Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these “unusual” PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

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Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability

Science Advances ◽

10.1126/sciadv.abf3072 ◽

2021 ◽

Vol 7 (13) ◽

pp. eabf3072

Author(s):

Y. Nagayoshi ◽

T. Chujo ◽

S. Hirata ◽

H. Nakatsuka ◽

C.-W. Chen ◽

...

Keyword(s):

Intellectual Disability ◽

State Level ◽

Memory Deficits ◽

Ribosome Profiling ◽

Translation Efficiency ◽

Trna Modification ◽

Synaptic Organization ◽

Transfer Rnas ◽

The Brain

FtsJ RNA 2′-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient–derived cells. Loss of 2′-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

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Selective Vulnerability of The Brain To Genetic Mutations And Unique Spatiotemporal Activities of Genes Are Associated with Intellectual Disability, Autism And Schizophrenia

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2016.09.482 ◽

2017 ◽

Vol 27 ◽

pp. S428 ◽

Cited By ~ 1

Author(s):

Shahar Shohat ◽

Eyal Ben-David ◽

Sagiv Shifman

Keyword(s):

Intellectual Disability ◽

Selective Vulnerability ◽

Genetic Mutations ◽

The Brain

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Behavioral problems in people with intellectual disability: Basic facts, incidence and risk factors

Specijalna edukacija i rehabilitacija ◽

10.5937/specedreh12-3395 ◽

2013 ◽

Vol 12 (2) ◽

pp. 203-219

Author(s):

Buha Natasa ◽

Gligorovic Milica

Keyword(s):

Risk Factors ◽

Intellectual Disability ◽

Behavioral Problems ◽

Basic Facts

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Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation

eLife ◽

10.7554/elife.50895 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Callison E Alcott ◽

Hari Krishna Yalamanchili ◽

Ping Ji ◽

Meike E van der Heijden ◽

Alexander Saltzman ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Level ◽

Alternative Polyadenylation ◽

Copy Number Variations ◽

Human Stem Cell ◽

Partial Loss ◽

Learning Deficits ◽

Cortical Hyperexcitability ◽

The Brain ◽

Cognate Protein

We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated with intellectual disability (Gennarino et al., 2015). However, the patients’ CNVs also included other genes. To determine if reduced NUDT21 function alone can cause disease, we generated Nudt21+/- mice to mimic NUDT21-deletion patients. We found that although these mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the Nudt21+/- mice have learning deficits, cortical hyperexcitability, and misregulated alternative polyadenylation (APA) in their hippocampi. Further, to determine the mediators driving neural dysfunction in humans, we partially inhibited NUDT21 in human stem cell-derived neurons to reduce CFIm25 by 30%. This induced APA and protein level misregulation in hundreds of genes, a number of which cause intellectual disability when mutated. Altogether, these results show that disruption of NUDT21-regulated APA events in the brain can cause intellectual disability.

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Intellectual disability and mental disorders in a US population representative sample of adolescents

Psychological Medicine ◽

10.1017/s0033291718001605 ◽

2018 ◽

Vol 49 (6) ◽

pp. 952-961 ◽

Cited By ~ 9

Author(s):

Jonathan M. Platt ◽

Katherine M. Keyes ◽

Katie A. McLaughlin ◽

Alan S. Kaufman

Keyword(s):

