Publications by authors named "Jonas Denecke"

74 Publications

Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study.

Lancet Child Adolesc Health 2021 Oct 28. Epub 2021 Oct 28.

Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups.

Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity.

Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings.

Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored.

Funding: None.

Translation: For the German translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2352-4642(21)00287-XDOI Listing
October 2021

Hypoglykämie+Septum pellucidum-Agenesie = septo-optische Dysplasie!

Z Geburtshilfe Neonatol 2021 Oct 7;225(5):445-446. Epub 2021 Oct 7.

Sektion Neonatologie und Pädiatrische Intensivmedizin, Zentrum für Geburtshilfe, Kinder-und Jugendmedizin, Universitätsklinikum Eppendorf, Hamburg.

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http://dx.doi.org/10.1055/a-1548-3453DOI Listing
October 2021

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

Ann Neurol 2021 11 14;90(5):738-750. Epub 2021 Oct 14.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.

Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.

Results: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.

Interpretation: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.
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http://dx.doi.org/10.1002/ana.26228DOI Listing
November 2021

Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort.

Clin Genet 2021 12 19;100(6):766-770. Epub 2021 Sep 19.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms, a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.
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http://dx.doi.org/10.1111/cge.14061DOI Listing
December 2021

Evaluation of putative CSF biomarkers in paediatric spinal muscular atrophy (SMA) patients before and during treatment with nusinersen.

J Cell Mol Med 2021 09 27;25(17):8419-8431. Epub 2021 Jul 27.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder leading to immobilization and premature death. Currently, three alternative therapeutic options are available. Therefore, biomarkers that might reflect or predict the clinical course of the individual patient with treatment are of great potential use. Currently, the antisense oligonucleotide nusinersen is the prevalent and longest validated therapy for SMA. We analysed CSF candidate biomarkers for degenerative CNS processes (namely phosphorylated heavy chain (pNf-H), light-chain neurofilaments (NfL), total tau protein (T-Tau), neurogranin, β-secretase BACE-1 and alpha-synuclein) in 193 CSF samples of 44 paediatric SMA types 1, 2 and 3 patients before and under nusinersen treatment and related them to standardized clinical outcome scores in a single-centre pilot study. pNf-H and NfL correlated with disease severity and activity, emphasizing their relevance as marker of neuronal loss and clinical outcome. T-Tau was significantly correlated with motor function scores in SMA type 1 making it an interesting marker for treatment response. Additionally, baseline T-Tau levels were elevated in most SMA patients possibly reflecting the extension of neuronal degeneration in paediatric-onset SMA. Further investigations of these CSF proteins might be beneficial for paediatric SMA subtypes and treatment modalities as an indicator for clinical outcome and should be analysed in larger cohorts.
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http://dx.doi.org/10.1111/jcmm.16802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419176PMC
September 2021

Whole-Exome Sequencing in Critically Ill Neonates and Infants: Diagnostic Yield and Predictability of Monogenic Diagnosis.

Neonatology 2021 8;118(4):454-461. Epub 2021 Jul 8.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Monogenic diseases play an important role in critically ill neonates and infants treated in the intensive care unit. This study aimed to determine the diagnostic yield of whole-exome sequencing (WES) for monogenic diseases and identify phenotypes more likely associated with a genetic etiology.

Methods: From March 2017 to 2020, a comprehensive diagnostic workup including WES in a single academic center was performed in 61 unrelated, critically ill neonates and infants with an unknown underlying disease within the first year of life. We conducted 59 trio-WES, 1 duo-WES, and 1 single-WES analyses. Symptoms were classified according to the Human Phenotype Ontology.

Results: The overall molecular genetic diagnostic rate within our cohort was 46% (28/61) and 50% (15/30) in the subgroup of preterm neonates. Identifying the genetic cause of disease facilitates individualized management in the majority of patients. A positive or negative predictive power of specific clinical features for a genetic diagnosis could not be observed.

Conclusion: WES is a powerful noninvasive diagnostic tool in critically ill neonates and infants with a high diagnostic rate. We recommend initiating WES as early as possible due to the impact on management and family counseling. Recommendations regarding the clinical utility of WES in critically ill neonates and infants should not be based on the phenotype alone. Here, we present a clinical workflow for the application of WES for critically ill neonates and infants in an interdisciplinary setting.
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http://dx.doi.org/10.1159/000516890DOI Listing
September 2021

ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants.

