Publications by authors named "Filip Roelens"

17 Publications

  • Page 1 of 1

De Novo Variants in LMNB1 Cause Pronounced Syndromic Microcephaly and Disruption of Nuclear Envelope Integrity.

Am J Hum Genet 2020 10 9;107(4):753-762. Epub 2020 Sep 9.

Center for Human Genetics, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for the Genetics of Cognition, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address:

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536573PMC
October 2020

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

J Inherit Metab Dis 2020 Jul 17. Epub 2020 Jul 17.

Pediatric Neurology Research Group, Hospital Vall d'Hebrón, Barcelona, Spain.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
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http://dx.doi.org/10.1002/jimd.12288DOI Listing
July 2020

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

JAMA Neurol 2018 04;75(4):495-502

Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.

Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.

Design, Setting, And Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.

Main Outcomes And Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.

Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions And Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
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http://dx.doi.org/10.1001/jamaneurol.2017.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933354PMC
April 2018

mutation in three siblings with familial hereditary spastic paraplegia.

Cold Spring Harb Mol Case Stud 2017 07 5;3(4). Epub 2017 Jul 5.

Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the gene, c.1369C>T (p.Arg457*), in the three affected boys.
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http://dx.doi.org/10.1101/mcs.a001537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495031PMC
July 2017

Bi-allelic variants in encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts.

J Med Genet 2017 06 3;54(6):432-440. Epub 2017 Mar 3.

Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.

Background: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by , is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations in give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations in are associated with a similar phenotype.

Methods: Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in were reviewed. Functional assays were performed on dermal fibroblasts.

Results: Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of . Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic mutations showed a brain phenotype similar to that associated with mutations in .

Conclusion: Homozygous or compound heterozygous mutations in are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic mutations emphasises the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.
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http://dx.doi.org/10.1136/jmedgenet-2016-104421DOI Listing
June 2017

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

Authors:
Claire Redin Harrison Brand Ryan L Collins Tammy Kammin Elyse Mitchell Jennelle C Hodge Carrie Hanscom Vamsee Pillalamarri Catarina M Seabra Mary-Alice Abbott Omar A Abdul-Rahman Erika Aberg Rhett Adley Sofia L Alcaraz-Estrada Fowzan S Alkuraya Yu An Mary-Anne Anderson Caroline Antolik Kwame Anyane-Yeboa Joan F Atkin Tina Bartell Jonathan A Bernstein Elizabeth Beyer Ian Blumenthal Ernie M H F Bongers Eva H Brilstra Chester W Brown Hennie T Brüggenwirth Bert Callewaert Colby Chiang Ken Corning Helen Cox Edwin Cuppen Benjamin B Currall Tom Cushing Dezso David Matthew A Deardorff Annelies Dheedene Marc D'Hooghe Bert B A de Vries Dawn L Earl Heather L Ferguson Heather Fisher David R FitzPatrick Pamela Gerrol Daniela Giachino Joseph T Glessner Troy Gliem Margo Grady Brett H Graham Cristin Griffis Karen W Gripp Andrea L Gropman Andrea Hanson-Kahn David J Harris Mark A Hayden Rosamund Hill Ron Hochstenbach Jodi D Hoffman Robert J Hopkin Monika W Hubshman A Micheil Innes Mira Irons Melita Irving Jessie C Jacobsen Sandra Janssens Tamison Jewett John P Johnson Marjolijn C Jongmans Stephen G Kahler David A Koolen Jerome Korzelius Peter M Kroisel Yves Lacassie William Lawless Emmanuelle Lemyre Kathleen Leppig Alex V Levin Haibo Li Hong Li Eric C Liao Cynthia Lim Edward J Lose Diane Lucente Michael J Macera Poornima Manavalan Giorgia Mandrile Carlo L Marcelis Lauren Margolin Tamara Mason Diane Masser-Frye Michael W McClellan Cinthya J Zepeda Mendoza Björn Menten Sjors Middelkamp Liya R Mikami Emily Moe Shehla Mohammed Tarja Mononen Megan E Mortenson Graciela Moya Aggie W Nieuwint Zehra Ordulu Sandhya Parkash Susan P Pauker Shahrin Pereira Danielle Perrin Katy Phelan Raul E Piña Aguilar Pino J Poddighe Giulia Pregno Salmo Raskin Linda Reis William Rhead Debra Rita Ivo Renkens Filip Roelens Jayla Ruliera Patrick Rump Samantha L P Schilit Ranad Shaheen Rebecca Sparkes Erica Spiegel Blair Stevens Matthew R Stone Julia Tagoe Joseph V Thakuria Bregje W van Bon Jiddeke van de Kamp Ineke van Der Burgt Ton van Essen Conny M van Ravenswaaij-Arts Markus J van Roosmalen Sarah Vergult Catharina M L Volker-Touw Dorothy P Warburton Matthew J Waterman Susan Wiley Anna Wilson Maria de la Concepcion A Yerena-de Vega Roberto T Zori Brynn Levy Han G Brunner Nicole de Leeuw Wigard P Kloosterman Erik C Thorland Cynthia C Morton James F Gusella Michael E Talkowski

Nat Genet 2017 01 14;49(1):36-45. Epub 2016 Nov 14.

Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
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http://dx.doi.org/10.1038/ng.3720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307971PMC
January 2017

Redefining the MED13L syndrome.

Eur J Hum Genet 2015 Oct 11;23(10):1308-17. Epub 2015 Mar 11.

Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.
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http://dx.doi.org/10.1038/ejhg.2015.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592099PMC
October 2015

Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.

Genet Med 2015 Jun 18;17(6):460-6. Epub 2014 Sep 18.

Center for Medical Genetics, Ghent University, Ghent, Belgium.

Purpose: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis.

Methods: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization.

Results: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain.

Conclusion: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.
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http://dx.doi.org/10.1038/gim.2014.124DOI Listing
June 2015

De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation.

Hum Genet 2014 Nov 19;133(11):1359-67. Epub 2014 Jul 19.

Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.

Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics.
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http://dx.doi.org/10.1007/s00439-014-1469-6DOI Listing
November 2014

Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations.

Eur J Hum Genet 2014 May 9;22(5):652-9. Epub 2013 Oct 9.

Center for Medical Genetics, Ghent University, Ghent, Belgium.

Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.
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http://dx.doi.org/10.1038/ejhg.2013.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992577PMC
May 2014

PRRT2 mutations: exploring the phenotypical boundaries.

J Neurol Neurosurg Psychiatry 2014 Apr 7;85(4):462-5. Epub 2013 Oct 7.

Neurogenetics Group, Department of Molecular Genetics, VIB, , Antwerp, Belgium.

Background: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy.

Methods: We screened a cohort of 460 patients with B(F)IC or ICCA, fever related seizures or infantile epileptic encephalopathies. All patients were tested for point mutations using direct sequencing.

Results: We identified heterozygous mutations in 16 individuals: 10 familial and 6 sporadic cases. All patients were diagnosed with B(F)IC, ICCA or PD. We were not able to detect mutations in any of the other epilepsy syndromes. Several mutation carriers had learning disabilities and/or impaired fine motor skills later in life.

Conclusions: PRRT2 mutations do not seem to be involved in the aetiology of FS or infantile epileptic encephalopathies. Therefore B(F)IC, ICCA and PD remain the core phenotypes associated with PRRT2 mutations. The presence of learning disabilities or neuropsychiatric problems in several mutation carriers calls for additional clinical studies addressing this developmental aspect in more detail.
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http://dx.doi.org/10.1136/jnnp-2013-305122DOI Listing
April 2014

KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.

Ann Neurol 2012 Jan;71(1):15-25

Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.

Objective: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists.

Methods: We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail.

Results: We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved.

Interpretation: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.
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http://dx.doi.org/10.1002/ana.22644DOI Listing
January 2012

Early onset collagen VI myopathies: Genetic and clinical correlations.

Ann Neurol 2010 Oct;68(4):511-20

Inserm, U582, Paris, France.

Objective: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.

Methods: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA.

Results: ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation).

Interpretation: This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
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http://dx.doi.org/10.1002/ana.22087DOI Listing
October 2010

Neuromyelitis optica-IgG+ optic neuritis associated with celiac disease and dysgammaglobulinemia: a role for tacrolimus?

Eur J Paediatr Neurol 2011 May 12;15(3):265-7. Epub 2010 Nov 12.

Pediatric Immune Deficiencies, University Hospitals Leuven, Leuven, Belgium.

We present a pediatric case of recurrent optic neuritis, celiac disease, partial IgA and IgG3 deficiency in the context of anti-aquaporin-4 auto-immunity and familial IgA deficiency with celiac disease. Treatment with tacrolimus was successful in preventing disease relapses. This case stresses the relevance of central nervous system anti-aquaporin-4 auto-immunity in a broader context of immune dysregulation and neuro-immunology.
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http://dx.doi.org/10.1016/j.ejpn.2010.09.005DOI Listing
May 2011

Encephalocraniocutaneous lipomatosis accompanied by the formation of bone cysts: Harboring clues to pathogenesis?

Am J Med Genet A 2007 Dec;143A(24):2973-80

Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring neurocutaneous disorder characterized by ocular anomalies, mainly choristomas; by skin lesions consisting of hairless fatty tissue nevi (nevus psiloliparus), focal dermal hypoplasia, alopecia, and periocular skin tags; and by CNS anomalies, including intracranial and spinal lipomas and often mental retardation and seizures. Here, we report on three boys with ECCL with typical abnormalities of the eyes, skin and brain and, in addition, coarctation of the aorta. All three children developed multiple cystic bone lesions, which progressively spread throughout the skeleton in Patient 1 and was shown histologically to be non-ossifying fibromas in Patient 2. We hypothesize that ECCL may be caused by mosaicism for a mutated gene involved in benign mesenchymal tumors and in vasculogenesis.
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http://dx.doi.org/10.1002/ajmg.a.31957DOI Listing
December 2007

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Brain 2006 Aug 19;129(Pt 8):2093-102. Epub 2006 May 19.

Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium.

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.
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http://dx.doi.org/10.1093/brain/awl126DOI Listing
August 2006

Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.

Ann Neurol 2005 Sep;58(3):400-10

Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.

In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes.
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http://dx.doi.org/10.1002/ana.20586DOI Listing
September 2005