Kristl G Claeys

Publications (22)143.5 Total impact

• Article: Morphological spectrum and clinical features of myopathies with tubular aggregates.

  Fabian Funk, Chantal Ceuterick-de Groote, Jean-Jacques Martin, Axel Meinhardt, Ana L Taratuto, Jan De Bleecker, Rudy Van Coster, Boel De Paepe, Ulrike Schara, Matthias Vorgerd, [......], Lionel Van Maldergem, Stéphane Noel, Christoph W Zimmermann, Stefan Wirth, Stefan Isenmann, Rudolf Stadler, J Michael Schröder, Jörg B Schulz, Joachim Weis, Kristl G Claeys
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  ABSTRACT: Tubular aggregates (TAs) are aggregates of densely packed tubules in human skeletal muscle fibers with particular histochemical and ultrastructural features that most probably arise from the sarcoplasmic reticulum. Some studies have shown an additional mitochondrial origin of TAs. We studied the histopathological spectrum and clinical features in a large cohort of patients with TAs in their muscle biopsy (106 biopsies), derived from our muscle biopsy archive (15,412 biopsies in total). In particular, we examined light microscopic, enzyme histochemical, immunohistochemical and ultrastructural features in the muscle biopsies, as well as the patients' clinical data. We found TAs in 0.5% of all muscle biopsies. Based on the size of TAs, we identified two sub-groups: (1) myopathies with large TAs (29 biopsies) in type 2 fibers and sometimes also in type 1 fibers, absence of any other associated disorder, and a familial history in half of the cases, and (2) myopathies with small TAs (77 biopsies), exclusively in type 2 fibers, presence of another associated disease in the majority of patients and mostly no familial history. In the sub-group with large TAs, we observed a high variability of ultrastructural changes. The most frequent clinical symptom in both groups was limb muscle weakness. No significant differences in clinical presentation, age at onset or disease duration at the time of biopsy were found between the two groups. In conclusion, myopathies with TAs can be sub-divided into a group with large TAs, probably corresponding to the so-called primary TA myopathies, and into a group with small TAs as a feature of another underlying condition.
  Histology and histopathology 03/2013; · 2.48 Impact Factor
• Article: Myofibrillar myopathies.

  Kristl G Claeys, Michel Fardeau
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  ABSTRACT: Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are defined morphologically by foci of myofibril dissolution that begins at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of a large number of proteins including desmin. To date, mutations in six genes are known to cause MFMs, accounting for approximately half of the MFM patients identified. The causative genes encode mainly sarcomeric Z-disk(-related) proteins: desmin, αB-crystallin, myotilin, Z-band alternatively spliced PDZ motif containing protein (ZASP), filamin C and the antiapoptotic BCL2-associated athanogene 3 (Bag3). Although in most MFM patients the disease presents in adulthood and evolves slowly, some patients with desminopathy, αB-crystallinopathy or Bag3opathies have an infantile or juvenile disease onset. Cardiac involvement is very common in desminopathies and can sometimes be the initial or only symptom of the disease. Respiratory symptoms are noted during childhood in αB-crystallinopathies. Early severe cardiac and respiratory involvement is seen in Bag3opathies. Optical microscopic and immunohistochemical features are similar in MFMs; however, ultrastructural findings can be useful to differentiate between the distinct MFM subtypes. No curative treatment for MFMs is currently available. Careful follow-up, especially of cardiac and respiratory function, is important.
  Handbook of Clinical Neurology 01/2013; 113:1337-42.
• Article: Myopathy with hexagonally cross-linked crystalloid inclusions: delineation of a clinico-pathological entity.

