Profound Mental Retardation Research Articles

Use of ICD-10 diagnoses in Danish psychiatric hospital-based services in 2001-2007

The Danish version of the ICD-10 chapter on mental and behavioural disorders has 380 different diagnoses when three digits are used. This study examines how many of the available diagnoses were used and to what extent in Danish psychiatric hospital-based services in the period from 2001 to 2007, through an analysis of the total number of diagnoses reported to the Danish Psychiatric Central Research Register (n=1,260,097). The 50th percentile (50.1%) was reached by using 16 diagnoses (4.2% of 380 available). The three most frequently registered diagnoses were paranoid schizophrenia, alcohol dependence and adjustment disorder, used 10.2%, 8.3% and 5.9% of the times, respectively. Seven diagnoses (1.8%) were used between 1 and 4 times during the 7-year period. One hundred nine (28.7% of available diagnoses) were used less than 100 times each. These data suggest that it may be sensible to reconsider the number of diagnoses needed in the revision of the ICD-10 chapter on mental and behavioural disorders.

Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations

Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.

Model of cryptogenic infantile spasms after prenatal corticosteroid priming

Infantile spasms (IS) is a devastating epilepsy syndrome of childhood. IS occurs in 3-12-month-old infants and is characterized by spasms, interictal electroencephalography (EEG) hypsarrhythmia, and profound mental retardation. Hormonal therapy [adrenocorticotropic hormone (ACTH), corticosteroids] is frequently used, but its efficacy is tainted by severe side effects. For research of novel therapies, a validated animal model of IS is required. We propose the model of spastic seizures triggered by N-methyl-d-aspartate (NMDA) in infant rats prenatally exposed to betamethasone. The spasms have remarkable similarity to human IS, including motor flexion spasms, ictal EEG electrodecrement, and responsiveness to ACTH. Interestingly, the spasms do not involve the hippocampus. Autoradiographic metabolic mapping as well as tagging of the areas of neuronal excitation with c-fos indicates a strong involvement of hypothalamic structures such as the arcuate nucleus, which has significant bilateral connections with other hypothalamic nuclei as well as with the brainstem.

The MECP2 duplication syndrome

In this review, we detail the history, molecular diagnosis, epidemiology, and clinical features of the MECP2 duplication syndrome, including considerations for the care of patients with this X-linked neurodevelopmental disorder. MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes that pre-date the birth of an affected son. Given what we know of the syndrome to date, we propose that genetic testing is warranted in cases of males with infantile hypotonia and in cases of boys with mental retardation and autistic features with or without recurrent infections, progressive spasticity, epilepsy, or developmental regression. We discuss recommendations for clinical management and surveillance as well as the need for further clinical, genotype-phenotype, and molecular studies to assist the patients and their families who are affected by this syndrome.

Diagnostic criteria for fetal alcohol syndrome and fetal alcohol spectrum disorders

Prenatal ethanol exposure, in our professional practice, is an almost neglected condition as an important etiological factor for the induction of a wide spectrum of neuropsychiatric diseases that may appear during childhood, adolescence or adulthood. Children born to alcoholic mothers may show a profound mental retardation ranging to an apparent normality, and extending through epilepsy, attention deficit disorders with or without hyperactivity, autism and pervasive developmental disorders, and different types of learning disorders. When adolescents, they may develop different kinds of personality disorders and substance abuse disorders. Finally, in adulthood, they may suffer from different types of affective and psychotic disorders, among others. A great number of those children may not develop their full mental and social potentiality as free individuals. They usually have diverse types of cognitive, attentional, mnemonic and affective impairments. Not infrequently, they engage in antisocial behaviors or have school or work troubles. In this work, the present clinical classifications and diagnostic criteria for the disorders emerging from a prenatal ethanol exposure are reviewed in order to call attention to the medical pediatric and neuropsychiatric community about the increasingly, although underdiagnosed, frequency of these disorders in our country.

