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ForskningVetenskapliga artiklar Omkring 70 nya medicinska vetenskapliga artiklar har publicerats det senaste halvåret. Merparten utgörs av molekylärbiologiska och genetiska artiklar. Här lyfts framför allt fram de kliniska fram i form av översättning av sammanfattningar. Ingegerd Witt Engerström
Social förmåga J Intellect Disabil Res. 2011 Mar 8. doi: 10.1111/j.1365-2788.2011.01404.x. Abstrakt Skelettet Pediatr Res. 2011 Apr;69(4):293-298. Abstrakt Pediatr Res. 2011 Apr;69(4):359-64. Abstrakt Folinsyrebehandling J Child Neurol. 2011 Mar 22. [Epub ahead of print] Abstrakt Motorik Brain Nerve. 2010 Nov;62(11):1211-20. Abstrakt Diagnos J Child Neurol. 2011 Feb;26(2):209-13. Abstract J Child Neurol. 2011 Jan;26(1):65-71. Abstrakt Ann Neurol. 2010 Dec;68(6):944-50. Abstrakt
December 2010
Epilepsi Epilepsy Behav. 2010 Aug 20. Abstract Epilepsy often occurs in Rett syndrome and is considered a major problem. The aim of this study was to define the clinical features of epilepsy and the correlation between seizures and both genotype and clinical phenotype in the Rett population. One hundred sixty-five patients with Rett syndrome referred to four Italian centers were recruited. All patients underwent video/EEG monitoring and molecular analysis of the MECP2 gene or, in negative cases, of the CDKL5 and FOXG1 genes. The frequency of epilepsy was 79%. Drug-resistant epilepsy occurred in 30% of all our patients with Rett syndrome and in 38% of those with epilepsy. Our findings demonstrate that epilepsy differs among the various phenotypes and genotypes with respect to age at onset, drug responsiveness, and seizure semiology. The Hanefeld and preserved speech variants represent the extremes of the range of severity of epilepsy: the preserved speech variant is characterized by the mildest epileptic phenotype as epilepsy is much less frequent, starts later, and is less drug resistant than what is observed in the other phenotypes. Another important find ing is that seizure onset before 1year of age and daily frequency are risk factors for drug resistance. Thus, this study should help clinicians provide better clinical counseling to the families of patients with Rett syndrome. Summering Epilepsi är vanligt vid Rett syndrom och betraktas som ett stort problem. Vid en undersökning av 65 patienter med Rett syndrom vid 4 centra i Italienj fann man att 79 % hade epilepsi, 38 % av dessa förbättrades inte av farmakologisk behandling. Det var stor variation mellan individerna avseende tidpunkt för krampdebut, hur de svarade på farmakologisk behandling, hur kramperna tedde sig. Hanefeld och Preserved speech-varianterna utgjorde extremer i fråga om svarighetsgrad av epilepsi.: Preserved speech-varianten karaktäriserades av den mildaste epilepsin, frekvensen var lägre och anfallen startade senare. Anfallsdebut före 1 års ålder och dagliga anfall var ofta kopplat till senare resistens mot farmakologisk behandling.
Epilepsia. 2010 Jul;51(7):1252-8. Epub 2010 May 13. Abstract PURPOSE: Rett syndrome (RTT), an X-linked, dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, presents with acquired microcephaly, autistic regression, hand usage loss, and stereotypies. Epilepsy is frequent and has been reported to correlate with mutation type, general disease severity, and BDNF polymorphism. Our purpose was a comprehensive description of epilepsy features and course in RTT. METHODS: Retrospective review of charts and electroencephalography (EEG) studies in 97 patients with RTT. RESULTS: Seventy-two percent of patients had epilepsy, appearing at a median age of 3 years. According to age of onset, we divided patients into three groups: 6 with early epileptic variant (0-1 year), 42 with early epilepsy (1-5 years), and 20 with late epilepsy (after 5 years). Early epileptic variant had severe seizure types in the first year of life, followed by a typical RTT picture; all were MECP2 negative. Early epilepsy and late epilepsy groups were similar with respect to Rett-related symptoms, but seizures were better controlled in the second group (p < 0.05). Epileptiform activity appeared earlier and was more confluent in the early epilepsy group, including nine patients with electrical s tatus epilepticus during sleep (ESES) versus one in the late epilepsy group (p < 0.05). No correlation was found between epilepsy onset or severity and genotype. BDNF val/met polymorphism correlated with earlier onset of seizures (p < 0.05). DISCUSSION: Epilepsy appears earlier than described previously, frequently during the regression stage. Early age of onset predicts a more severe course of seizures. ESES is common among those with early onset epilepsy. BDNF polymorphism was the only genetic correlate with seizure onset, whereas MECP2 mutation type and location did not influence epilepsy. Summering En retrospektiv undersökning av 97 patienter med Rett syndrom gjordes i Israel. 72 % av dem hade epilepsi som började vid en medelålder av 3 år. Patienterna delades upp i 3 grupper beroende på debutålder för anfall: 0-1 år, 1-5 år och över 5 år. Tidigare debut av anfall förebådade ett svårare förlopp hos anfallen. Anfall debuterade tidigare än man tidigare beskrivit, vanlighe redan under regressionsstadiet. Man fann ingen korrelation mellan debutålder, symtomens svårighetsgrad eller mutation.