  Kristl G Claeys, Jean-François Pellissier, Federico Garcia-Bragado, Joachim Weis, Andoni Urtizberea, Juan-Jose Poza, Ana-Maria Cobo, Gisela Stoltenburg, Dominique Figarella-Branger, Patrick J Willems, [......], Jean Pouget, Monique Piraud, Guy Brochier, Norma B Romero, Michel Fardeau, Hans H Goebel, Carsten G Bönnemann, Thomas Voit, Bruno Eymard, Pascal Laforêt
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  ABSTRACT: A novel myopathy characterized by hexagonally cross-linked tubular arrays has been reported in five patients. We studied the clinical and histopathological features of five additional unrelated patients with this myopathy. Patients experienced exercise intolerance with exercise-induced myalgia and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Age at onset varied between 13 and 56 years. The inclusions were eosinophilic on H and E, bright red with modified Gomori's trichrome stains, present in type 2 fibers, and revealed immunoreactivity selectively for a caveolin-3-antibody. Ultrastructurally, the inclusions showed a highly organized, hexagonally cross-linked crystalloid structure. Mutations in the caveolin-3 encoding gene were excluded. Biochemical assessment of glycogenolysis in muscle was normal. Inherited or sporadic myopathy with hexagonally cross-linked tubular arrays is associated with a homogeneous clinical and histopathological phenotype. This myopathy should be included in the differential diagnosis of patients with exercise intolerance and myalgia.
  Neuromuscular Disorders 11/2010; 20(11):701-8. · 2.80 Impact Factor
• Source

  Available from: Jorge A Bevilacqua

  Article: Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.

  J A Bevilacqua, N Monnier, M Bitoun, B Eymard, A Ferreiro, S Monges, F Lubieniecki, A L Taratuto, A Laquerrière, K G Claeys, I Marty, M Fardeau, P Guicheney, J Lunardi, N B Romero
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  ABSTRACT: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.
  Neuropathology and Applied Neurobiology 11/2010; 37(3):271-84. · 3.80 Impact Factor
• Article: De novo RYR1 heterozygous mutation (I4898T) causing lethal core-rod myopathy in twins.

  Aurelio Hernandez-Lain, Isabelle Husson, Nicole Monnier, Caroline Farnoux, Guy Brochier, Emmanuelle Lacène, Maud Beuvin, Mait Viou, Linda Manéré, Kristl G Claeys, Michel Fardeau, Joël Lunardi, Thomas Voit, Norma Beatriz Romero
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  ABSTRACT: "Core-rod myopathy" is a rare congenital myopathy characterized by the presence of "cores" and "rods" in distinct locations in the same or different muscle fibres. This association is linked currently to mutations in RYR1, NEB and ACTA1 genes. We report identical twins who presented with polyhydramnios and loss of fetal motility during pregnancy; hypotonia, arthrogryposis and swallowing impairment at birth; need of immediate respiratory support and death at 27 and 50 days of life. Muscle biopsies, performed at 27 days of life in twin 1 and at 49 days in twin 2, showed the presence of separate cores and rods in the muscle fibres, both at light and electron microscopy. The molecular analysis showed a heterozygous de novo mutation (Ile4898Thr) of the RYR1 gene. The molecular study of ACTA1, TMP2 and TMP3 genes did not show abnormalities. This is the first report of a lethal form of congenital "core-rod myopathy". The mutation Ile4898Thr has been previously described in central core disease but not in core-rod myopathy. The report enlarges the phenotypic spectrum of "core-rod myopathy" and highlights the morphological variability associated to special RYR1 mutations.
  European journal of medical genetics 09/2010; 54(1):29-33. · 1.57 Impact Factor
• Article: Investigating glycogenosis type III patients with multi-parametric functional NMR imaging and spectroscopy.

  Claire Wary, Aleksandra Nadaj-Pakleza, Pascal Laforêt, Kristl G Claeys, Robert Carlier, Aurélien Monnet, Servanne Fleury, Céline Baligand, Bruno Eymard, Philippe Labrune, Pierre G Carlier
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  ABSTRACT: Debranching enzyme deficiency (Glycogen storage disease (GSD) type III) causes progressive muscle wasting myopathy. A comprehensive nuclear magnetic resonance study involving spectroscopy (NMRS) and imaging (NMRI) evaluated status and function of calf muscles in 18 GSDIII patients. At rest, (31)P NMRS showed elevated pH and accumulation of anomalous phosphomonoesters, (13)C NMRS quantified excess glycogen accumulation and NMRI demonstrated progressive fat replacement that paralleled muscle weakness. Multi-parametric functional NMR, performed at recovery from a single bout of aerobic exercise, simultaneously assessed oxidative phosphorylation from (31)P NMRS, muscle perfusion and BOLD, a marker of blood oxygenation, from arterial spin labeled NMRI, and oxygen uptake from deoxymyoglobin proton NMRS. While blocked glycogenolysis caused inadequate substrate supply to the mitochondria, combined measurements suggested that altered perfusion was also responsible for impaired post-exercise phosphocreatine recovery and could contribute to exercise intolerance in GSDIII. These non-invasive investigations provide new indices to quantify the progression of GSDIII.
  Neuromuscular Disorders 08/2010; 20(8):548-58. · 2.80 Impact Factor
• Article: DNAJB2 expression in normal and diseased human and mouse skeletal muscle.

