GAMT deficiency

Noniron deficiency microcytic anemia, dysmorphic features, and intellectual disability: Diagnostic clues for α-thalassemia/mental retardation associated with chromosome 16 syndrome

Editorial: Introduction to Special Section on Evidence-Based Practices for Persons With Intellectual and Developmental Disabilities

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis that results in intellectual disability, epilepsy, expressive language delay, and dystonia. We report data from two siblings with an uncommon GAMT deficiency phenotype and their clinical, biochemical, imaging, and treatment findings. The older sibling had intellectual disability, epilepsy, and generalized dystonia. The younger sibling had intellectual disability and generalized dystonia. After treatment with creatine, verbal fluency improved, as well as dystonia and aggression. This study confirms that in patients with unexplained intellectual disability, epilepsy, and/or movement disorders, GAMT deficiency should be considered. GAMT-associated cerebral creatine deficiency syndrome is a potentially treatable condition and can be identified by elevated levels of guanidinoacetate in plasma or urine or by a significantly decreased creatine peak on magnetic resonance spectroscopy.

Self-determination is a key construct to guarantee the development of skills that enable people with disabilities to acquire control over their lives. This concept is understood as a set of volitional actions or abilities that help the person to act as the primary causal agent in their own life without unnecessary external influences. Progressively, this construct has been shaped as a personal disposition to exercise control over one's own behavior, becoming a priority educational goal and an indicator of quality of life in the field of intellectual disability. However, people with intellectual disabilities have premature aging processes generally accompanied by mental health disorders or emotional problems that hinder the performance of self-determination skills. Specifically, they have difficulties in developing actions aimed at promoting positive attributions of effectiveness or aimed at establishing personal goals. This complicates the acquisition of skills for self-regulation and the increase of personal empowerment skills. This study seeks to know the self-determination levels of 516 aging adults with intellectual disabilities aged between 45 and 86 years (M = 68.32; S = 4.95). Most of them live in the Metropolitan Region (Chile), have severe intellectual disabilities, are men and live with the family. From a quantitative approach and under an inclusive research model, the data have been collected using an ad hoc scale as a result of the revision of the ARC-INICO Self-determination Assessment Scale (Verdugo et al., 2015) and the Self-determination Scale ARC staff (Wehmeyer, 1995). The results have been analyzed using descriptive and inferential statistics that have preceded the use of parametric statistics. The self-determination levels of the majority of the participants (39.1 %) are in a low range. In addition, the development of competencies related to self-defense or self-knowledge are greatly diminished, unlike other skills such as making choices or solving problems. Likewise, the analysis shows how those participants who reside in the family home present higher averages in their self-determination than those who live outside the family home. Similarly, participants with mental health disorders have lower averages in their self-determination than those who do not present these pathologies. Regarding the degree of disability, the levels of self-determination of the mild group are higher than those of the group of adults with severe intellectual disability. Those who most often have family support have higher levels of self-determination than those who receive only professional support. With regard to age, the youngest participants have higher averages than the rest in terms of their self-determination. The discussion highlights, among others, the need to prioritize the learning of skills related to self-realization as the basis of the proposals for intervention in self-determination at this stage of life. The results suggest some implications to consider for the planning of interventions, for example, they should seek the development of skills that strengthen the self-defense capacity of people with intellectual disabilities, promote the increase of opportunities for the realization of meaningful choices, adapt to the scenarios in which aging people with intellectual disabilities usually operate, and involve families and professionals to achieve skills related to self-determination in old age. Despite the fact that one of the main limitations of this research is that the results are not generalizable, this study contributes to enriching the bulk of research on self-determination in late adulthood, this being an aspect barely addressed in the literature. In addition, it suggests the development of future lines of research related to the impact of technological supports on the quality of life of people with intellectual disabilities who age or with the study of cognitive impairment or the presence of mental health disorders in the levels of self-determination of these people. https://doi.org/10.16888/interd.2021.38.3.8