Neurogenetics 2021 10 3;22(4):263-269. Epub 2021 Jul 3.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.
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http://dx.doi.org/10.1007/s10048-021-00655-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426245PMC
October 2021

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

Genome Med 2021 05 21;13(1):90. Epub 2021 May 21.

Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.

Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.

Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.

Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.
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http://dx.doi.org/10.1186/s13073-021-00900-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140440PMC
May 2021

The natural history of Canavan disease: 23 new cases and comparison with patients from literature.

Orphanet J Rare Dis 2021 05 19;16(1):227. Epub 2021 May 19.

Department of Neurology, MGH, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA.

Background: Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients).

Results: Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed.

Conclusions: Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.
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http://dx.doi.org/10.1186/s13023-020-01659-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132415PMC
May 2021

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

Am J Hum Genet 2021 06 27;108(6):1138-1150. Epub 2021 Apr 27.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206162PMC
June 2021

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Am J Hum Genet 2021 06 27;108(6):1053-1068. Epub 2021 Apr 27.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206150PMC
June 2021

CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders.

Brain 2021 08;144(7):2092-2106

Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria.

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.
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http://dx.doi.org/10.1093/brain/awab101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422349PMC
August 2021

MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency.

Eur J Hum Genet 2021 07 2;29(7):1110-1120. Epub 2021 Mar 2.

Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication.
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http://dx.doi.org/10.1038/s41431-021-00839-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298597PMC
July 2021

Development of the "Hamburg Best Practice Guidelines for ICV-Enzyme Replacement therapy (ERT) in CLN2 Disease" Based on 6 Years Treatment Experience in 48 Patients.

J Child Neurol 2021 07 5;36(8):635-641. Epub 2021 Feb 5.

Department of Pediatrics, 37734University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Intracerebroventricular enzyme replacement therapy (ICV-ERT) for CLN2 disease represents the first approved treatment for neuronal ceroid lipofuscinosis (NCL) diseases. It is the first treatment where a recombinant lysosomal enzyme, cerliponase alfa, is administered into the lateral cerebral ventricles to reach the central nervous system, the organ affected in CLN2 disease. If untreated, CLN2 children show first symptoms such as epilepsy and language developmental delay at 2-4 years followed by rapid loss of motor and language function, vision loss, and early death. Treatment with cerliponase alfa has shown to slow the rapid neurologic decline. However, the mode of administration by 4 hour-long intracerebroventricular infusions every 14 days represents a potentially greater risk of infection compared to intravenous enzyme replacement therapies. The Hamburg NCL Specialty Clinic was the first site worldwide to perform intracerebroventricular enzyme replacement therapy in children with CLN2 disease. In order to ensure maximum patient safety, we analysed data from our center from more than 3000 intracerebroventricular enzyme replacement therapies in 48 patients over 6 years with regard to the occurrence of device-related adverse events and device infections. Since starting intracerebroventricular enzyme replacement therapy, we have also developed and continuously improved the "Hamburg Best Practice Guidelines for ICV-Enzyme Replacement Therapy (ERT) in CLN2 Disease." Results from this study showed low rates for device-related adverse events and infections with 0.27% and 0.33%, respectively. Therefore, following our internal procedural guidelines has shown to improve standardization and patient safety of intracerebroventricular enzyme replacement therapy for CLN2 disease.
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http://dx.doi.org/10.1177/0883073821989154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255505PMC
July 2021

Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

Mol Genet Metab Rep 2021 Mar 14;26:100704. Epub 2021 Jan 14.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce.

Methods: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor.

Results: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia.

Conclusions: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815485PMC
March 2021

Quality of Life and Mental Health in Mothers and Fathers Caring for Children and Adolescents with Rare Diseases Requiring Long-Term Mechanical Ventilation.

Int J Environ Res Public Health 2020 12 2;17(23). Epub 2020 Dec 2.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.

(1) Parents caring for children and adolescents with rare diseases fear the long-term progression of the child's disease and the loss of their parental role. The aim of this study was to examine the quality of life, mental health and associated protective factors of mothers and fathers caring for children with rare diseases requiring mechanical long-term ventilation. (2) In a cross-sectional design, data on quality of life, mental health, coping mechanisms, social support and family functioning from = 75 affected families were collected using standardized psychometric questionnaires. (3) Mothers compared to fathers were significantly more impaired in their quality of life and mental health. Protective factors significantly associated with the respective outcomes for mothers were coping mechanisms, social support and family functioning, whereas for fathers solely the latter was found to be significant. Multiple regression analyses showed that family functioning may be the most important predictor of quality of life and mental health. (4) The results support the need for family-oriented care in parents of children with rare diseases. To reach optimal efficiency, health care providers should not only screen parents for psychosocial impairment but also provide interventions that consider gender-specific differences in psychological health.
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http://dx.doi.org/10.3390/ijerph17238975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731445PMC
December 2020

Intrathecal Administration of Nusinersen in Pediatric SMA Patients with and without Spine Deformities: Experiences and Challenges over 3 Years in a Single Center.

