Profound Mental Retardation Research Articles

372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment

Several cases of interstitial deletion encompassing band 18q12.3 are described in patients with mild dysmorphic features, mental retardation and impairment of expressive language. The critical deleted region contains SETBP1 gene (SET binding protein 1). Missense heterozygous mutations in this gene cause Schinzel-Giedion syndrome (SGS, MIM#269150), characterized by profound mental retardation and multiple congenital malformations. Recently, a 18q12.3 microdeletion causing SETBP1 haploinsufficiency has been described in two patients that show expressive speech impairment, moderate developmental delay and peculiar facial features. The phenotype of individual with partial chromosome 18q deletions does not resemble SGS. The deletion defines a critical region in which SETBP1 is the major candidate gene for expressive speech defect. We describe an additional patient with the smallest 18q12.3 microdeletion never reported that causes the disruption of SETBP1. The patient shows mild mental retardation and expressive speech impairment with striking discrepancy between expressive and receptive language skills. He is able to communicate using gestures and mimic expression of face and body with surprising efficacy. The significant phenotypic overlap between this patient and the cases previously reported enforce the hypothesis that SETBP1 haploinsufficiency may have a role in expressive language development.

Le parcours de santé de l’enfant polyhandicapé

Little is known about the clinical profile of COVID-19 infection in polyhandicapped persons. This study aimed to describe the characteristics of this infection among individuals with polyhandicap.This was a retrospective observational study. Polyhandicap was defined by the combination of motor deficiency, profound mental retardation, and age at onset of cerebral lesion younger than 6 years. A positive COVID-19 status was considered for patients with a positive COVID-19 laboratory test result, or patients presenting with compatible symptoms and living in an institution or at home with other patients or relatives who had laboratory-confirmed COVID-19 infection. Data collection included sociodemographic data, clinical and paraclinical characteristics, as well as the management and treatment for COVID-19 infection.We collected 98 cases, with a sex ratio of 0.98 and a mean age of 38.5 years (3 months to 73 years). COVID-19 infection was paucisymptomatic in 46% of patients, 20.6% of patients presented with dyspnea, while the most frequent extra-respiratory symptoms were digestive (26.5%) and neurological changes (24.5%); 18 patients required hospital admission, four adults died. The mean duration of infection was longer for adults than for children, and the proportion of taste and smell disorders was higher in older patients.These findings suggest that PLH persons often develop paucisymptomatic forms of COVID-19 infection, although they may also experience severe outcomes, including death. Clinicians should be aware that COVID-19 symptoms in PLH persons are often extra-respiratory signs, mostly digestive and neurologic, which may help in the earlier identification of COVID-19 infection in this particular population of patients.

Analyse fonctionnelle des comportements de pica d’un enfant présentant un syndrome de pallister killian associe à un autisme

Objective : Through a case study, the paper deals with persistent pica behaviour in a child of 12 with Pallister Killian syndrome associated with autism and profound mental retardation. Method : Pica behaviour may have a functional role. We thus carried out a functional assessment in order to make functional assumptions before targeting our interventions. Our methodology was divided into three parts: observations for 6 days – six sessions of 5hours during which different activities were carried out; interviews with parents and members of the multidisciplinary team; making functional hypotheses; interventions: adapted to these hypotheses. In order to assess their efficiency, the frequency of targeted behaviour was measured out after the intervention. Results : Step 1: functional analysis: data gathered from indirect observation displayed an early occurrence and an evolution of pica behaviour. Moreover, significant change in the child’s environment resulted in an increase of these types of behaviour. In the medical histories, numerous dental diseases were noted (aching tooth eruption, dental decay, recurrent abscess and moth ulcer); blood tests showed iron deficiency. Step 2: functional hypotheses: after the observations, we could make four functional assumptions explaining the apparition or the continuation of the behaviour: relieving the toothache; compensation for nutritional deficiency of trace elements; management of stressful situations; sensory stimulations. Step 3: intervention: according to the assumptions, several types of intervention were suggested in order to reduce or even to stop pica behaviour: the child’s environment was asked to improve or intensify the dental care; after an operation which took place a few days later, four decayed teeth were pulled out – teeth that could have ached if they had not been pulled out; a treatment in trace elements was prescribed during that period in order to readjust the iron deficiency; the child’s environment was told to anticipate important daily changes; a behavioural intervention was scheduled in order to counter-balance the reinforcement caused by self-stimulation. Conclusion : The observations carried out during three days three weeks after the behavioural intervention depicted no pica behaviour.