A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

Phenotypic correlations in a patient with ring chromosome 22

Ring chromosome 22, a rare cytogenetic anomaly, has been described in over 60 cases in the medical literature. The aim of this report was to present a case carrying ring chromosome 22, and her family.It is a case report of a patient presented at Medical Faculty of Çukurova University in Turkey.An 8-year-old girl with ring chromosome 22 and her family were evaluated cytogenetically and clinically.A chromosome analysis of the proband revealed a de novo 46, XX, r(22)(p11.2;q13) karyotype. Our subject demonstrated the prominent features of this syndrome including profound mental retardation, language impairment, dysmorphic features, lack of speech, hyperactivity, and behavioral disorders.There is lack of consistency between the physical abnormalities that we observed in our subject and those observed for such patients in the literature. The wide range of manifestations observed in patients with this cytogenetic alteration is probably due to size differences in the deleted region.

Sapropterin dihydrochloride: A new drug and a new concept in the management of phenylketonuria

Phenylketonuria (PKU) is characterized by persistent hyperphenylalaninemia, due to mutations in the gene coding for phenylalanine hydroxylase (PAH). If untreated, patients develop profound mental retardation. The principal treatment for PKU is lifelong dietary phenylalanine restriction, requiring the administration of special phenylalanine-free protein supplements. Adhering to the diet is burdensome, and poor compliance and control of blood phenylalanine are common, especially in adolescents and adults. A subset of patients, particularly those with milder forms of PKU, shows a clinically significant reduction in blood phenylalanine when treated with pharmacological doses of tetrahydrobiopterin, the cofactor of PAH. A tablet formulation of sapropterin dihydrochloride is approved for therapeutic use in Europe and the USA. Clinical trials have demonstrated durable reductions in blood phenylalanine, and/or increased dietary phenylalanine tolerance, in some patients with hyperphenylalaninemia due to PKU. Although further data are needed, especially with regard to long-term neuropsychological outcomes or possible use in pregnancy, sapropterin appears to represent a useful addition to the management of PKU.

Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11

Interstitial deletions of chromosome band 10q22 are rare. We report on the characterization of three overlapping de novo 10q22 deletions by high-resolution array comparative genomic hybridization in three unrelated patients. Patient 1 had a 7.9 Mb deletion in 10q21.3-q22.2 and suffered from severe feeding problems, facial dysmorphisms and profound mental retardation. Patients 2 and 3 had nearly identical deletions of 3.2 and 3.6 Mb, the proximal breakpoints of which were located at an identical low-copy repeat. Both patients were mentally retarded; patient 3 also suffered from growth retardation and hypotonia. We also report on the results of breakpoint analysis by array painting in a mentally retarded patient with a balanced chromosome translocation 46,XY,t(10;13)(q22;p13)dn. The breakpoint in 10q22 was found to disrupt C10orf11, a brain-expressed gene in the common deleted interval of patients 1-3. This finding suggests that haploinsufficiency of C10orf11 contributes to the cognitive defects in 10q22 deletion patients.

Fire Safety Skills Training for Individuals with Severe and Profound Mental Retardation

The purpose of this research was to evaluate behavioral skills training procedures for teaching individuals with severe and profound mental retardation to exit their residence upon hearing a smoke detector. Assessments took place in the participants’ group homes while the participants were unaware that an assessment was taking place. Training consisted of behavioral skills training and in situ training. Following training, it was anticipated that the participants would be able to initiate exiting behaviors within 10 s of the activation of a smoke detector and exit the building within 30 s of initiating exiting behaviors. The results showed that one participant out of seven met these criteria following training. However, data gathered on the level of prompting needed for participants to exit the building showed that four of the seven participants exited the building with a less intrusive level of prompting from staff.

Multi-sensory rooms: Comparing effects of the Snoezelen and the Stimulus Preference environment on the behavior of adults with profound mental retardation

The present study examined whether Snoezelen and Stimulus Preference environments have differential effects on disruptive and pro-social behaviors in adults with profound mental retardation and autism. In N = 27 adults these target behaviors were recorded for a total of 20 sessions using both multi-sensory rooms. Three comparison groups were created by diagnosis and motor respective linguistic abilities. Each client was exposed to only one multi-sensory room. Results showed that Snoezelen intervention decreased disruptive behaviors only in individuals with autism, while Stimulus Preference increased pro-social behaviors only in participants with profound mental retardation with co-occurring poor motor and linguistic abilities. Furthermore, several trend analyses of the improved behaviors were conducted throughout all sessions toward short and mid term effects of the multi-sensory room applications. These findings support both the prudence of using the Snoezelen room in individuals with developmental disabilities and the importance of using a Stimulus Preference assessment in multi-sensory environments in clients with profound mental retardation.