Neuropediatrics 2021 06 4;52(3):179-185. Epub 2020 Dec 4.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Spinal muscular atrophy (SMA) is a rare neurodegenerative disease leading to progressive muscular atrophy, respiratory failure, and premature death. Secondary thorax and spine deformities are frequent. In July 2017, the antisense oligonucleotide nusinersen (Spinraza) was approved for the recurrent lifelong intrathecal treatment of SMA in Europe. Lumbar punctures are challenging especially in SMA patients with severe spine deformities and after spine surgery. In the light of alternative SMA therapies that are available or are expected to be available soon and which are administered orally or via one-time infusion, an appraisal of the established therapy is significant. Discussion about which therapy is the best for each individual patient will have to include not only the safety and efficacy of data but also the application form and its burden for the patient and the health care system. Therefore, we analyzed our 3-year experiences and challenges with 478 lumbar puncture procedures in 61 pediatric SMA patients with and without spine deformities or instrumentation.
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http://dx.doi.org/10.1055/s-0040-1718916DOI Listing
June 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Evaluation of two family-based intervention programs for children affected by rare disease and their families - research network (CARE-FAM-NET): study protocol for a rater-blinded, randomized, controlled, multicenter trial in a 2x2 factorial design.

BMC Fam Pract 2020 11 20;21(1):239. Epub 2020 Nov 20.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Families of children with rare diseases (i.e., not more than 5 out of 10,000 people are affected) are often highly burdened with fears, insecurities and concerns regarding the affected child and its siblings. Although families caring for children with rare diseases are known to be at risk for mental disorders, the evaluation of special programs under high methodological standards has not been conducted so far. Moreover, the implementation of interventions for this group into regular care has not yet been accomplished in Germany. The efficacy and cost-effectiveness of a family-based intervention will be assessed.

Methods/design: The study is a 2x2 factorial randomized controlled multicenter trial conducted at 17 study centers throughout Germany. Participants are families with children and adolescents affected by a rare disease aged 0 to 21 years. Families in the face-to-face intervention CARE-FAM, online intervention WEP-CARE or the combination of both will be treated over a period of roughly 6 months. Topics discussed in the interventions include coping, family relations, and social support. Families in the control condition will receive treatment as usual. The primary efficacy outcome is parental mental health, measured by the Structured Clinical Interview for DSM-IV (SCID-I) by blinded external raters. Further outcomes will be assessed from the parents' as well as the children's perspective. Participants are investigated at baseline, 6, 12 and 18 months after randomization. In addition to the assessment of various psychosocial outcomes, a comprehensive health-economic evaluation will be performed.

Discussion: This paper describes the implementation and evaluation of two family-based intervention programs for Children Affected by Rare Disease and their Family's Network (CARE-FAM-NET) in German standard care. A methodologically challenging study design is used to reflect the complexity of the actual medical care situation. This trial could be an important contribution to the improvement of care for this highly burdened group.

Trial Registration: German Clinical Trials Register: DRKS00015859 (registered 18 December 2018) and ClinicalTrials.gov : NCT04339465 (registered 8 April 2020). Protocol Version: 15 August 2020 (Version 6.1). Trial status: Recruitment started on 1 January 2019 and will be completed on 31 March 2021.
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http://dx.doi.org/10.1186/s12875-020-01312-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678588PMC
November 2020

A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl/H-Exchanger, Causes Early-Onset Neurodegeneration.