Neuropsychological evaluation and follow-up of children with cerebellar cortical dysplasia

To describe neuropsychological disturbances and the developmental course associated with cerebellar cortical dysplasia (CCD). The neuroimaging findings from 10 children (five males, five females; aged 3-10 y) with CCD were reviewed and classified. These children all underwent clinical neurological examination and neuropsychological assessment (NPA) on admission, then were followed for an average of 6 years using the cognitive Wechsler Scale, Vineland Adaptive Behavior Scales, and Rey-Osterrieth Complex Figure/McCarthy Drawing subtests. Based on magnetic resonance imaging, CCD was categorized as minor (n = 4), moderate (n = 1), and severe (n = 5). The first NPA disclosed mental retardation* in six (profound, three; moderate, one; mild, two) and normal intelligence in four (low, two; average, one; high, one), but with verbal/performance dissociation in three cases. Socio-adaptive functions were altered in all children except one. Visuospatial abilities were delayed in eight children. In the follow-up, no progression was observed in the three cases with profound mental retardation, whereas the remainder showed homogeneous or disharmonic progression, including improvement or deterioration of verbal/performance function. Cognitive impairment and evolution was not associated with the degree of cerebellar involvement. The neuropsychological profile and evolution associated with CCD do not appear to be predictable, and some features might improve over time.

Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.

Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.

Acrofrontofacionasal dysostosis 1 in two sisters of Indian origin

American Journal of Medical Genetics Part AVolume 155, Issue 12 p. 3125-3127 Research Letter Acrofrontofacionasal dysostosis 1 in two sisters of Indian origin† Paolo Prontera, Corresponding Author Paolo Prontera pprontera@hotmail.com CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalyUniversità ed Azienda Ospedaliera di Perugia, Sezione di Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Via E. dal Pozzo, Pad W, Piano I, 06123 Perugia, Italy.Search for more papers by this authorRiccardo Urciuoli, Riccardo Urciuoli Istituto Padre Ludovico da Casoria, Assisi, ItalySearch for more papers by this authorSabrina Siliquini, Sabrina Siliquini Clinica Neurologica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorSara Macone, Sara Macone S.C. Neurofisiopatologia, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorGabriela Stangoni, Gabriela Stangoni CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorEmilio Donti, Emilio Donti CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorTeresa Anna Cantisani, Teresa Anna Cantisani S.C. Neurofisiopatologia, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorMaurizio Elia, Maurizio Elia U.O.C. di Neurologia e Neurofisiopatologia Clinica e Strumentale, IRCCS “Associazione Oasi Maria SS”, Troina (EN), ItalySearch for more papers by this authorVincenzo Belcastro, Vincenzo Belcastro U.O. Neurologia, Dipartimento di Neuroscienze, Azienda Ospedaliera S. Anna, Como, ItalySearch for more papers by this author Paolo Prontera, Corresponding Author Paolo Prontera pprontera@hotmail.com CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalyUniversità ed Azienda Ospedaliera di Perugia, Sezione di Genetica Medica, Dipartimento di Medicina Clinica e Sperimentale, Via E. dal Pozzo, Pad W, Piano I, 06123 Perugia, Italy.Search for more papers by this authorRiccardo Urciuoli, Riccardo Urciuoli Istituto Padre Ludovico da Casoria, Assisi, ItalySearch for more papers by this authorSabrina Siliquini, Sabrina Siliquini Clinica Neurologica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorSara Macone, Sara Macone S.C. Neurofisiopatologia, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorGabriela Stangoni, Gabriela Stangoni CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorEmilio Donti, Emilio Donti CRR Genetica Medica, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorTeresa Anna Cantisani, Teresa Anna Cantisani S.C. Neurofisiopatologia, Università ed Azienda Ospedaliera di Perugia, Perugia, ItalySearch for more papers by this authorMaurizio Elia, Maurizio Elia U.O.C. di Neurologia e Neurofisiopatologia Clinica e Strumentale, IRCCS “Associazione Oasi Maria SS”, Troina (EN), ItalySearch for more papers by this authorVincenzo Belcastro, Vincenzo Belcastro U.O. Neurologia, Dipartimento di Neuroscienze, Azienda Ospedaliera S. Anna, Como, ItalySearch for more papers by this author First published: 03 November 2011 https://doi.org/10.1002/ajmg.a.34295Citations: 8 † How to Cite this Article: Prontera P, Urciuoli R, Siliqini S, Macone S, Stangoni G, Donti E, Cantisani TA, Elia M, Belcastro V. 2011. Acrofrontofacionasal dysostosis 1 in two sisters of Indian origin. Am J Med Genet Part A 155: 3125–3127. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume155, Issue12December 2011Pages 3125-3127 RelatedInformation

Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS.