Although important progress has been made during the past decade, research on pain in people with intellectual disabilities is still scarce. Pain assessment in people with intellectual disabilities is a frequent and difficult problem, especially for nurses working with people with intellectual disabilities on a daily basis. Gathering more information about pain in people with intellectual disabilities is of major importance and relevance for nursing, and adds to the developing body of knowledge. To investigate the nature and relative importance of non-verbal indicators used by nurses to assess pain in people with a severe or profound intellectual disability. A questionnaire consisting of 158 indicators of pain was used. A total of 135 nurses from nine institutions specializing in the care of people with intellectual disability were asked to rate each indicator on a scale of 1-10 to show which non-verbal expressions they considered important in diagnosing pain. A total of 109 nurses responded. All 158 indicators were mentioned as being important to indicate pain. All except four had a range of 9. Seven (moaning during manipulation, crying during manipulation, painful facial expression during manipulation, swelling, screaming during manipulation, not using (affected) body part, and moving the body in a specific way of behaving) were reported as 'very important' by more than 50% of nurses. The lowest score (median 5.5; minimum 1, maximum 10) was given to the indicator 'waving arm movements'. The pain of people with severe intellectual disability appeared to be assessed differently from that of people with profound intellectual disability. Indicators belonging to the 'physiological' category scored relatively higher in the group of nurses specializing in profound disability. In contrast, indicators belonging to the 'social-emotional' category were scored relatively higher by nurses specializing in severe disability. Nurses used a wide range of indicators to assess pain in people with intellectual disability. Functional abilities and level of disability seem to influence the indicators used.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.

People with severe and profound levels of intellectual disability (ID) are frequently examined as a single group in research. However, these two groups may be significantly different, particularly in the area of emotional and behavioural difficulties. The Developmental Behaviour Checklist (DBC) was completed by parents and caregivers of 107 people with severe ID and 22 people with profound ID at four time periods across 12 years. Regression analyses were used to examine trends in sub-scale scores across time and groups. Significant differences between the groups of people with severe and profound ID were found. People with profound ID had significantly lower scores across all sub-scales except Social Relating. This was usually related to fewer items being selected as present for people with profound ID, as opposed to the scores being attributable to lower item severity scores. There are significant differences between groups of people with severe and profound ID in scores on the DBC, indicating differences in behavioural and emotional problems. Caution should be exercised by researchers treating these two disparate groups as a single group, and by practitioners translating such findings into practice.

Between 1% and 3% of persons in general population are estimated to have some degree of intellectual disability. A diagnosis of intellectual disability is based on clinical history, level of intellectual ability and level of adaptive function. Both, the intellectual and adaptive functioning are measured using individually administered standardized tests. More than 75% of persons who have intellectual disability have mild intellectual disability and an underlying specific etiology is less likely to be identified; whereas, in a small percentage of persons with severe intellectual disability, an underlying specific biologic cause is highly likely to be identified. Genetic abnormalities, inborn errors of metabolism and brain malformations are major categories of causes identified in severe to profound intellectual disability. The initial clinical presentation and recognition depends on the severity and underlying cause of intellectual disability. The etiology, severity, cognitive abilities, and adaptive function, vary among persons with intellectual disability and need consideration in developing a treatment plan. The physician plays an essential role in the evaluation, treatment of associated medical conditions and preventive care, and in facilitating and coordinating consultative services and community based care.

The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.

BackgroundCalcium ions are involved in several human cellular processes; nevertheless, the relationship between calcium channelopathies (CCs) and autism spectrum disorder (ASD) or intellectual disability (ID) has been previously investigated. We delineate the spectrum of clinical phenotypes and the symptoms associated with a syndrome caused by an inherited gain-of-function mutation in CACNA1D in a family with a history of neuropsychiatric disorders. We also review the clinical and molecular phenotype of previously reported variants of CACNA1D.Case presentationWe report the case of a 9-year-old female patient, diagnosed with ASD, severe ID, hyperactivity, and aggressive impulsive behaviors. The father, who was a 65-year-old at the time of his death, had ID and developed major depressive disorder with catatonic features and nihilistic delusion, followed by rapidly progressive dementia. He died after experiencing prolonged seizures followed by post-cardiac arrest. The patient’s sister was a 30-year-old woman, known to have a severe ID with aggressive behaviors and sleep disorders. The sister has been diagnosed with bipolar disorder and psychosis. Through whole exome sequencing, a heterozygous previously identified and functionally characterized missense likely pathogenic variant was identified in the CACNA1D gene NM_001128840.3: c.2015C > T (p.Ser672Leu). These findings are consistent with the genetic diagnosis of autosomal dominant primary aldosteronism, seizures, and neurological abnormalities. This variant was found in the heterozygous status in the patient, her father, and her affected sister.ConclusionThis case report will help to determine the key clinical features of this syndrome, which exhibits variable clinical presentations.