Am J Hum Genet 2020 12 19;107(6):1062-1077. Epub 2020 Nov 19.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13125 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany. Electronic address:

Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl/H exchangers function as electric shunts for proton pumping and in luminal Cl accumulation. We now report three unrelated children with severe neurodegenerative disease, who carry the same de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6, encoding the late endosomal Cl/H-exchanger ClC-6. Whereas Clcn6 mice have only mild neuronal lysosomal storage abnormalities, the affected individuals displayed severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. The p.Tyr553Cys amino acid substitution strongly slowed ClC-6 gating and increased current amplitudes, particularly at the acidic pH of late endosomes. Transfection of ClC-6, but not ClC-6, generated giant LAMP1-positive vacuoles that were poorly acidified. Their generation strictly required ClC-6 ion transport, as shown by transport-deficient double mutants, and depended on Cl/H exchange, as revealed by combination with the uncoupling p.Glu200Ala substitution. Transfection of either ClC-6 or ClC-6 generated slightly enlarged vesicles, suggesting that p.Glu200Ala, previously associated with infantile spasms and microcephaly, is also pathogenic. Bafilomycin treatment abrogated vacuole generation, indicating that H-driven Cl accumulation osmotically drives vesicle enlargement. Our work establishes mutations in CLCN6 associated with neurological diseases, whose spectrum of clinical features depends on the differential impact of the allele on ClC-6 function.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820737PMC
December 2020

Germline AGO2 mutations impair RNA interference and human neurological development.

Nat Commun 2020 11 16;11(1):5797. Epub 2020 Nov 16.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
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http://dx.doi.org/10.1038/s41467-020-19572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670403PMC
November 2020

The Clinical Picture of a Bilateral Perisylvian Syndrome as the Initial Symptom of Mega-Corpus-Callosum Syndrome due to a MAST1-Gene Mutation.

Neuropediatrics 2020 12 20;51(6):435-439. Epub 2020 Aug 20.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Congenital bilateral perisylvian syndrome (CBPS) is a rare neurological disorder associated with typical clinical and imaging features such as bilateral symmetrical polymicrogyria, either exclusively or mainly affecting the perisylvian region of the brain. We present a girl with the typical clinical picture of a CBPS and a complex migration disorder, predominantly presenting as bilateral symmetrical polymicrogyria associated with corpus callosum hyperplasia, ventricular dilation, and pontine hypoplasia. At the age of 6 months, the girl showed a profound global developmental delay, seizures refractory to treatment, and severe oromotor dysfunction. Exome analysis revealed a mutation in microtubule-associated serine/threonine kinase 1 (MAST1). Recently, mutations in this gene were described in six patients with a cortical migration disorder named mega-corpus-callosum syndrome with cerebellar hypoplasia. Although all patients present the clinical and imaging features of CBPS, a clear assignment between CBPS and MAST1 mutations has not been reported yet.
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http://dx.doi.org/10.1055/s-0040-1710588DOI Listing
December 2020

The impact of long-term ventilator-use on health-related quality of life and the mental health of children with neuromuscular diseases and their families: need for a revised perspective?

Health Qual Life Outcomes 2020 Jul 9;18(1):219. Epub 2020 Jul 9.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Martinistr, 52 20246, Hamburg, Germany.

Background: Life extension by medical interventions and health-related quality of life (HRQOL) are sometimes conflicting aspects of medical care. Long-term ventilation in children with neuromuscular disease is a well-established life-extending procedure and often at the center of this conflict. HRQOL and the mental health of affected children and their families become even more important in respect to emerging therapies in neuromuscular diseases with longer life-expectancy of treated patients and considerable costs of medical treatment.

Methods: We performed a questionnaire survey in a total of forty-three families of children with neuromuscular disease treated in the University Medical Center Hamburg-Eppendorf and the Children's Hospital Altona. We evaluated self- and proxy-reported HRQOL and mental health outcomes of affected children and their parents using validated and age-appropriate instruments.

Results: Compared to normative data, children with neuromuscular diseases and their families experienced a lower HRQOL and mental health. However, there was no additional negative influence on the overall HRQOL by ventilator use.

Conclusions: As ventilator use was not responsible for the reduction of HRQOL and mental health our data contributes an important aspect to the discussion about life-prolonging procedures, in particular mechanical ventilation, in severly disabled patients.
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http://dx.doi.org/10.1186/s12955-020-01467-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346376PMC
July 2020

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Clinical Geneticist Medical Genetics Department, CHUQ-CHUL, Quebec, Canada.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

Nine newly identified individuals refine the phenotype associated with MYT1L mutations.

Am J Med Genet A 2020 05 17;182(5):1021-1031. Epub 2020 Feb 17.

Institute of Human Genetics, University of Bonn, University Hospital Bonn, Bonn, Germany.

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.
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http://dx.doi.org/10.1002/ajmg.a.61515DOI Listing
May 2020

Defining and expanding the phenotype of -associated developmental epileptic encephalopathy.

