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Prenatal Diagnosis May 2024Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed...
Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis. Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo. c.1324 C > T; p.(Arg442*) is a nonsense variant resulting in protein truncation reported to be associated with RRS. c.1366dup; p.(Leu456Profs*3) is a frameshift variant predicted to result in protein truncation reported to segregate with the disease in multiple affected individuals from a single large family with distal symphalangism of the fourth finger. Fetal autopsy following pregnancy termination showed a large head with low-set ears, facial abnormalities, mesomelic bone shortening, hemivertebra, fused S3 and S4 vertebral bodies, several fused rib heads and short penis with buried shaft.
Topics: Humans; Female; Pregnancy; Receptor Tyrosine Kinase-like Orphan Receptors; Ultrasonography, Prenatal; Limb Deformities, Congenital; Adult; Spine; Craniofacial Abnormalities; Fingers; Abnormalities, Multiple; Male; Exome Sequencing; Dwarfism; Urogenital Abnormalities
PubMed: 38504427
DOI: 10.1002/pd.6543 -
Clinical Neurophysiology Practice 2024Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features....
INTRODUCTION
Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features. Expressivity is variable, patients exhibit a combination of intellectual disability, macrocephaly and epilepsy. The diagnosis can be missed, failing to detect the causative pathogenic mutation in patients with somatic mosaicism or even skipping to analyze when the phenotype is not completely expressed.
CASE STUDY
Herein, we report two children harboring the same MTOR recurring mutation (c.5395G>A/p.Glu1799Lys) whose EEG displayed a peculiar combination of midline rhythmic waveforms and asynchronous spike-and-wave discharges with anterior fast activity in sleep and wake. : We suggest these features might be considered as possible hallmarks of the syndrome and could aid to expedite the diagnosis when the phenotype is incomplete.
PubMed: 38495955
DOI: 10.1016/j.cnp.2024.02.001 -
Clinica Chimica Acta; International... Apr 2024Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its...
BACKGROUND
Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns.
METHODOLOGY
DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites.
RESULTS
582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples.
CONCLUSIONS
A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.
Topics: Humans; Infant, Newborn; Glutaryl-CoA Dehydrogenase; Brain Diseases, Metabolic; Biomarkers; Amino Acid Metabolism, Inborn Errors; Metabolomics
PubMed: 38490341
DOI: 10.1016/j.cca.2024.117861 -
Frontiers in Genetics 2024The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white...
The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white matter. With delayed onset, patients typically experience motor problems, epilepsy and slow cognitive decline. No treatment is available. Classic MLC is caused by bi-allelic recessive pathogenic variants in or (also called ). Heterozygous dominant pathogenic variants in lead to remitting MLC, where patients show a similar phenotype in early life, followed by normalization of white matter edema and no clinical regression. Rare patients with heterozygous dominant variants in and classic MLC were recently described. In addition, two siblings with bi-allelic recessive variants in and remitting MLC have been identified. The last systematic overview of variants linked to MLC dates back to 2006. We provide an updated overview of published and novel variants. We report on genetic variants from 508 patients with MLC as confirmed by MRI diagnosis (258 from our database and 250 extracted from 64 published reports). We describe 151 unique variants, 29 variants, 2 variants and 1 variant observed in these MLC patients. We include experiments confirming pathogenicity for some variants, discuss particularly notable variants, and provide an overview of recent scientific and clinical insight in the pathophysiology of MLC.
PubMed: 38487253
DOI: 10.3389/fgene.2024.1352947 -
Molecular Cytogenetics Mar 2024Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and...
BACKGROUND
Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging.
CASE PRESENTATION
A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome.
CONCLUSIONS
The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.
PubMed: 38486332
DOI: 10.1186/s13039-024-00672-6 -
American Journal of Medical Genetics.... Jul 2024Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a...
Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.
Topics: Humans; Megalencephaly; Mutation, Missense; Proto-Oncogene Proteins c-akt; Germ-Line Mutation; Male; Child, Preschool; Phenotype; Hypothyroidism; Female; Human Growth Hormone
PubMed: 38459620
DOI: 10.1002/ajmg.a.63585 -
Journal of Neurointerventional Surgery Mar 2024Infantile-type dural arteriovenous shunts (IDAVS) are rare and heterogeneous vascular lesions, complicating their classification and management. The current tripartite...
BACKGROUND
Infantile-type dural arteriovenous shunts (IDAVS) are rare and heterogeneous vascular lesions, complicating their classification and management. The current tripartite classification of pediatric dural arteriovenous shunts (DAVS) into dural sinus malformation, infantile-type, and adult-type, does not stand up to scrutiny, given the variable presentations of the latter two types in children. We estimate the prevalence of IDAVS and evaluate the long term outcomes after endovascular treatment (EVT).
METHODS
A retrospective review of a pediatric cerebrovascular database between 2006 and 2023 was conducted. Clinical and radiographic data were analyzed to evaluate the presentation and long term outcomes of IDAVS.
RESULTS
IDAVS were identified in 8 (0.5%) of 1463 patients, with mean age at diagnosis of 34.7 months; male infants comprised 62.5%. The most common clinical presentations included macrocephaly (37.5%), seizures (25%), and dilated scalp veins (25%). EVT was performed in 87.5% of cases, averaging 5.8 procedures per patient. Radiographic obliteration was observed in 28.6%. Good clinical outcomes (modified Rankin Scale score of ≤2) were achieved in 85.7%. Our findings showcased discrepancies and limitations in the current classification of pediatric DAVS, prompting a re-evaluation.
CONCLUSION
IDAVS accounted for a small proportion of pediatric cerebrovascular pathologies, with markedly heterogeneous presentations. Stepwise selective embolization was associated with favorable outcomes, and is recommended over an aggressive approach with the goal of complete angiographic obliteration. Our proposed revised classification system bifurcates pediatric DAVS into dural sinus malformations and all other DAVS that are manifest in children, thereby enhancing diagnostic clarity and therapeutic approaches.
PubMed: 38453460
DOI: 10.1136/jnis-2023-021355 -
BMC Medical Genomics Mar 2024Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and... (Review)
Review
Heterozygous truncating variant of TAOK1 in a boy with periventricular nodular heterotopia: a case report and literature review of TAOK1-related neurodevelopmental disorders.
BACKGROUND
Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility.
CASE PRESENTATION
We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia.
CONCLUSIONS
To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.
Topics: Animals; Male; Child; Humans; Periventricular Nodular Heterotopia; Amino Acids; Phosphorylation; Brain; Neurodevelopmental Disorders
PubMed: 38443934
DOI: 10.1186/s12920-024-01840-8 -
Journal of Neurology May 2024Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related...
BACKGROUND
Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition.
CASE SERIES PRESENTATION
We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum.
CONCLUSIONS
This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.
Topics: Humans; Female; Phenotype; DNA-Binding Proteins; Dystonia; Transcription Factors; Child; Adolescent; Neurodevelopmental Disorders; Adult; Dystonic Disorders; Frameshift Mutation; Young Adult; Child, Preschool
PubMed: 38441608
DOI: 10.1007/s00415-024-12271-x