De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforløb).Peer reviewe

Natural history of KBG syndrome in a large European cohort

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.</p

Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder

Purpose: The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated. Methods: We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing. Results: We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%). Conclusion: We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity

Differentiell exprimierte Gene in Neurofibromatose Typ 1 assoziierten gutartigen und bösartigen Nervenscheidentumoren

Neurofibromatosis type 1 (NF1) is one of the most frequent dominantly inherited diseases. The incidence is about 1:3,500 newborn. NF1 patients harbour an increased risk of developing benign nerve sheath tumours such as dermal neurofibromas (dNFs) and plexiform neurofibromas (pNFs) and a 10% lifetime risk of developing malignant peripheral nerve sheath tumours (MPNST). MPNST that usually arise from pre-existing pNFs are highly aggressive malignancies and have a dismal prognosis. To identify genes involved in NF1-tumourigenesis we performed gene expression analysis applying cDNA array technology. 26 NF1-associated tumours and 2 MPNST cell cultures were examined. Using immunohistochemistry and/or Western blotting, 8 genes were evaluated on the protein level. Thus, TP53 gene status was screened by single strand conformational polymorphism in 36 MPNST patients. Expression of 57 genes differed significantly between dNFs, pNFs and MPNST. MMP-13, p53, Syn-1 and PDGFR-α were confirmed on the protein level to be overexpressed in MPNST while Syn-4, PrP and ApoD showed increased expression in neurofibromas. MMP-13 expression was significantly associated with p53 accumulation and with a higher risk of relapse in MPNST patients. TP53 mutants were observed in 11% of MPNST patients. Polymorphism TP53Pro72 was associated with the development of metastases. A panel of genes useful for subclassification of nerve sheath tumours was identified by expression analysis. NF1-associated and sporadic MPNST could not be distinguished by this approach. MMP-13, a matrix metalloproteinase involved in tumour invasion and dissemination, was reported to be stimulated by certain TP53 mutants. The observation that most MMP-13 positive MPNST carried wild-type TP53 suggests the existence of other regulation mechanisms. Nevertheless, MMP-13 expression might be considered a risk factor for relapse. This doctoral thesis has identified several proteins likely to be involved in NF-1 tumourigenesis. The existence of medicines that inhibit MMP-13 and PDGFR-α expression might help to improve therapy for MPNST patients.Die Neurofibromatose Typ 1 (NF1) ist eine der häufigsten dominant vererbten Erkrankungen. Die Inzidenz liegt bei 1:3.500 Neugeborenen. Patienten mit NF1 haben ein erhöhtes Risiko gutartige Nervenscheidentumore wie dermale Neurofibrome (dNFs) und plexiforme Neurofibrome (pNFs) zu entwickeln und ein 10%iges Risiko im Laufe ihres Lebens an einem malignen peripheren Nervenscheidentumor (MPNST) zu erkranken. MPNST, die in der Regel aus pNFs hervorgehen, sind sehr aggressiv und haben eine schlechten Prognose. Um Gene zu identifizieren, die eine Rolle bei der NF1-assoziierten Tumorgenese spielen, wurde eine Genexpressionsanalyse mittels cDNA-Array Technologie durchgeführt. 26 NF1-assoziierte Tumore und 2 MPNST Zelllinien wurden untersucht. 8 Gene wurden auf Proteinebene mittels Immunhistochemie und/ oder Western blot untersucht. Insgesamt wurden Tumore von 56 NF1 Patienten analysiert. Außerdem wurde das TP53 Gen mittels single strand conformational polymorphism (SSCP) auf Mutationen untersucht. Siebenundfünfzig Gene zeigten signifikante Expressionsunterschiede zwischen dNF, pNF und MPNST. Auf Proteinebene konnte eine stärkere Expression von MMP-13, p53, Syn-1 und PDGFR-α in MPNST nachgewiesen werden. Syn-4, PrP und ApoD zeigten erhöhte Expression in Neurofibromen. MMP-13 Expression korrelierte mit p53 Ablagerung und einem erhöhtem Rezidivrisiko. TP53 Mutanten wurde nur in 11% der MPNST detektiert. Die p53Pro72 Variante zeigte eine Assoziation mit Metastasierung. Die Studie identifizierte eine Serie von Genen, die bei der Subklassifizierung von Nervenscheidentumoren hilfreich sein können. NF1-assoziierte und sporadische MPNST konnten nicht differenziert werden. Frühere Studien zeigten, dass die Matrixmetalloproteinase MMP-13, welche eine Rolle bei Invasion und Metastasierung spielt, durch p53 Mutanten stimuliert wird. Die Beobachtung, dass die Mehrheit der hier untersuchten MMP-13-positiven Tumore wildtyp TP53 trugen, weißt auf andere Regulationsmechanismen. MMP-13 könnte sich allerdings als prognostischer Marker eignen. Diese Doktorarbeit hat Proteine identifiziert, die mutmaßlich eine Rolle bei Entwicklung von Nervenscheidentumoren spielen. Bereits vorhandene Medikamente, die MMP-13 und PDGFR-α inhibieren, könnten zu verbesserter Behandlung von MPNST Patienten beitragen