Neurol Genet 2019 Dec 10;5(6):e373. Epub 2019 Dec 10.

Department of Epilepsy Genetics and Precision Medicine (K.J.M., E.G., G.R., R.S.M.), The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.J.M., E.G., R.S.M.), University of Southern Denmark, Odense; Institute of Human Genetics (D.M., R. Jamra, A.F., J.R.L.), University of Leipzig Medical Center, Germany; Institute of Structural Biology (R. Janowski, D.N.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Paediatric Radiology (C.R.), University of Leipzig Medical Center, Germany; Department of Epilepsy, Sleep and Pediatric Neurophysiology (J.T.), Lyon University Hospital, France; Neuropediatric Unit (A.-L.P., D.M.V., G.L.), Lyon University Hospital, France; Department of Medical Genetics (N.C., G.L.), Lyon University Hospital, France; GenDev Team (N.C.), CNRS UMR 5292, INSERM U1028, CNRL and University of Lyon, France; Department of Genetics (E.B.), University Medical Center Utrecht, The Netherlands; Department of Child Neurology (K.G.), Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; Department of Paediatrics (A.P.B.), Copenhagen University Hospital Rigshospitalet, Denmark; Baylor College of Medicine (S.M., K.N.), Children's Hospital of San Antonio; Undiagnosed Diseases Program (G.B., C.P.), Genetic Services of Western Australia, Department of Health, Government of Western Australia, Perth; Western Australian Register of Developmental Anomalies (G.B., D.G.), Australia; Telethon Kids Institute and the School of Paediatrics and Child Health (G.B.), University of Western Australia, Perth; Linear Clinical Research (L.D.), WA, Australia; Center of Human Genetics (S.S), Jena University Hospital, Germany; Department of Neuropediatrics (A.D.), Jena University Hospital, Germany; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Division of Neuropediatrics (A.M.), University of Leipzig Medical Center, Germany; Amplexa Genetics (H.H.), Odense, Denmark; Clinic for Children (H.H.), Værløse, Denmark; Center for Integrative Brain Research (G.M.), Seattle Children's Research Institute, WA; Department of Pediatrics (G.M.), University of Washington, Seattle; Medical Genetics Unit (F.B.), Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Istituto Dermopatico dell'Immacolata (F.B.), IDI-IRCCS, Rome, Italy; Institute of Human Genetics (T.B., M.H.), University Medical Center Hamburg-Eppendorf, Germany; Childrens Hospital (J.D.), University Medical Center Hamburg-Eppendorf, Germany; University of Copenhagen (G.R.), Denmark; Institute for Human Genetics (P.M.), University Hospital Magdeburg, Germany; Children's Hospital A. Meyer (R.G., A.V.), University of Florence, Italy; and Institute of Pharmaceutical Biotechnology (D.N.), Ulm University, Germany.

Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in encephalopathy.

Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.

Results: Biallelic pathogenic variants in cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.

Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new variants and well-founded genetic counseling.
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http://dx.doi.org/10.1212/NXG.0000000000000373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927360PMC
December 2019

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

Hum Mutat 2020 04 14;41(4):837-849. Epub 2020 Jan 14.

Department of Allergy/Immunology, Spectrum Health Helen Devos Children's Hospital, Michigan State University College of Human Medicine, East Lansing, Michigan.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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http://dx.doi.org/10.1002/humu.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457149PMC
April 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

GeneDx, Gaithersburg, MD, USA.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
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http://dx.doi.org/10.1093/brain/awz379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962909PMC
January 2020

Excessive Seizure Clusters in an Otherwise Well-Controlled Epilepsy as a Possible Hallmark of Untreated Vitamin B6-Responsive Epilepsy due to a Homozygous Missense Variant.

J Pediatr Genet 2019 Dec 20;8(4):222-225. Epub 2019 Apr 20.

Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Recently, mutations in the gene were described as a novel cause for vitamin B6-responsive epilepsy. We report the outcome in case of a male adolescent with a novel homozygous missense variant in who was never treated with pyridoxine until the age of 16 years. He presented with only mild cognitive impairment and an early-onset, well-controlled epilepsy. In our patient, excessive seizure clusters and anxiety states occurred intermittently, suggesting that the combination might be a hallmark in untreated patients. Thus, mutations in should be addressed even in adolescent patients with only mild learning disabilities and relatively good seizure control over the years.
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http://dx.doi.org/10.1055/s-0039-1685501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824897PMC
December 2019
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