  Kristl G Claeys, Magdalena Sozanska, Jean-Jacques Martin, Emmanuelle Lacene, Ludivine Vignaud, Daniel Stockholm, Pascal Laforêt, Bruno Eymard, Antoine Kichler, Daniel Scherman, Thomas Voit, David Israeli
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  ABSTRACT: DNAJB2, a co-chaperone regulator of Hsp70 that is expressed principally in the nervous system, has been recently reported to be up-regulated in human skeletal muscle during its recovery from damage. Here we identified DNAJB2 expression in regenerating fibers in skeletal muscles of the dystrophic mdx mouse and patients with Duchenne muscular dystrophy. Surprisingly, in both dystrophic and control mice and patients, DNAJB2 was also expressed in non-regenerating fibers at the postsynaptic side of the neuromuscular junction. DNAJB2 functions as an adaptor molecule for the evacuation and degradation of proteins through the ubiquitin-proteasome system, and overexpression of DNAJB2 in models of the neurodegenerative disease spinobulbar muscular atrophy was shown to result in the reduction of protein inclusions. We therefore studied the possible relation of DNAJB2 expression to protein inclusion formation in skeletal muscle in biopsies of several muscle pathologies associated with protein aggregation and found in all of them a strong immunoreactivity with anti-DNAJB2 in aggregates and vacuoles. We conclude that DNAJB2 is expressed in mouse and human skeletal muscle at the neuromuscular junction of normal fibers, in the cytoplasm and membrane of regenerating fibers, and in protein aggregates and vacuoles in protein aggregate myopathies. Therefore, we propose a role for DNAJB2 in protein turnover processes in skeletal muscle.
  American Journal Of Pathology 06/2010; 176(6):2901-10. · 4.89 Impact Factor
• Article: Rigid spine syndrome revealing late-onset Pompe disease.

  Pascal Laforêt, Valérie Doppler, Catherine Caillaud, Kenza Laloui, Kristl G Claeys, Pascale Richard, Ana Ferreiro, Bruno Eymard
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  ABSTRACT: The authors describe a 50-year-old man who was evaluated for a rigid spine syndrome with onset at age 15, and subsequent walking difficulties. Cardiac and pulmonary functions were normal. Deltoid biopsy revealed the presence of small vacuoles and increased glycogen with Periodic Acid Schiff staining in a limited number of fibers. Acid alpha-glucosidase staining was decreased in leucocytes, and genetic analysis identified the presence of two mutations in that gene. This observation suggests that Pompe disease should be considered in the differential diagnosis of rigid spine syndrome, even in patients without respiratory involvement or with a muscle biopsy showing only mild histopathological changes.
  Neuromuscular Disorders 12/2009; 20(2):128-30. · 2.80 Impact Factor
• Article: Muscle glycogenosis due to phosphoglucomutase 1 deficiency.

  Tanya Stojkovic, John Vissing, François Petit, Monique Piraud, Mette C Orngreen, Grete Andersen, Kristl G Claeys, Claire Wary, Jean-Yves Hogrel, Pascal Laforêt
  New England Journal of Medicine 08/2009; 361(4):425-7. · 53.30 Impact Factor
• Article: Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.

  Kristl G Claeys, Stephan Züchner, Marina Kennerson, José Berciano, Antonio Garcia, Kristien Verhoeven, Elsdon Storey, John R Merory, Henriette M E Bienfait, Martin Lammens, Eva Nelis, Jonathan Baets, Els De Vriendt, Zwi N Berneman, Ilse De Veuster, Jefferey M Vance, Garth Nicholson, Vincent Timmerman, Peter De Jonghe
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  ABSTRACT: Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.
  Brain 08/2009; 132(Pt 7):1741-52. · 9.46 Impact Factor
• Source

  Available from: Pilar Camaño

  Article: Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget's disease of bone and frontotemporal dementia.