Bipolar Disorder ◽

Intellectual Disability ◽

Mental Disorders ◽

Mental Disorder ◽

Behavioral Problems ◽

Behavior Disorders ◽

Representative Sample ◽

Age Of Onset ◽

Population Sample ◽

Clinical Samples

AbstractBackgroundMost research on the prevalence, distribution, and psychiatric comorbidity of intellectual disability (ID) relies on clinical samples, limiting the generalizability and utility of ID assessment in a legal context. This study assessed ID prevalence in a population-representative sample of US adolescents and examined associations of ID with socio-demographic factors and mental disorders.MethodsData were drawn from the National Comorbidity Survey Adolescent Supplement (N= 6256). ID was defined as: (1) IQ ⩽ 76, measured using the Kaufman Brief Intelligence Test; (2) an adaptive behavior score ⩽76, and (3) age of onset ⩽18 measured using a validated scale. The Composite International Diagnostic Interview assessed 15 lifetime mental disorders. The Sheehan disability scale assessed disorder severity. We used logistic regression models to estimate differences in lifetime disorders for adolescents with and without ID.ResultsID prevalence was 3.2%. Among adolescents with ID, 65.1% met lifetime criteria for a mental disorder. ID status was associated with specific phobia, agoraphobia, and bipolar disorder, but not behavior disorders after adjustment for socio-demographics. Adolescents with ID and mental disorders were significantly more likely to exhibit severe impairment than those without ID.ConclusionsThese findings highlight how sample selection and overlap between ID and psychopathology symptoms might bias understanding of the mental health consequences of ID. For example, associations between ID and behavior disorders widely reported in clinical samples were not observed in a population-representative sample after adjustment for socio-demographic confounders. Valid assessment and understanding of these constructs may prove influential in the legal system by influencing treatment referrals and capital punishment decisions.General Scientific SummaryCurrent definitions of intellectual disability (ID) are based on three criteria: formal designation of low intelligence through artificial problem-solving tasks, impairment in one's ability to function in his/her social environment, and early age of onset. In a national population sample of adolescents, the majority of those with ID met criteria for a lifetime mental disorder. Phobias and bipolar disorder, but not behavior disorders, were elevated in adolescents with ID. Findings highlight the need to consider how behavioral problems are conceptualized and classified in people with ID.

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Antipsychotic Drug Prescription and Behavioral Problems in Individuals with Intellectual Disability

NeuroPsychopharmacotherapy ◽

10.1007/978-3-319-56015-1_445-1 ◽

2021 ◽

pp. 1-21

Author(s):

Gerda Margaretha de Kuijper ◽

Albert Willem Lenderink

Keyword(s):

Intellectual Disability ◽

Antipsychotic Drug ◽

Behavioral Problems ◽

Drug Prescription

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Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

Journal of Pediatric Neurology ◽

10.1055/s-0039-1698437 ◽

2019 ◽

Vol 18 (04) ◽

pp. 210-213

Author(s):

Yohei Harada ◽

Seth T. Sorensen ◽

Akilandeswari Aravindhan ◽

Vikki Stefans ◽

Aravindhan Veerapandiyan

Keyword(s):

Intellectual Disability ◽

Muscular Dystrophy ◽

Behavioral Problems ◽

Nonsense Mutation ◽

Neuromuscular Disorders ◽

Elevated Serum ◽

Becker Muscular Dystrophy ◽

Genetic Changes ◽

Dmd Gene ◽

Neurobehavioral Deficits

AbstractDystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

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Worster-Drought Syndrome Associated With LINS Mutations

Child Neurology Open ◽

10.1177/2329048x18791083 ◽

2018 ◽

Vol 5 ◽

pp. 2329048X1879108 ◽

Cited By ~ 1

Author(s):

Hugh J. McMillan ◽

Anne-Lise Holahan ◽

Julie Richer

Keyword(s):

Intellectual Disability ◽

Neuropsychological Testing ◽

Receptive Language ◽

Receptive Vocabulary ◽

Tongue Movement ◽

Nonsense Mutations ◽

Prior Testing ◽

Molecular Etiology ◽

Nonverbal Reasoning ◽

The Brain

Worster-Drought syndrome is a congenital, pseudobulbar paresis. There is no identified molecular etiology despite familial cases reported. The authors report a boy who was diagnosed with Worster-Drought syndrome due to longstanding drooling, dysphagia, and impaired tongue movement. Magnetic resonance imaging of the brain was unrevealing. At 14 years old, he remains aphonic with normal facial and extraocular movements. Nonsense mutations in the LINS gene, p.Glu366X and p.Lys393X, were found. Results from neuropsychological testing at 14 years old were consistent with a diagnosis of intellectual disability and revealed nonverbal reasoning skills at a 5-year-old level with relative sparing of his receptive vocabulary and visual attention. Compared to prior testing at 9 years old, his receptive language improved from a 6-year-old to an 8.5-year-old level. The authors report LINS mutations associated with Worster-Drought syndrome. This highlights that despite severe and persistent aphonia, receptive language improvements can be observed within the context of intellectual disability.

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