BackgroundMED13L-related intellectual disability is a new syndrome that is characterized by intellectual disability (ID), motor developmental delay, speech impairment, hypotonia and facial dysmorphism. Both the MED13L haploinsufficiency mutation and missense mutation were reported to be causative. It has also been reported that patients carrying missense mutations have more frequent epilepsy and show a more severe phenotype.Case presentationWe report a child with ID, speech impairment, severe motor developmental delay, facial deformity, hypotonia, muscular atrophy, scoliosis, odontoprisis, abnormal electroencephalogram (EEG), and congenital ureteropelvic junction obstruction (UPJO) combined with high ureter attachment. We used whole-exome sequencing (WES) to detect the genetic aberration of the child and found a de novo mutation, c.2605C > T (p.Pro869Ser), in the MED13L gene. Neither of her parents carried the mutation. Additionally, we review the literature and summarize the phenotypes and features of reported missense mutations. After reviewing the literature, approximately 17 missense mutations in 20 patients have been reported thus far. For 18 patients (including our case) whose clinical manifestations were provided, 100% of the patients had ID or developmental delay (DD). A total of 88.9, 83.3 and 66.7% of the patients had speech impairment, delayed milestones and hypotonia, respectively. A total of 83.3% of the patients exhibited craniofacial deformity or other dysmorphic features. Behavioral difficulties and autistic features were observed in 55.6% of the patients. Cardiac anomalies were seen in only 27.8% of the patients. Of these patients, 44.4% had epileptic seizures. Of the 17 mutations, 2 were located in the N-terminal domain, 8 were located in the C-terminal domain, and 1 was located in an α-helical sequence stretch. One of them was located in the MID domain of the MedPIWI module.ConclusionsWe report a new patient with a reported missense mutation, c.2605C > T (p.Pro869Ser), who exhibited some infrequent manifestations except common phenotypes, which may broaden the known clinical spectrum. Additionally, by reviewing the literature, we also found that patients with missense mutations have a higher incidence of seizures, MRI abnormalities, autistic features and cardiac anomalies. They also have more severe ID and hypotonia. Our case further demonstrates that Pro869Ser is a hotspot mutation of the MED13L gene.

ABSTRACTBackground The social relationships model was developed to describe positive relationships between support staff and people with intellectual disability. We evaluated an educational intervention based on this model.Method Eighteen staff supporting 5 adult service users with severe or profound intellectual disability from 3 day services received the intervention. Mixed methods were used. A multiple baseline design determined changes in relationship processes between staff and service users following intervention. Descriptive field notes and staff interviews provided qualitative data.Results Positive changes in relationship processes were found, but the results were variable. Of note was a high effect for 1 service user, a minimal effect for 2, and no effect for 2 service users. Field notes revealed contributors to variable results, and interview data highlighted changes not captured by quantitative measures.Conclusions An educational intervention based on the social relationship model shows promise as a means to enhance staff relationships with people with intellectual disability.

BackgroundOne-third to half of people with intellectual disabilities suffer from chronic constipation (defined as two or fewer bowel movements weekly or taking regular laxatives three or more times weekly), a cause of significant morbidity and premature mortality. Research on risk factors associated with constipation is limited.AimsTo enumerate risk factors associated with constipation in this population.MethodA questionnaire was developed on possible risk factors for constipation. The questionnaire was sent to carers of people with intellectual disabilities on the case-loads of four specialist intellectual disability services in England. Data analysis focused on descriptively summarising responses and comparing those reported with and without constipation.ResultsOf the 181 people with intellectual disabilities whose carers returned the questionnaire, 42% reported chronic constipation. Constipation was significantly associated with more severe intellectual disability, dysphagia, cerebral palsy, poor mobility, polypharmacy including antipsychotics and antiseizure medication, and the need for greater toileting support. There were no associations with age or gender.ConclusionsPeople with intellectual disabilities may be more vulnerable to chronic constipation if they are more severely intellectually disabled. The associations of constipation with dysphagia, cerebral palsy, poor mobility and the need for greater toileting support suggests people with intellectual disabilities with significant physical disabilities are more at risk. People with the above disabilities need closer monitoring of their bowel health. Reducing medication to the minimum necessary may reduce the risk of constipation and is a modifiable risk factor that it is important to monitor. By screening patients using the constipation questionnaire, individualised bowel care plans could be implemented.

The present research study was aimed at assessing and comparing the type and level of coping strategies among the parents of 150 intellectually disabled children, who were selected from 3 RCI (Rehabilitation Council of India) recognized special schools of Delhi across child's degree of intellectual disability.Sample was drawn randomly in equal proportions from three categories of intellectual disability namely mild, moderate and severe.The coping strategies of parents were assessed using Family Interview for Stress and Coping in Mental Retardation (Section-II) developed by NIMHANS.The findings of the present study revealed that parents having children with severe intellectual disability had low expectations, more negative attitudes towards child management and rearing practices as compare to parents with mildly and moderately disabled children.Coping strategies among these components were decreasing with the severity of child's intellectual disability.Overall it was observed that families of mildly challenged children were comparatively better coped up.