Does mental retardation affect masticatory efficiency in children with cerebral palsy?

The aim of the study was to assess the influence of cognitive abilities on the masticatory system functions in children with cerebral palsy. Forty-three children suffering from cerebral palsy and having different levels of cognitive impairment (aged 6-16 years) were evaluated with regard to their masticatory efficiency using a sieving test. Cognitive abilities were taken from medical documentation of the patients at University Department of Pediatrics, Rijeka University Hospital Center, Rijeka, Croatia. Study subjects were divided into two groups: children with severe and profound mental retardation (group 1) and children with no mental retardation or with mild mental retardation (group 2). There were no subjects with moderate mental retardation. Study results showed that masticatory efficiency values were lower in group 1 including children with severe and profound mental retardation as compared with group 2 that included children with no mental retardation or with mild mental retardation. Comparison of mastication efficiency index in children with cerebral palsy according to the grade of mental retardation yielded a statistically significant difference between the two groups (Z=92.50; p<0.001). It is concluded that the grade of mental retardation plays a major role in the level of masticatory efficiency.

重症心身障害児 (者) における死亡例の検討

重症心身障害児 (者) における死亡例の検討

Autism in Dravet syndrome: Prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation

Autism is a pervasive developmental disorder that frequently co-occurs with epilepsy. Dravet syndrome is a severe epileptic encephalopathy associated with psychomotor developmental delay. Autism in Dravet syndrome, however, has rarely been studied. In this study, the prevalence and features of autism in patients with Dravet syndrome, their potential association with mental retardation, and the clinical characteristics of epilepsy were investigated. Clinical data of 37 patients with Dravet syndrome were collected, and evaluations of autism and mental retardation were performed. Nine patients (24.3%) met the criteria for autism. All patients with autism showed speech delay, no emotional reciprocity, and narrow interests, whereas 89.3, 46.4, and 39.9% of patients without autism had speech delay, short temper, and narrow interests, respectively. Mental retardation was observed in 94.6% of patients with Dravet syndrome, with more frequent severe or profound mental retardation in those with autism. The clinical features of epilepsy did not statistically differ between the patients with autism and the patients without autism.

Clinical and Imaging Observations in Isolated Sulfite Oxidase Deficiency

Isolated sulfite oxidase deficiency is a rare neurometabolic disorder that closely mimics hypoxic ischemic encephalopathy both clinically and radiologically. Phenotypic and imaging observations in 2 children (aged 14 months and 8 years) with this disease are described. Both had profound mental retardation, microcephaly, spastic quadriparesis, and uncontrolled seizures from the neonatal period. Diagnosis was established by demonstrating the presence of sulfites in urine and genetic analysis. Magnetic resonance imaging of the brain revealed severe cystic leukomalacia, cortical atrophy with ulegyric pattern, and cerebellar hypoplasia that progressed over time in both the patients. Early diagnosis of this devastating disorder will provide an opportunity for genetic counseling and prenatal testing.

The Essential Role of Centrosomal NDE1 in Human Cerebral Cortex Neurogenesis

We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Otherbody systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.

Tackling frontal lobe–related functions in PKU through functional brain imaging: a Stroop task in adult patients

Profound mental retardation in phenylketonuria (PKU) can be prevented by a low phenylalanine (Phe) diet. However, even patients treated early have inconsistently shown deficits in several frontal lobe-related neuropsychological tasks such as the widely accepted Stroop task. The goal of this study was to investigate whether adult patients exhibit altered brain activation in Stroop-related locations in comparison to healthy controls and if an acute increase in blood Phe levels in patients has an effect on activation patterns. Seventeen male, early-treated patients with classic PKU (mean ± SD age: 31.0 ± 5.2years) and 15 male healthy controls (32.1 ± 6.4years) were compared using a color-word matching Stroop task in a functional magnetic resonance imaging (fMRI) study at 3T. Participants were scanned twice, and an oral Phe load (100mg/kg body weight) was administered to patients prior to one of the fMRI sessions (placebo-controlled). Activity in brain regions that are known to be involved in Stroop tasks was assessed. PKU patients exhibited poorer accuracy in incongruent trials. Reaction times were not significantly different. There were no consistent differences in BOLD activations in Stroop-associated brain regions. The oral Phe administration had no significant effect on brain activity. Neither a generally slower task performance nor distinctively altered functioning of brain networks involved in a task representing a subset of dopamine-dependent executive functions could be proven. Decreased accuracy and inconsistent findings in posterior areas necessitate further study of frontal-lobe functioning in PKU patients in larger study samples.

