PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

2018 ◽  
Vol 49 (05) ◽  
pp. 330-338 ◽  
Author(s):  
Anna Schossig ◽  
Tobias Haack ◽  
Reka Kovács-Nagy ◽  
Matthias Braunisch ◽  
Christine Makowski ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Brain Mri ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Multiplex Family ◽  
Consistent Finding ◽  
Whole Exome ◽  
Severe Developmental Disabilities ◽  
Stem Lesions

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

scholarly journals SAT-081 Hidden in Plain Sight: Rethinking Our Approach to Allan-Herndon-Dudley Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alyssa M Dye ◽  
Grace Bazan Nelson ◽  
Alicia Marie Diaz-Thomas
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Brain Mri ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Neurological Manifestations ◽  
Free T4 ◽  
Phase 2 Trial ◽  
Whole Exome

Abstract Background: Allan-Herndon-Dudley (AHD) is a rare X-linked disorder with neurological manifestations secondary to a mutation in monocarboxylate transporter 8, a protein that transports T3 into nerve cells in the brain. AHD is characterized by increased serum free T3, decreased serum free T4 and normal serum TSH levels as well as the severe neurological manifestations including global developmental delay, hypotonia, and joint contractures (1). A phase 2 trial using triodyothyroacetic acid has shown promise in treating this disorder (2). We report on three children who were diagnosed by whole exome sequencing after presenting with neurological manifestations. Clinical Cases: Patient 1 presented at 4 months to the neurology clinic for seizures. He had a normal newborn screen. Worsening developmental delays and central hypotonia prompted a brain MRI that revealed delayed myelination for age. At 6 months a chromosomal microarray and metabolic work-up were performed and were nondiagnostic. Whole exome sequencing was obtained at the age of 4.5 years revealing a mutation in the SLC16A2 gene (p.Ser210Tyr). Thyroid studies were consistent with the diagnosis. Patient 2 presented to neurology at 9 months for developmental delay. A brain MRI was obtained which was within normal limits. At 14 months an acylcarnitine profile was obtained which indicated a possible CPT1 deficiency, which did not fit his clinical picture. Chromosomal microarray as well as work-up for inborn errors of metabolism were performed and were nondiagnostic. Thyroid studies were obtained which showed low free T4 with normal TSH. Whole exome sequencing was obtained at the age of 2.5 years, which revealed a mutation in SLC16A2 (p.R371C). Patient 3 presented as sibling of patient 2 with known AHD syndrome. Testing for SLC16A2 was performed at the age of 5 months and returned positive for same mutation as sibling (p.R371C). Conclusion: Allan-Herndon-Dudley syndrome is a rare neurological disease secondary to a mutation in the T3 transporter protein to nervous tissue. A high index of suspicion as well as thyroid studies should be obtained in patients presenting with central hypotonia and global developmental delay with normal newborn screens, particularly in states that use TSH as a screening test. This is especially important as treatments are becoming available that may help prevent neurological devastation seen in these patients. References: 1. Dumitrescu AM, Fu J, Dempsey MA, Refetoff S. MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993 2. Groeneweg S, Peeters RP, Moran C, et al. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(9):695-706.

scholarly journals Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novoGRIN2Amutation

Epilepsia ◽  
2014 ◽  
Vol 55 (7) ◽  
pp. e75-e79 ◽  
Author(s):  
Sunita Venkateswaran ◽  
Ken A. Myers ◽  
Amanda C. Smith ◽  
Chandree L. Beaulieu ◽  
Jeremy A. Schwartzentruber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Intractable Epilepsy ◽  
Global Developmental Delay ◽  
Whole Exome

scholarly journals P.133 Expanding the phenotype of TRNT1 mutations to include Leigh syndrome

2018 ◽  
Vol 45 (s2) ◽  
pp. S51-S51
Author(s):  
C Gorodetsky ◽  
CF Morel ◽  
I Tein
Keyword(s):  
Developmental Delay ◽  
Early Adulthood ◽  
Leigh Syndrome ◽  
Global Developmental Delay ◽  
High Dose ◽  
Sideroblastic Anemia ◽  
Whole Exome ◽  
Mitochondrial Transfer ◽  
Neurological Phenotype ◽  
Biallelic Mutations

Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, -B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported. Methods:Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slow neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS. Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual. Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.

Whole exome sequencing identifies a novel 5 Mb deletion at 14q12 region in a patient with global developmental delay, microcephaly and seizures

Gene ◽  
2018 ◽  
Vol 673 ◽  
pp. 56-60 ◽  
Author(s):  
Venugopal S. Vineeth ◽  
Usha R. Dutta ◽  
Karthik Tallapaka ◽  
Aneek Das Bhowmik ◽  
Ashwin Dalal
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Global Developmental Delay ◽  
Whole Exome

scholarly journals KCNQ2 mutations: genotype-phenotype association beyond epilepsy

2015 ◽  
Vol 42 (S1) ◽  
pp. S8-S8
Author(s):  
SE Buerki ◽  
GA Horwath ◽  
MI Van Allen ◽  
A Datta ◽  
C Boelman ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Autonomic Dysfunction ◽  
De Novo ◽  
Focal Epilepsy ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
High Signal ◽  
Brain Volume Loss ◽  
Hyperkinetic Movement Disorder

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

scholarly journals Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

2020 ◽  
pp. 1-8
Author(s):  
Lindsey Schmidt ◽  
Karen E. Wain ◽  
Catherine Hajek ◽  
Juvianee I. Estrada-Veras ◽  
Maria J. Guillen Sacoto ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Case Series ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Cortical Dysplasia ◽  
Global Developmental Delay ◽  
Tubulin Genes ◽  
Pathogenic Variants ◽  
Brain Malformations ◽  
History Of

Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is <i>TUBB2A</i>-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the <i>TUBB2A</i> gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in <i>TUBB2A</i> (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of <i>TUBB2A</i>-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.

scholarly journals Case Report: De novo Variants of KMT2E Cause O'Donnell-Luria-Rodan Syndrome: Additional Cases and Literature Review

2021 ◽  
Vol 9 ◽  
Author(s):  
Yang Li ◽  
Lijuan Fan ◽  
Rong Luo ◽  
Zuozhen Yang ◽  
Meng Yuan ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Clinical Manifestations ◽  
Global Developmental Delay ◽  
Feeding Difficulties ◽  
Gene Testing ◽  
Whole Exome ◽  
Systemic Disorder ◽  
Synonymous Variant ◽  
Genetics And Genomics

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties.Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations.Results: A 186 G&gt;A synonymous variant [NM_182931.3:exon4: c.186G&gt;A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C&gt;T transition variant [NM_182931.3:exon27: c.5417C&gt;T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing.Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.

A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay

Neurogenetics ◽  
2018 ◽  
Vol 19 (3) ◽  
pp. 151-156 ◽  
Author(s):  
Jessika Johannsen ◽  
Fanny Kortüm ◽  
Georg Rosenberger ◽  
Kristin Bokelmann ◽  
Markus A. Schirmer ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Complete Loss ◽  
Wwox Gene
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