attacks were mentioned in one patient, and three had cardiological abnormalities, including intraventricular septum thickening (2) and hypertrophic cardiomyopathy (1). SCK was 10-25 times the upper limit of normal (ULN). In 8 patients (all male) from 6 MMD families mutations were identified. Age at onset ranged from 18-51 years and age at examination from 30-67. Uni- or bilateral calf muscle weakness had been the presenting symptom in 7 patients and one had been asymptomatic at time of diagnosis. SCK was 20-40 times ULN. None had associated symptoms and cardiological examination was normal. Exon 5 c.191dupA was the most frequently observed mutation and in addition novel mutations were identified. Conclusions: 1. LGMD 2L is found in 16% of the Dutch LGMD families and MMD3 in 40% of the MMD families.2. In three LGMD2L patients heart involvement was found and in none of the MMD3 patients. Disclosure: Dr. De Visser has received research support from Biogen Idec. Dr. van der Kooi has received research support from Biogen Idec. Dr. Linssen has nothing to disclose. Dr. Ginjaar has nothing to disclose. Dr. Wokke has received research support from Genzyme Corporation. Dr. van Doorn has received personal compensation for activities with Talecris, ZLB, Baxter, and Octapharma. Dr. van Doorn has received research support from Baxter.

Neuromuscular Disorders, Jun 1, 1999

X-linked Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the emerin gene. Since... more X-linked Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the emerin gene. Since the emerin gene is ubiquitously expressed and since all EMD mutations published so far should be detectable by an RNA-based mutation assay, we have designed a protein truncation test for emerin. To facilitate the detection of mutations in the translation initiation site, reported for several EMD-cases, the standard tailed forward PTT-primer had to be modified. The effectiveness of the assay was established by a mutation scan in four EMD-patients. Two patients could be shown to carry emerin mutations, one affecting the ATG translation initiation codon. The PTT-assay did not detect a mutation in the two other patients. Since an immunohistochemical analysis of patient-derived cells revealed normal emerin levels, these patients are thus affected by another muscular dystrophy, most likely autosomal dominant EMD.

Humana Press eBooks, Feb 17, 2004

The aim of this study was to determine the response to an oral glucose tolerance test (OGTT) in a... more The aim of this study was to determine the response to an oral glucose tolerance test (OGTT) in adult males with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD), and to investigate whether body composition contributes to any variance in the glucose response. Twenty-eight adult males with dystrophinopathy (BMD, n = 13; DMD, n = 15) and 12 non-dystrophic controls, ingested 75 g oral anhydrous glucose solution. Fingertip capillary samples were assessed for glucose at 30-min intervals over 2-h post glucose ingestion. Fat free mass relative to body mass (FFM/BM) and body fat (BF%) was assessed using bioelectrical impedance. Vastus lateralis muscle anatomical cross sectional area (VL ACSA) was measured using B-mode ultrasonography. Blood glucose was higher in MD groups than control at 60, 90 and 120 min post ingestion of glucose. Compared to controls, FFM/BM and VL ACSA were lower in MD groups compared to controls (p < 0.001). Glucose tolerance values at 120 min were correlated with FFM/BM and BF% in the BMD group only. Our results suggest that glucose tolerance is impaired following OGTT in adult males with BMD and DMD. It is recommended that adults with BMD and DMD undertake routine glucose tolerance assessments to allow early detection of impaired glucose tolerance.

Clinical Genetics, May 6, 2019

Limb girdle muscular dystrophies ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor ... more Limb girdle muscular dystrophies ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 23 oktober 2020, te 13.00 uur door Leroy ten Dam geboren te Dordrecht

Neuromuscular Disorders, Jun 1, 2013

LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in AN... more LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies. Limb-girdle muscular dystrophies (LGMD) form a group of inherited myopathies showing progressive limb-girdle weakness with sparing of the facial and distal muscles. According to the inheritance mode, LGMD is classified into two general categories: autosomal dominant (LGMD1) and autosomal recessive (LGMD2) forms. So far, 33 genes have been associated with the disease, nine dominant and 26 recessive 1-3. Molecular pathophysiology and therefore clinical phenotypes of the LGMDs are highly heterogeneous as the mechanisms of disease include defects in numerous proteins 1,4. The observation that mutations within the same gene could be associated with variable phenotypes was made for numerous LGMD associated genes, including desmin and dysferlin 1,4-8. It is noteworthy that variable symptoms are often observed even within a family with the same causative mutation, indicating that a primary pathogenic variant combined with potentially modifying variants may exacerbate or mitigate the phenotype (for example 9). The LGMD2L subtype is associated with mutations in the anoctamin-5 gene (ANO5). ANO5 is localized to chr11p14.3, spans 90,192 bp and contains 22 exons. The gene encodes anoctamin-5 (ANO5), a ~100-kDa protein composed of 913 amino acids, containing eight transmembrane domains 10,11. The protein belongs to a family of