Arch Di s Child. 2010 Jun;95(6):444-8. Abstract OBJECTIVES: Some associations between antiepileptic drugs (AEDs) and fracture risk have been reported in the general population. This study investigated the relationships between fracture risk and commonly used AEDs in Rett syndrome, a genetic disorder associated with intellectual and physical disability. STUDY DESIGN: Cases (n=233) were sourced from the population-based Australian Rett Syndrome Database and longitudinal data were used. The Cox proportional hazard model was used to analyse relationships between fracture and prescribed AEDs, mobility, epilepsy diagnosis and genotype. RESULTS: After controlling for mobility, epilepsy diagnosis and genotype, use of valproate increased the risk of fracture threefold after at least 1 year (HR 3.56; 9 5% CI 1.85 to 6.82) and after 2 or more years (HR 3.02; 95% CI 1.90 to 4.80). There was a lesser increased risk (HR 1.99; 95% CI 0.99 to 4.02) with lamotrigine in the first year of use but not for subsequent years of use. Carbamazepine slightly decreased the risk (HR 0.60; 95% CI 0.35 to 1.02) after 2 or more years of use. CONCLUSIONS: The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect. Summering 233 patienter togs ur den australiska databasen. Efter kontroll för mobilitiet, epilepsidiagnos och genotyp ökade valproat risken för frakturer 3-falt efter mer än 1 års användning. Riskökningen var mindre för lamotrigin under det första året men inte för de följande åren. Karbamazepin minskade risken nägot. Man tror att många olika mekanismer bidrar till denna effekt.
Pediatric Neurology Volume 43, Issue 5, Pages 320-324 (November 2010) Abstract Evidence suggests that carbamazepine affects bone metabolism by altering vitamin D status. We prospectively compared 25-hydroxyvitamin D, parathormone, calcium, phosphorus, and alkaline phosphatase levels at initiation and 6 months of carbamazepine therapy in children, and correlated them with carbamazepine levels. We included 47 children newly diagnosed with partial epilepsy, initiated on carbamazepine therapy. Of these, 32 were studied for 6 months. Children were managed according to standard protocol. Various parameters were measured at initiation and at 6 months. Carbamazepine levels were estimated after 6 months. Mean age was 6.72 ± 2.22 years S.D. Mean 25-hydroxyvitamin D was 14.45 ± 9.77 ng/mL S.D. and 11.31 ± 9.15 ng/mL S.D. at baseline and 6 months (P = 0.023), respectively (21.7% decline). Mean parathormone increased from 34.24 ± 21.38 pg/mL S.D. to 45.01 ± 24.46 pg/mL S.D. (P = 0.001). Change in vitamin D correlated negatively with change in parathormone (r = −0.404, P = 0.022). Serum alkaline phosphatase increased from 283.50 ± 100.10 IU/L S.D. to 364.25 ± 126.98 IU/L S.D. (P < 0.001). Changes in vitamin D and parathormone did not correlate significantly with carbamazepine level. Carbamazepine therapy decreased levels of vitamin D. Hence vitamin D monitoring and supplementation may help prevent alterations in bone metabolism. Summering Evidens talar för att Karbamazepin påverkar benmetabolismen genom att ändra D-vitaminstatus. 47 barn som nyligen påbörjat Karbamazepinbehandling följdes under 6 månader. Före behandlingens början undersöktes 25-hydroxyvitamin D, parathormon, kalk, fosfor och alkaliska fosfataser, dessa jämfördes med nya prover efter 6 månaders behandling. Och korrelerades till Karbamacepinnivåer. Förändringar i D-vitamin och Parathormon korrelerade inte signifikant med Karbamazepinnivåer. Karbamazepibehandling minskade D-vitaminnivåerna. Undersökning av D-vitamin och eventuell supplementering kan bidra till att förhindra förändringar i benmetabolismen.