SPECIESISM AND MORAL STATUS

Abstract: Many people believe that all human life is of equal value. Most of them also believe that all human beings have a moral status superior to that of nonhuman animals. But how are these beliefs to be defended? The mere difference of species cannot in itself determine moral status. The most obvious candidate for regarding human beings as having a higher moral status than animals is the superior cognitive capacity of humans. People with profound mental retardation pose a problem for this set of beliefs, because their cognitive capacities are not superior to those of many animals. I argue that we should drop the belief in the equal value of human life, replacing it with a graduated view that applies to animals as well as to humans.

Facilitating Family Occupations: Family Member Perceptions of a Specialized Environment for Children With Mental Retardation

We studied the experience of family occupations in the Snoezelen context (i.e., a highly specialized therapeutic room for family gatherings) and analyzed how it facilitated occupations for parents of children with severe and profound mental retardation living in residential facilities. In-depth interviews and participatory observations were held with 10 families of children with mental retardation living in a long-term residential facility for children with mental retardation in Haifa, Israel. Two main themes emerged: The Snoezelen environment was experienced as another world, where parents sensed detachment from external reality and a transition to relaxation and intimacy. The intimacy of the Snoezelen world fostered the experience of being together as a family, where all family members shared fun activities and strengthened their relationship. A sense of intimacy and relaxation, provided by the Snoezelen environment, is important in facilitating family occupations for this population. Interventions in occupational therapy must be designed that take these requirements into consideration.

CDKL5 MUTATIONS IN BOYS WITH SEVERE ENCEPHALOPATHY AND EARLY-ONSET INTRACTABLE EPILEPSY

Objective: To search for CDKL5 gene mutations in boys presenting with severe early-onset encephalopathy and intractable epilepsy, a clinical picture very similar to that already described in girls with CDKL5 mutations. Methods: Eight boys (age range 3–16 years, mean age 8.5 years, SD 4.38) with severe or profound mental retardation and early-onset intractable seizures were selected for CDKL5 gene mutation screening by denaturing high-performance liquid chromatography analysis. Results: We found three unrelated boys carrying three different missense mutations of the CDKL5 gene: c.872G>A (p.C291Y), c.863C>T (p.T288I), and c.533G>C (p.R178P). They presented early-onset, polymorphous, and drug-resistant seizures, mostly myoclonic and tonic or spasms. EEG showed epileptiform abnormalities which were multifocal during wakefulness, and pseudoperiodic bisynchronous during sleep. Conclusions: This study describes three boys carrying CDKL5 missense mutations and their detailed clinical and EEG data, and indicates that CDKL5 gene mutations may represent a cause of severe or profound mental retardation and early-onset intractable seizures, also in boys. Screening for CDKL5 mutations is strongly recommended in individuals with these clinical features.

Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome

Angelman syndrome (AS) (MIM #105530) is a neurodevelopmental disorder characterized by a broad range of clinical features, such as profound mental retardation, impairment of verbal language, usually ataxia, subtle dysmorphic facial features, a peculiar behavioral profile, with a happy disposition and outbursts of laughter, and a seizure disorder associated with a characteristic electroencephalographic pattern.1 It affects between 1:15 000 and 1:40 000 newborn children depending on ethnical and geographical areas.2, 3, 4, 5 Most cases of AS are sporadic, although several familial cases have been reported. A variety of different genetic mechanisms involving chromosome 15q11.2-13 (deletion, paternal uniparental disomy, imprinting center abnormality, and UBE3A (MIM #601623; 15q11.2) mutations) have been described in association with AS, all resulting in a deficiency of the ubiquitin-protein ligase E3A, which is involved in the process of ubiquitination.6 In some cases, patients with AS share common features with patients affected by Rett syndrome (MIM #312750).7 After extensive cytogenetic and molecular analysis of chromosome 15q11-13, there remains a small group of about 10–15% of AS patients, in whom no abnormality can be identified.

Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Sanfilippo syndrome type B (mucopolysaccharidosis III B, MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of alpha-N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu(-/-) and Naglu(+/-) mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu(-/-) mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments, P-tau aggregates characteristic of tauopathies-a group of age-related dementias that include Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy.