Blunted circadian variation of blood pressure in individuals with neurofibromatosis type 1

Abstract Background Cardiovascular events such as myocardial infarction and stroke are life-threatening complications associated with Neurofibromatosis type 1 (NF1). As previous studies observed an association between cardiovascular events and the loss of circadian variations of blood pressure, we investigated the 24 h circadian rhythm of blood pressure (BP) in 24 NF1 patients (10 males and 14 females, with a mean age of 39.5 years ± 14 years) by using ambulatory blood pressure monitoring (ABPM). Results Only one-third of the patient were dippers, 50% were non-dippers, and 17% were risers. Reduced variability of systolic and diastolic nocturnal blood pressure was observed in NF1 patients compared with several studies of normotensive individuals (p = 0.024). In NF1 patients, the blunted systolic nocturnal decline was significantly associated with the number of neurofibromas (p = 0.049) and the presence of a plexiform neurofibroma (p = 0.020). Conclusions Most NF1 patients in this study showed a “non-dipper” pattern with a blunted nocturnal BP decline, which is considered an independent risk factor for cardiovascular events in normotensive and hypertensive individuals. Periodic monitoring of BP should be included in NF1 follow-up guidelines to diagnose masked hypertension or a non-dipper/riser pattern which would significantly increase the morbidity and mortality of NF1 patients to implement therapeutic strategies

Impact of Neurofibromatosis Type 1 on Quality of Life Using the Skindex-29 Questionnaire Quality of Life in Nf1

Abstract Background: Neurofibromatosis type 1 (NF1) is the most common genodermatose which predisposed affected patients to melanic lesions and benign tumors. NF1 is associated with considerable esthetic and functional burden affecting negatively patients’ quality of life (QoL). This study aims to assess the clinical features of NF1 patients and evaluate their impact on QoL. NF1 patients were identified from a public health database of a region in Spain. All patients underwent clinical and ophthalmological evaluation for NF1 features. QoL was measured with the Spanish version of the Skindex-29. Logistic regression was performed to determine the factors associated with quality of life. Results: Fourty patients fulfilling NF1 National Institute of Health criteria were recruited (40.95 years ± 16.1 SD). The mean total Skindex-29 score was 14 ± 11 (emotion: 20 ±18, symptoms 10±11, functioning 9±10).Woman, NF1 patients with lower educational level or macrocephaly were associated with poorer quality of life scores. Itching, headaches and sleep troubles were identified to negatively influence quality of life of NF1 patients. Conclusion: NF1 considerably influences the psychological well-being of NF1 patients. We observed that female patients, low-educated patients and macrocephalic patients scored higher on the emotional dimension of the skindex-29 and could therefore be more at risk of depression. We also pointed out some “minor symptoms” that negatively impacts NF1 patients QoL such as itching, sleep troubles or headache which could be treated if seek by doctors.</jats:p

Spinal Cerebrotendinous Xanthomatosis: An Easily Overlooked Treatable Disorder

Abstract Background: Classic cerebrotendinous xanthomatosis (CTX; OMIM #213700) manifests itself in childhood with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. Biallelic inactivation of CYP27A1 is responsible for cholesterol 27-hydroxylation, leading to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas. Methods: We report on a 28-year old woman diagnosed with CTX who worsened, under treatment, a spinal form of CTX. A review of spinal CTX in the literature is also described. Spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. Only patients with clinical features of spinal CTX and/or with a typical spinal MRI were included.Results: A woman presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Treatment was discontinued several times and patient developed psychosis and an ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts, compatible with spinal CTX. Thirty-three patients with spinal CTX were identified in the literature. All patients presented pyramidal signs and 48% dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ2; p&lt;0.00001).Conclusions: The diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.</jats:p