Publications by authors named "Stefanie Beck-Woedl"

11 Publications

  • Page 1 of 1

Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder.

Hum Mutat 2021 Jun 22. Epub 2021 Jun 22.

Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

SYNCRIP encodes for the Synaptotagmin-binding cytoplasmic RNA-interacting protein, involved in RNA-binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic-atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA-binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype-phenotype correlations. Our study provides further evidence for a SYNCRIP-associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic-atonic epilepsy.
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http://dx.doi.org/10.1002/humu.24245DOI Listing
June 2021

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

Am J Hum Genet 2020 08 23;107(2):364-373. Epub 2020 Jul 23.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413886PMC
August 2020

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C.

Neuropediatrics 2020 02 22;51(1):37-44. Epub 2019 Oct 22.

Department of Neuropaediatrics, Developmental Neurology, Social Paediatrics, University Children's Hospital Tuebingen, Tuebingen, Germany.

Aim: The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms.

Methods: Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy.

Results: Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2-6 years), six scans from four with juvenile onset (6-15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms and were prominent in the later forms already early in the disease course.

Conclusion: This is the first systematic and comparative MRI analysis in the different onset groups of NPC using a scoring system. Early during disease course, MRI showed different patterns in infantile compared with juvenile and adult onset NPC patients, for example, only supratentorial atrophy in juvenile versus global atrophy in adult onset patients. MRI changes provide an additional, early biomarker for NPC.
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http://dx.doi.org/10.1055/s-0039-1698451DOI Listing
February 2020

KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.

Ann Clin Transl Neurol 2019 07 7;6(7):1319-1326. Epub 2019 Jun 7.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.
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http://dx.doi.org/10.1002/acn3.50799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649617PMC
July 2019

SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy.

J Hum Genet 2019 Jul 24;64(7):609-616. Epub 2019 Apr 24.

Institut für Medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.
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http://dx.doi.org/10.1038/s10038-019-0602-8DOI Listing
July 2019

Blue Diaper Syndrome and Mutations.

Pediatrics 2018 04;141(Suppl 5):S501-S505

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (; NM_000439.4: c.679del, p.[Val227Leufs*12]). encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by mutations.
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http://dx.doi.org/10.1542/peds.2017-0548DOI Listing
April 2018

Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition.

Eur J Hum Genet 2017 02 30;25(2):183-191. Epub 2016 Nov 30.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.

Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.
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http://dx.doi.org/10.1038/ejhg.2016.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5255962PMC
February 2017

Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome.

Eur J Paediatr Neurol 2016 Jul 28;20(4):661-5. Epub 2016 Apr 28.

Department of Medical Genetics and Applied Genomics, University of Tübingen, Germany; Rare Disease Center Tübingen, University of Tübingen, Germany.

Background: Mutations in the STXBP1 gene (MUNC18-1) were first described to cause Ohtahara syndrome (Early infantile epileptic encephalopathy, EIEE)(12-14) characterized by very early infantile epileptic encephalopathy with frequent tonic spasms and a suppression-burst pattern on electroencephalogram. In the following years a wider phenotype was recognized having milder forms of epilepsies. All patients showed also intellectual disability and movement disorders.

Methods: Here, we present three female patients with an ataxia-tremor-retardation syndrome caused by a de novo STXBP1 mutation. Two of the girls were diagnosed through next-generation-sequencing as mutations in STXBP1 were not suspected. The third patient was diagnosed by targeted genetic testing due to its clinical features strikingly similar to the first two girls.

Results: The characteristic feature of our three patients is the lack of epilepsy which is in contrast to the majority of the patients with STXBP1 mutation.

Conclusion: Hence, epilepsy is not a mandatory feature of patients with a STXBP1 mutation.
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http://dx.doi.org/10.1016/j.ejpn.2016.04.005DOI Listing
July 2016

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

J Med Genet 2016 08 17;53(8):511-22. Epub 2016 Mar 17.

Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow, Russia.

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations.

Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.

Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15.

Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
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http://dx.doi.org/10.1136/jmedgenet-2015-103451DOI Listing
August 2016

Next-generation sequencing in X-linked intellectual disability.

Eur J Hum Genet 2015 Nov 4;23(11):1513-8. Epub 2015 Feb 4.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.
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http://dx.doi.org/10.1038/ejhg.2015.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613482PMC
November 2015

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation.

Eur J Hum Genet 2011 May 16;19(5):507-12. Epub 2011 Feb 16.

Department of Medical Genetics, University of Tübingen, Tübingen, Germany.

Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X-inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood.
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http://dx.doi.org/10.1038/ejhg.2010.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083613PMC
May 2011
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