Use of treatment analysis following ambiguous functional analysis results

AbstractThe present study used a treatment analysis following ambiguous functional analysis results to evaluate potential treatments to reduce the SIB of a 32‐year‐old male with profound mental retardation. In addition, effective treatments were determined for increasing compliance with increasingly more complex self‐care tasks. The results indicated that a positive reinforcement procedure with extinction was useful toward reducing SIB and increasing compliance during three increasingly more complex tasks. The usefulness of treatment analysis procedures following ambiguous functional analysis results are discussed. Copyright © 2009 John Wiley & Sons, Ltd.

Costello syndrome H-Ras alleles regulate cortical development

Genetic mutations in H-Ras cause Costello syndrome (CS), a complex developmental disorder associated with cortical abnormalities and profound mental retardation. Here, we have asked whether there are perturbations in precursor cell proliferation, differentiation, or survival as a consequence of expressing CS H-Ras alleles that could explain the cognitive deficits seen in this disorder. Two different H-Ras alleles encoding mutations present in CS patients, H-RasG12V and H-RasG12S were expressed in cortical progenitors in culture and in vivo by in utero electroporation and their effects on cortical precursor cell fate examined. Expression of both mutants in cultured precursors inhibited neurogenesis and promoted proliferation and astrogenesis. In vivo, expression of either form of CS H-Ras promoted cell proliferation and inhibited neurogenesis. Moreover, these H-Ras mutants promoted premature gliogenesis, causing formation of astrocytes at a time when normal gliogenesis has not yet begun, ultimately leading to an increase in the number of astrocytes postnatally. Thus, aberrant H-Ras activation enhances neural precursor cell proliferation, and perturbs the normal genesis of neurons and glial cells, effects that likely contribute to the cortical abnormalities and cognitive dysfunction seen in CS.

Prenatal diagnosis of a novel mutation, c.529C>T (p.Q177X), in the BCKDHA gene in a family with maple syrup urine disease

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder caused by defective activity of the branched-chain alpha-keto-acid dehydrogenase (BCKD) complex. The disease-causing mutations can affect the BCKDHA, BCKDHB or DBT genes encoding for the E1a, E1b, and E2 subunits, respectively, of the BCKD complex. Here we report a girl who first presented to our clinic at 4 years of age with profound mental retardation. A diagnosis of MSUD was subsequently made based on the results of plasma amino acid analysis. Mutation analysis confirmed that she was homozygous for a novel mutation, c.529C>T (p.Q177X) in BCKDHA, while both parents, who were first cousins, were heterozygous. This enabled us to give an option of prenatal diagnosis to the parents. The prenatal testing for MSUD was performed during the mother's subsequent pregnancy and revealed that the fetus was heterozygous for the mutation. The healthy male neonate was born and his genotype was tested by restriction enzyme analysis, which confirmed the result of the prenatal testing. In summary, a late diagnosis of MSUD in patients without an unusual odour could occur especially in countries without neonatal screening programs as seen in the index patient. Mutation detection was, however, still beneficial to the family since prenatal testing could be performed in subsequent pregnancies. In addition, a novel mutation was found, expanding the mutation spectrum of this disease.

5.9 Mb microdeletion in chromosome band 17q22–q23.2 associated with tracheo-esophageal fistula and conductive hearing loss

Only eight cases involving deletions of chromosome 17 in the region q22–q24 have been reported previously. We describe an additional case, a 7-year-old boy with profound mental retardation, severe microcephaly, facial dysmorphism, symphalangism, contractures of large joints, hyperopia, strabismus, bilateral conductive hearing loss, genital abnormality, psoriasis vulgaris and tracheo-esophageal fistula. Analysis with whole-genome SNP genotyping assay detected a 5.9 Mb deletion in chromosome band 17q22–q23.2 with breakpoints between 48,200,000–48,300,000 bp and 54,200,000–54,300,000 bp (according to NCBI 36). The aberration was confirmed by real-time quantitative PCR analysis. Haploinsufficiency of NOG gene has been implicated in the development of conductive hearing loss, skeletal anomalies including symphalangism, contractures of joints, and hyperopia in our patient and may also contribute to the development of tracheo-esophageal fistula and/or esophageal atresia.