  Tanya Stojkovic, El Hadi Hammouda, Pascale Richard, Adolfo López de Munain, Javier Ruiz-Martinez, Pilar Camaño, Pilar Camaño Gonzalez, Pascal Laforêt, Isabelle Pénisson-Besnier, Xavier Ferrer, Arnaud Lacour, Lucette Lacomblez, Kristl G Claeys, Claude-Alain Maurage, Michel Fardeau, Bruno Eymard
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  ABSTRACT: We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget's disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget's disease or cognitive impairment.
  Neuromuscular Disorders 05/2009; 19(5):316-23. · 2.80 Impact Factor
• Article: Epilepsy as part of the phenotype associated with ATP1A2 mutations.

  Liesbet Deprez, Sarah Weckhuysen, Katelijne Peeters, Tine Deconinck, Kristl G Claeys, Lieve R F Claes, Arvid Suls, Tine Van Dyck, André Palmini, Gert Matthijs, Wim Van Paesschen, Peter De Jonghe
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  ABSTRACT: Mutations in the ATP1A2 gene have been described in families with familial hemiplegic migraine (FHM). FHM is a variant of migraine with aura characterized by the occurrence of hemiplegia during the aura. Within several FHM families, some patients also had epileptic seizures. In this study we tested the hypothesis that mutations in ATP1A2 may be common in patients presenting with epilepsy and migraine. We selected 20 families with epilepsy and migraine and performed mutation analysis of ATP1A2 in the probands by direct sequencing of all exons and splice-site junctions. Novel ATP1A2 mutations were found in two of the 20 families (10%). The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation occurred in a family with occipitotemporal epilepsy and migraine with and without visual aura. In the two families together, six mutation carriers had the combination of epilepsy and migraine, two had only epilepsy, and six had only migraine. This study shows that a history of migraine and a family history of both epilepsy and migraine should be obtained in all patients presenting with epilepsy in the epilepsy clinic. It may be worthwhile to screen patients with a combination of epilepsy and migraine and a positive family history of either migraine or epilepsy for mutations in the ATP1A2 gene.
  Epilepsia 04/2008; 49(3):500-8. · 3.96 Impact Factor
• Article: Tacrolimus-related polyneuropathy: case report and review of the literature.

  Annick De Weerdt, Kristl G Claeys, Peter De Jonghe, Dirk Ysebaert, Thiery Chapelle, Geert Roeyen, Philippe G Jorens
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  ABSTRACT: Patients, in particular recipients of orthotopic liver transplants, receiving the immunosuppressant tacrolimus (FK-506), are at risk for developing central neurotoxic adverse events. We report the occurrence of a tacrolimus-induced peripheral neurotoxic event, i.e. pure motor axonal polyneuropathy of the lower limbs in a 44-year-old woman, 9 days after combined orthotopic liver and pancreas transplantation. She was treated for 5 days with intravenous immunoglobulins. Partial recovery followed over months to years. An overview of all 11 reported FK506-associated polyneuropathies is given.
  Clinical Neurology and Neurosurgery 04/2008; 110(3):291-4. · 1.58 Impact Factor
• Article: Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN).

  Olga Koop, Anja Schirmacher, Eva Nelis, Vincent Timmerman, Peter De Jonghe, Bernd Ringelstein, Vedrana Milic Rasic, Philippe Evrard, Jutta Gärtner, Kristl G Claeys, Silke Appenzeller, Bernd Rautenstrauss, Kathrin Hühne, Maria A Ramos-Arroyo, Helmut Wörle, Jukka S Moilanen, Simon Hammans, Gregor Kuhlenbäumer
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  ABSTRACT: Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions.
  Neuromuscular Disorders 09/2007; 17(8):624-30. · 2.80 Impact Factor
• Source

  Available from: Paul M Parizel

  Article: Epilepsy and migraine in a patient with Urbach-Wiethe disease.

  Kristl G Claeys, Lieve R F Claes, Johan W M Van Goethem, Sandy Sercu, Joseph Merregaert, Julien Lambert, Eric A Van Marck, Paul M Parizel, Peter De Jonghe
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  ABSTRACT: We report the clinical, neuroradiological, and molecular genetic findings in a patient with lipoid proteinosis or Urbach-Wiethe disease. Interestingly, in this patient epilepsy and migraine were the symptoms leading to the diagnosis of the disease, contrary to most patients in whom skin abnormalities are the first recognized symptoms.
  Seizure 07/2007; 16(5):465-8. · 1.80 Impact Factor
• Article: Hereditary spastic paraplegia 3A associated with axonal neuropathy.