Pediatr Res. 2010 Nov;68(5):446-51. Abstract Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. In 49 female RTT children, aged 1.9-17 y, bone mass was assessed and correlated with clinical parameters and mutations involving the MECP2 gene. We also studied five adult females, aged 20-33 y, and one male child, aged 6 y. Lumbar spine bone mineral content (BMC) and bone mineral density (BMD) were correlated with weight, height, BMI, clinical severity, degree of scoliosis, use of anticonvulsants, and ambulatory status. L1-L4 BMD and BMC showed that 48.9% of them had BMD values >2 SD below age-related norms. BMD values were in the osteoporotic range in the five adult females with RTT. Eleven percent of the children and adults with RTT experienced fractures. Low bone mass was correlated with marginal significance to clinical severity and ambulation but not to scoliosis or anticonvulsant use. Lowest bone mass occurred in patients with T158M or R270X mutations but without statistical significance. Studies in a murine model of RTT confirmed low bone mass as an inherent component of this syndrome. MECP2 mutations and clinical parameters impact bone mass in RTT, but an association with a specific mutation was not demonstrable. Summering Hos 49 flickor med Rett syndrom, 1.9 – 17 år gamla, undersöktes skelett-täthet och mineralinnehåll och korrelerades med kliniska parametrar och mutationer på MECP2-genen. Fem vuxna kvinnor (20-33 år) och en pojke (6 år) undersöktes också. Mineralinnehåll och bentäthet korrelerades till längd, vikt, BMI, symtomens svårighetsgrad, gradtal för skolios, användning av krampmediciner och förmåga att förflytta sig. Låg bentäthet korrelerade med marginell signifikans till symtomens allvarlighetsgrad och förflyttningsförmåga men inte till skolios eller användning av epilepsimedicin. Lägst bentäthet sågs hos dem med mutationerna T158M och R270X men utan statistisk signifikans. Studierna har bekräftat att låg bentäthet är en ingående del i Rett syndrom men man kunde inte peka ut någon specifik mutation.
Bone. 2010 Sep;47(3):701-5. Abstract Rett syndrome (RTT) is a common X-linked neurodevelopmental disorder caused by mutations in the coding region of methyl-CpG-binding 2 (MECP2) gene. Patients with RTT have a low bone mineral density and increased risk of fracture. However, very little is known if bone matrix mineralization is altered in RTT. A 17-year-old girl with a classical form of RTT with a heterozygous nonsense mutation in exon 3 in the MECP2-gene was treated in our hospital. Her femoral neck BMD is 43.3% below the 3rd percentile when compared to age and sex-matched controls. She underwent surgery for correction of her scoliosis, which provided a unique opportunity to obtain bone tissue to study bone matrix mineralization (Bone Mineralization Density Distribution-BMDD) using quantitative backscattered electron imaging (qBEI) and histomorphometry. BMDD outcomes were compared to recently published normative reference data for young individuals. qBEI analysis showed a significant shift to lower matrix mineralization despite histomorphometric indices indicate a low bone turnover. There was a reduction in CaMean (-7.92%) and CaPeak (-3.97%), which describe the degree of mineralization. Furthermore the fraction of low mineralized matrix (CaLow: +261.84%) was dramatically increased, which was accompanied with an increase in the heterogeneity of mineralization (CaWidth: +86.34%). Our findings show a significantly altered bone matrix mineralization of a typical patient with RTT. This may partly explain the low bone density seen in these patients. These results also warrant further studies on the molecular role of MECP2 in bone matrix mineralization. Summering Patienter med Rett syndrom har låg bentäthet och minsealisering och ökad risk för frakturer. Men mycket lite är känt om mineraliseringen av benmassan är ändrad vid Rett syndrom. En 17-årig flicka med klassiskt Rett syndrom och en heterozygot nonsensemutation i exon 3 på MECP2-genen behandlades vid för skoliosuperation. Man gjorde då ingående undersökningar av mineralisering och bentäthet. Undersökningen visade signifikant skifte till sänkt matrixmineralisering trots att låg ”turn över” ( långsam nedbrytning) förelåg. Fraktionen med lågt mineraliserad benmatrix var dramatiskt ökad kombinerat med ökade skillnader i mineraliseringsgrad. Undersökningen visar signifikant förändrad benmineralisering hos en typisk patient med Rett syndrom. Detta kan delvis förklara den låga bentätheten hos dessa patienter. Undersökningenkräver också ytterligare studier av MeCP2s roll i mineraliseringen av benmatrix.