Journal of Medical Genetics, Sep 1, 1993

This report is the second part of a trilogy from a multidisciplinary study which was undertaken t... more This report is the second part of a trilogy from a multidisciplinary study which was undertaken to record the relationships between clinical severity and dystrophin gene and protein expression. The aim in part 2 was to correlate the effect of gene deletions on protein expression in individual patients with well defined clinical phenotypes. Among the DMD patients, most of the deletions/duplications disrupted the open reading frame, but three patients had in frame deletions. Some of the intermediate D/BMD patients had mutations which were

Journal of Medical Genetics, Sep 1, 1993

This multidisciplinary study was undertaken to record the variation in gene and protein expressio... more This multidisciplinary study was undertaken to record the variation in gene and protein expression in a large cohort of patients with well defined clinical phenotypes. The patients, whose ages ranged from 4 years to 66 years, spanned a wide range of disease severity. They represented the first 100 patients who had been examined in Newcastle, had undergone a muscle biopsy, and provided a blood sample for DNA analysis. The study had three aims: to observe any trends in the analyses across the clinical groups, to correlate gene and protein expression in individual patients, and to use the data collected to assess the relative usefulness of different techniques in the diagnosis and prognosis of patients with Duchenne and Becker dystrophy (DMD/BMD). In on February 22, 2022 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmg.30.9.728 on 1 September 1993. Downloaded from * = Predicted dystrophin sizes for patients with frameshifting deletions are calculated so [A] = size to premature stop codon, and [B] = size if reading frame immediately restored (see part 2).-= data not available. ? or parentheses = data not certain. dup = exons duplicated rather than deleted. J = junctional fragment. ICC = immunocytochemistry. V,P, = verbal IQ, performance IQ. ESN = classified as educationally subnormal. Patients F58 and F59, and patients F67 and F94 are related.

Neuromuscular Disorders, Oct 1, 2008

Journal of Medical Genetics, Oct 1, 1997

Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystroph... more Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% ofpatients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a non-quantitative test method. Detection of microlesions in Duchenne and Becker muscular dystrophy is currently under way. Single strand conformational analysis, heteroduplex analysis, and the protein truncation test are mostly used for this purpose. In this paper we review the available methods for detection of large and small mutations in patients and in carriers and propose a systematic approach for genetic analysis and genetic counselling of DMD and BMD families, including prenatal and preimplantation diagnosis.

Journal of neuromuscular diseases, Mar 2, 2021

Background:A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patient... more Background:A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patients from 68 families has been subject to genetic testing over the last 20 years. After subsequent targeted gene analysis around two thirds (45/68) of the families had received a genetic diagnosis in 2013.Objective:To describe the results of further genetic testing in the remaining undiagnosed limb girdle muscular dystrophy families in this cohort.Methods:In the families of the cohort for whom no genetic diagnosis was established (n = 23) further testing using Sanger sequencing, next generation sequencing with gene panel analysis or whole-exome sequencing was performed. In one case DNA analysis for facioscapulohumeral dystrophy type 1 was carried out.Results:In eight families no additional genetic tests could be performed. In 12 of the remaining 15 families in which additional testing could be performed a genetic diagnosis was established: two LGMDR1 calpain3-related families with CAPN3 mutations, one LGMDR2 dysferlin-related family with DYSF mutations, three sarcoglycanopathy families (LGMDR3-5 α-, β- and γ-sarcoglycan-related) with SGCA/SGCB/SGCG mutations, one LGMDR8 TRIM 32-related family with TRIM32 mutations, two LGMDR19 GMPPB-related families with GMPPB mutations, one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1. At this moment a genetic diagnosis has been made in 57 of the 60 families of which DNA was available (95%).Conclusion:A genetic diagnosis is obtained in 95% of the families of the original Dutch LGMD cohort of which DNA was available.

Annals of Neurology, 2014

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD g... more Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative magnetic resonance (MR) imaging to study brain microstructure in DMD. T1-weighted and diffusion tensor images were obtained on a 3T MR scanner from 30 patients and 22 age-matched controls (age = 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and diffusion tensor imaging parameters were made between DMD patients and controls, and between 2 DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140(+) and DMD_Dp140(-) ). DMD patients had smaller total brain volume, smaller gray matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140(-) subjects contributed most to the gray matter volume differences and performed worse on information processing. Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.

Journal of Medical Genetics, Dec 1, 1992

Among 85 patients with Duchenne and Becker muscular dystrophy, 29 were found to have mutations wh... more Among 85 patients with Duchenne and Becker muscular dystrophy, 29 were found to have mutations which disrupted the open reading frame for dystrophin. Thus any dystrophin detected in this group of patients should consist of the severely truncated polypeptides that represent prematurely terminated translation products. Dystrophin was detected in blots from 17/29 biopsies and the observed sizes of the polypeptides were compared with predicted sizes calculated in two ways: if translation was terminated at the stop codon generated by each frameshifting deletion, and if the reading frame was restored and translation proceeded. In every case the observed size matched the size predicted on the basis of a restored reading frame. This was in accord with immunocytochemical labelling of scattered dystrophin positive fibres which were found on serial sections labelled with antibodies to both the rod and C-terminal domains. Thus analysis at the protein level supports genetic evidence of exon skipping as a mechanism which restores frameshifting mutations in some fibres.