  Neviana Ivanova, Kristl G Claeys, Tine Deconinck, Ivan Litvinenko, Albena Jordanova, Michaela Auer-Grumbach, Jana Haberlova, Ann Löfgren, Gisele Smeyers, Eva Nelis, [......], Josef Zámecník, Berten Ceulemans, Anne Kjersti Erichsen, Erik Björck, Garth Nicholson, Michael W Sereda, Pavel Seeman, Ivo Kremensky, Vanio Mitev, Peter De Jonghe
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  ABSTRACT: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.
  Archives of Neurology 06/2007; 64(5):706-13. · 7.58 Impact Factor
• Article: Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.

  Arvid Suls, Kristl G Claeys, Dirk Goossens, Boris Harding, Rob Van Luijk, Stefaan Scheers, Liesbet Deprez, Dominique Audenaert, Tine Van Dyck, Sabine Beeckmans, Iris Smouts, Berten Ceulemans, Lieven Lagae, Gunnar Buyse, Nina Barisic, Jean-Paul Misson, Jan Wauters, Jurgen Del-Favero, Peter De Jonghe, Lieve R F Claes
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  ABSTRACT: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
  Human Mutation 10/2006; 27(9):914-20. · 5.69 Impact Factor
• Article: MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

  Kristien Verhoeven, Kristl G Claeys, Stephan Züchner, J Michael Schröder, Joachim Weis, Chantal Ceuterick, Albena Jordanova, Eva Nelis, Els De Vriendt, Matthias Van Hul, [......], Filip Roelens, Peter Vieregge, Paolo Vinci, Maria Teresa Moreno, H-J Christen, Michael E Shy, James R Lupski, Jeffery M Vance, Peter De Jonghe, Vincent Timmerman
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  ABSTRACT: Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.
  Brain 09/2006; 129(Pt 8):2093-102. · 9.46 Impact Factor
• Article: Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.

  Stephan Züchner, Peter De Jonghe, Albena Jordanova, Kristl G Claeys, Velina Guergueltcheva, Sylvia Cherninkova, Steven R Hamilton, Greg Van Stavern, Karen M Krajewski, Jeffery Stajich, Ivajlo Tournev, Kristien Verhoeven, Christine T Langerhorst, Marianne de Visser, Frank Baas, Thomas Bird, Vincent Timmerman, Michael Shy, Jeffery M Vance
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  ABSTRACT: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.
  Annals of Neurology 03/2006; 59(2):276-81. · 11.09 Impact Factor
• Article: Unraveling the genetics of distal hereditary motor neuronopathies.

  Joy Irobi, Ines Dierick, Albena Jordanova, Kristl G Claeys, Peter De Jonghe, Vincent Timmerman
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  ABSTRACT: The hereditary motor neuronopathies (HMN [MIM 158590]) are a heterogeneous group of disorders characterized by an exclusive involvement of the motor part of the peripheral nervous system. They are usually subdivided in proximal HMN, i.e., the classical spinal muscular atrophy syndromes and distal hereditary motor neuronopathies (distal HMN) that clinically resemble Charcot-Marie-Tooth syndromes. In this review, we concentrate on distal HMN. The distal HMN are clinically and genetically heterogeneous and were initially subdivided in seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been delineated. Since the introduction of positional cloning, 13 chromosomal loci and seven disease-associated genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive distal HMN. Most of the genes involved encode protein with housekeeping functions, such as RNA processing, translation synthesis, stress response, apoptosis, and others code for proteins involved in retrograde survival. Motor neurons of the anterior horn of the spinal cord seems to be vulnerable to defects in these housekeeping proteins, likely because their large axons have higher metabolic requirements for maintenance, transport over long distances and precise connectivity. Understanding the molecular pathomechanisms for mutations in these genes that are ubiquitous expressed will help unravel the neuronal mechanisms that underlie motor neuropathies leading to denervation of distal limb muscles, and might generate new insights for future therapeutic strategies.
  NeuroMolecular Medicine 02/2006; 8(1-2):131-46. · 5.00 Impact Factor