Rett syndrome 환자의 증례보고

레트 증후군은 X-염색체 연관 신경발달 장애로 주로 여아에서 발병하며 특히 언어 표현, 손의 사용 발달의 퇴행 및 심각한 지적 장애를 동반한다. 구강내 증상은 경련, 구강 위생 불량, 보행 장애, 구강 습관과 관련이 있고, 특히 이갈이가 가장 흔한 증상이다. 본 증례에서 레트 증후군 환아는 치아우식증을 주소로 내원하여 전신마취 하에 치료를 받았으며, 손의 상동증(stereotypic hand movement), 이갈이, 손가락 빨기 등의 전형적인 증상을 보였다. Rett syndrome is a X-linked genetic neurological disorder characterized by developmental regression, particularly in relation to expressive language and use of the hands, together with profound mental retardation, that almost exclusively affects females. Oral manifestations of the disease are commonly associated with the clinical conditions such as convulsion activity, difficulties for oral hygiene behavior, walking problems and oral/digitalmanual habits. Bruxism is the most frequently observed oral habit in patients with Rett syndrome. Two cases with the Rett syndrome were reported. Both patients had the typical manifestations like stereotypic hand movement, bruxism and digit-hand sucking. Caries control for the patients was perfomed under general anesthesia.

Iodine Deficiency in Pregnancy: The Effect on Neurodevelopment in the Child

Iodine is an integral part of the thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), necessary for normal growth and development. An adequate supply of cerebral T3, generated in the fetal brain from maternal free T4 (fT4), is needed by the fetus for thyroid hormone dependent neurodevelopment, which begins in the second half of the first trimester of pregnancy. Around the beginning of the second trimester the fetal thyroid also begins to produce hormones but the reserves of the fetal gland are low, thus maternal thyroid hormones contribute to total fetal thyroid hormone concentrations until birth. In order for pregnant women to produce enough thyroid hormones to meet both her own and her baby’s requirements, a 50% increase in iodine intake is recommended. A lack of iodine in the diet may result in the mother becoming iodine deficient, and subsequently the fetus. In iodine deficiency, hypothyroxinemia (i.e., low maternal fT4) results in damage to the developing brain, which is further aggravated by hypothyroidism in the fetus. The most serious consequence of iodine deficiency is cretinism, characterised by profound mental retardation. There is unequivocal evidence that severe iodine deficiency in pregnancy impairs brain development in the child. However, only two intervention trials have assessed neurodevelopment in children of moderately iodine deficient mothers finding improved neurodevelopment in children of mothers supplemented earlier rather than later in pregnancy; both studies were not randomised and were uncontrolled. Thus, there is a need for well-designed trials to determine the effect of iodine supplementation in moderate to mildly iodine deficient pregnant women on neurodevelopment in the child.

Prenatal Brain Disruption in Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures and be mistaken for ischemic encephalopathy. We describe a patient whose prenatal sonography at 35 weeks' gestation revealed diffuse brain damage with multiple subcortical cavities, ventriculomegaly, dysgenesis of the corpus callosum, and a hypoplastic cerebellum with an enlarged cisterna magna. Magnetic resonance imaging (MRI) later revealed brain atrophy, and multicystic encephalomalacia with hypoplastic vermis and cerebellum. Neurological examination at 10 months showed microcephaly, profound mental retardation, and spasticity. Uric acid was low, and taurine and xanthine were increased in the urine. A sulfite test was positive. The diagnosis of molybdenum cofactor deficiency was made. Sulfite oxidase activity in fibroblasts was undetectable. The patient was found to be homozygous for the 251-418del in the MOCS1 gene. This is the first description of the prenatal development of severe brain disruption in molybdenum cofactor deficiency.

