Two new cases of nonepileptic neurodevelopmental disorder due to GRIN2B variants and detailed clinical description of the behavioral phenotype

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage. Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.

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NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity

Human Molecular Genetics ◽

10.1093/hmg/ddaa237 ◽

2020 ◽

Author(s):

Harikiran Nistala ◽

John Dronzek ◽

Claudia Gonzaga-Jauregui ◽

Shek Man Chim ◽

Saathyaki Rajamani ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Neurodevelopmental Disorder ◽

Cortical Atrophy ◽

Global Developmental Delay ◽

Compound Heterozygous ◽

Genetic Ablation ◽

Severe Intellectual Disability ◽

Disease Biology ◽

Variant Alleles ◽

Clinical Description

Abstract Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

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Associations Among Diurnal Salivary Cortisol Patterns, Medication Use, and Behavioral Phenotype Features in a Community Sample of Rett Syndrome

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944-7558-125.5.353 ◽

2020 ◽

Vol 125 (5) ◽

pp. 353-368

Author(s):

Breanne J. Byiers ◽

Ameante Payen ◽

Timothy Feyma ◽

Angela Panoskaltsis-Mortari ◽

Michael J. Ehrhardt ◽

...

Keyword(s):

Rett Syndrome ◽

Hpa Axis ◽

Stress Responses ◽

Salivary Cortisol ◽

Community Sample ◽

Neurodevelopmental Disorder ◽

Medication Use ◽

Behavioral Phenotype ◽

Anticonvulsant Medication ◽

Mutation Type

Abstract Rett syndrome (RTT) is a severe neurodevelopmental disorder resulting from mutations of the MECP2 gene. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal stress responses have been observed in animal models of RTT, but little is known about HPA axis function among individuals with RTT. Diurnal salivary cortisol patterns from 30 females with RTT were examined in relation to mutation type, medication use, and features of the RTT behavioral phenotype. Cortisol patterns were significantly related to mutation severity, anticonvulsant medication status, and bruxism (tooth grinding). This study provides preliminary support for the hypothesis that RTT may be at risk for outcomes associated with aberrant HPA axis function, and that this risk may be mediated by mutation type.

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Functional modeling of NMIHBA-causing PRUNE1 variants reveals a requirement for its exopolyphosphatase activity

10.1101/2020.03.02.973909 ◽

2020 ◽

Author(s):

Harikiran Nistala ◽

John Dronzek ◽

Claudia Gonzaga-Jauregui ◽

Shek Man Chim ◽

Saathyaki Rajamani ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Neurodevelopmental Disorder ◽

Cortical Atrophy ◽

Global Developmental Delay ◽

Compound Heterozygous ◽

Genetic Ablation ◽

Severe Intellectual Disability ◽

Disease Biology ◽

Variant Alleles ◽

Clinical Description

AbstractNeurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G>A (p.Arg128Gln), c.520G>T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

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Clinical Characterization of a 6-Year-Old Patient with Autism and Two Adjacent Duplications on 10q11.22q11.23. A Case Report

Children ◽

10.3390/children8060518 ◽

2021 ◽

Vol 8 (6) ◽

pp. 518

Author(s):

Giovanna Tritto ◽

Ivana Ricca ◽

Marco Turi ◽

Andrea Gemma ◽

Filippo Muratori ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Molecular Genetic ◽

Copy Number Variant ◽

Autism Spectrum ◽

Clinical Genetic ◽

Genetic Studies ◽

Genome Wide ◽

Patterns Of Behavior ◽

Clinical Description ◽

Candidate Regions

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the core areas of social communication and interaction and restricted, repetitive patterns of behavior, interests or activities. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of the involvement of genetic factors in etiology. Molecular genetic studies report some associations with candidate genes, and candidate regions have emerged from several genome-wide linkage studies. Here, we report a clinical case of autism in a 6-year-old boy with double duplication on 10q11.22q11.23 with ASD (Autism Spectrum Disorder), intellectual disability, developmental delay, hypotonia, gross-motor skills deficit, overgrowth and mild dysmorphic features. In the literature, only five cases of ASD with 10q11.21q11.23 duplication are reported. This is the first extensive clinical description of an ASD subject with 10q11.22q11.23 duplication. Our findings suggest that 10q11.21q11.23 microduplication could represent a copy number variant that predisposes to autism.

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RLS May Be a Neurodevelopmental Disorder

Internal Medicine News ◽

10.1016/s1097-8690(08)71143-0 ◽

2008 ◽

Vol 41 (20) ◽

pp. 17

Author(s):

PATRICE WENDLING

Keyword(s):

Neurodevelopmental Disorder

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Sleep and its Disorders in Children and Adolescents with a Neurodevelopmental Disorder

10.1017/cbo9780511972935 ◽

2014 ◽

Cited By ~ 11

Author(s):

Gregory Stores

Keyword(s):

Children And Adolescents ◽

Neurodevelopmental Disorder

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Moving Beyond the Clinical Description of People With Developmental Disabilities

Contemporary Psychology ◽

10.1037/031396 ◽

1992 ◽

Vol 37 (3) ◽

pp. 254-255

Author(s):

Valerie J. Janesick

Keyword(s):

Developmental Disabilities ◽

Clinical Description

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Reconsidering NMIHBA Core Features: Macrocephaly Is Not a So Unusual Sign in PRUNE1-Related Encephalopathy

Journal of Pediatric Neurology ◽

10.1055/s-0040-1715526 ◽

2020 ◽

Author(s):

Roberta Battini ◽

Enrico Bertini ◽

Roberta Milone ◽

Chiara Aiello ◽

Rosa Pasquariello ◽

...

Keyword(s):

Nervous System ◽

Differential Diagnosis ◽

Clinical Features ◽

Neurodevelopmental Disorder ◽

Recurrent Mutation ◽

Clinical Suspicion ◽

Alexander Disease ◽

Brain Anomalies ◽

Progressive Encephalopathy ◽

Core Features

Abstract PRUNE1-related disorders manifest as severe neurodevelopmental conditions associated with neurodegeneration, implying a differential diagnosis at birth with static encephalopathies, and later with those manifesting progressive brain damage with the involvement of both the central and the peripheral nervous system.Here we report on another patient with PRUNE1 (p.Asp106Asn) recurrent mutation, whose leukodystrophy, inferior olives hyperintensity, and macrocephaly led to the misleading clinical suspicion of Alexander disease. Clinical features, together with other recent descriptions, suggest avoiding the term “microcephaly” in defining this disorder that could be renamed “neurodevelopmental disorder with progressive encephalopathy, hypotonia, and variable brain anomalies” (NPEHBA).

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Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721371 ◽

2020 ◽

Author(s):

Divya Nagabushana ◽

Aparajita Chatterjee ◽

Raghavendra Kenchaiah ◽

Ajay Asranna ◽

Gautham Arunachal ◽

...

Keyword(s):

Late Onset ◽

Neurodevelopmental Disorder ◽

Epileptic Encephalopathy ◽

Infantile Spasms ◽

The Past ◽

Resource Limited ◽

The Central Nervous System ◽

Motor Milestone ◽

Behavior And Cognition ◽

Atypical Rett Syndrome

Abstract Introduction IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system. Case Report We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence. Conclusion IQSEC2-related encephalopathy may present with atypical Rett phenotype and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.

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