Oral findings in Rett syndrome: A systematic review of the dental literature

Rett syndrome (RS) is a chromosome X-linked genetic neurological disorder characterized by developmental regression, particularly in relation to expressive language and use of the hands, together with profound mental retardation, that almost exclusively affects females. The present review describes the 35 cases of RS published in the indexed literature (Medline)--the first corresponding to 1985 and the last to the year 2007. Certain oral manifestations of the disease are derived from the drug treatment prescribed to control the disease, while others are common to other clinical conditions characterized by convulsion activity, difficulties for correct oral hygiene, walking problems and/or an excess of oral/digital-manual habits. In any case, bruxism is the oral habit most frequently associated with RS--the treatment of which remains the subject of controversy.

Four sisters compound heterozygotes for the pre- and full mutation in fragile X syndrome and a complete inactivation of X-functional chromosome: implications for genetic counseling

Fragile X syndrome (FXS) is a neurodevelopmental disorder and a leading monogenic form of cognitive impairment and autism. It is the most common form of inherited mental retardation in males and a significant cause of mental retardation in females. It is caused by the instability and subsequent expansion of the CGG repeat in the promoter region of the FMR1 (fragile X mental retardation 1) gene at Xq27.3. We describe a double consanguineous family with four sisters compound heterozygotes for the full and pre-mutation CGG repeat size. The index case shows clinical features of the affected males with profound mental retardation; the other three sisters also suffer from mental retardation, ranging from mild to severe. Molecular analysis reveals very similar ranges for the CGG expansions for both chromosomes in all four sisters. The phenotypic differences observed in the index case and her sisters are the total inactivation of X premutated chromosome and the total absence of FMRP (fragile X mental retardation protein). This family case raises important issues for genetic counseling in families with consanguinity and with cases of idiopathic mental retardation.

Role of low-voltage-activated calcium current on the firing pattern alterations induced by hypothyroidism in the rat hippocampus

Thyroid hormone deficiency during a critical period of development severely affects cognitive functions, resulting in profound mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the development of the intrinsic properties of CA1 hippocampal pyramidal cells. These cells are known to exhibit different firing patterns during development, being classified as either regular-spiking or burst-spiking cells. Patch-clamp experiments showed that hypothyroid rats presented a larger number of regular-spiking cells at early postnatal age (P9–11). This difference in firing-pattern distribution disappeared at the pre-weanling age (P17–19), when almost every cell displayed bursting behavior in both control and hypothyroid rats. However, when studied in detail, weanling hypothyroid rats presented a smaller number of spikes per burst than did control animals. One of the major factors behind bursting behavior is sustained depolarization following an action potential. In this study, we show that action potential afterdepolarizations of hypothyroid animals registered shorter half-durations than did controls, a fact which could explain the smaller number of action potentials per burst. Additionally, the afterdepolarizations observed on both hypothyroid and control neurons were highly sensitive to low concentrations of nickel, suggesting that a low-threshold Ca 2+ current is key in the generation of spike afterdepolarizations and in the control of the bursting pattern of firing of these neurons. In agreement with this, experiments performed on dissociated hippocampal neurons have shown that this current is significantly depressed in hypothyroid animals. Therefore, we conclude that an alteration of the low-threshold calcium current is the basic factor explaining the differences observed in the firing behavior of hypothyroid animals.

Strategies for Treatment in Alexander Disease

Alexander disease is a rare and generally fatal disorder of the CNS, originally classified among the leukodystrophies because of the prominent myelin deficits found in young patients. The most common form of this disease affects infants, who often have profound mental retardation and a variety of developmental delays, but later onset forms also occur, sometimes with little or no white matter pathology at all. The pathological hallmark of Alexander disease is the inclusion body, known as Rosenthal fiber, within the cell bodies and processes of astrocytes. Recent genetic studies identified heterozygous missense mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes, as the cause of nearly all cases of Alexander disease. These studies have transformed our view of this disorder and opened new directions for investigation and clinical practice, particularly with respect to diagnosis. Mechanisms by which expression of mutant forms of glial fibrillary acidic protein (GFAP) lead to the pleiotropic manifestations of disease (afflicting cell types beyond the ones expressing the mutant gene) are slowly coming into focus. Ideas are beginning to emerge that suggest several compelling therapeutic targets for interventions that might slow or arrest the evolution of the disease. This review will outline the rationale for pursuing these strategies, and highlight some of the critical issues that must be addressed in the planning of future clinical trials.