Skolioser Chir Narzadow Ruchu Ortop Pol. 2010 Jan-Feb;75(1):17-23. Abstract Rett syndrome (RS) is a rare genetic disorder affecting only girls. The prevalence is 1:15000. The most characteristic features of RS are: lack of development, wringing of the hands. Musculoskeletal system is also affected and scoliosis remains the biggest challenge. Aim of paper is to describe the curve progression pre -operatively, course of surgery and finally radiological and subjective results of treatment. Postoperative follow-up was 3.1 year. We describe a series of 9 girls with RS and scoliosis treated surgically in single Institution. All presented scoliosis that increased with a rate of mean 16.1 degrees per year. Preoperatively curves ranged from 52 degrees up to 120 degrees Cobb angle. Curve pattern was similar in all cases, long thoraco-lumbar curve with thoracic hyperkyphoisis. All girls underwent surgery. Posterior fusion with Luque-Galvestone technique, posterior hybdrid fusion or anterior fusion was performed depending on the degree of scoliosis. Surgery and postoperative period were uneventful. Mean blood loss was 650 ml; mean obtained correction was 38%, with minimal correction loss at final follow-up. No additional surgery was required. Most caregivers were subjectively satisfied with surgery. Scoliosis in RS patients is progressive, with a high annual rate. Surgery should be performed I cases of curves of 40-50 degrees in specialized centers. The procedure is safe, and does not affect general condition nor deteriorate neurological status. In non-ambulant patients fusion should be carried out to the pelvis. Summering Detta är en rapport om skoliosoperationer av 9 flickor med Rett syndrom. De har följts 3.1 år efter operationerna. Alla hade skolioser som ökade med i medeltal 16,1 grader/år. Före operationen var skoliosvinklarna mellan 52 och 120 grader (Cobbs vinkel). Alla hade långsträckta thoracolumbala skolioser med kyfos i övre bröstryggen. Fusioner bakifrån och framifrån genomfördes beroende av skoliosens grad. Minsta uppnådda korrektion var 38 grader med minimal korrektionsförlust vid uppföljning. Ingen ytterligare operation behövdes. Konklusionen är att operativ behandling ska göras när Cobbs vinkel når 40-50 grader. Hos icke gående ska fusionen gå ända ner i bäckenet.
Åldrande ScientificWorldJournal. 2010 May 4;10:778-87. Abstract Rett syndrome (RS) is a neurological disease affecting mainly females, characterized by an arrest of brain development caused by an X-linked mutation. Rett syndrome is the first human disease found to be caused by defects in a protein involved in regulating gene expression through its interaction with methylated DNA. The disease has been traced to a defective gene called MECP2. The case stories presented here and recent findings show that females with RS are able to live into old age. Due to the observed longevity of individuals with RS, and the fact that individuals with RS present the therapist/physician with specific clinical challenges, it is suggested that proper, long-term, and individually tailored, intensive care should be provided at all ages in the hope to prevent or at least reduce the age-related deterioration that is typical of this population. Summering Av de fallbeskrivningar som presenteras framgår att personer med Rett syndrom kan leva till hög ålder. På grund av detta och på grund av att personer med Rett syndrom ställer sjukgymnasten inför specifika kliniska utmaningar föreslås att kvalificerad och individuellt anpassad, intensiv långtidsbehandling ges i alla åldrar, för att försöka förhindra eller åtminstone reducera åldersrelaterad försämring som är typisk för denna grupp.
Smärta Am J Med Genet A. 2010 May;152A(5):1197-205. Abstract Recent animal studies suggest links between MeCP2 function and sensitivity to pain. This study investigated the nature and prevalence of atypical pain responses in Rett syndrome and their relationships with specific MECP2 mutations. Families enrolled in the Australian Rett Syndrome Database (ARSD) and InterRett database participated in this study. Cases with a known MECP2 pathogenic mutation, whose families had completed a questionnaire on registration and had answered questions on pain sensitivity were included (n = 646). Logistic regression was used to analyze relationships between the atypical pain responses and genotype. Descriptions of decreased pain sensitivity were content analyzed. The prevalence estimate of reporting an abnormal pain response was 75.2% and a decreased sensitivity to pain was 65.0% in the population-based ARSD. Families of ARSD and InterRett subjects with a C-terminal (OR 2.6; 95% CI 0.8-8.0), p.R168X (OR 2.1; 95% CI 0.7-6.1), or p.R306C (OR 2.7; 95% CI 0.8-9.6) mutation were more likely to report decreased sensitivity to pain. Parents and carers described decreased and delayed responses in situations judged likely to cause pain such as injections, falls, trauma, and burns. This study has provided the first precise estimate of the prevalence of abnormal sensitivity to pain in Rett syndrome but specific relationships with genotype are not yet clear. Clinical practice should include a low threshold for the clinical assessment of potential injuries in Rett syndrome. Summering Ny forskning antyder samband mellan mutationer på MeCP2-genen och känslighet för smärta. Däremot har man inte sett något särskilt mönster knutet till vissa genotyper. Man tillråder att omgivningen ska ha en låg tröskel för klinisk undersökning av misstänkta skador.
Effekt av sedering vid hjärnstamsaudiometri. Pediatr Neurol. 2010 May;42(5):331-4. Abstract Prolongation of the I-V interpeak latency intervals have been reported in Rett syndrome and other neurodevelopmental disorders. It has been suggested that the use of sedation may account for differences in the interpeak latency intervals when comparisons are made across diagnostic groups if sedated control groups are not used for the basis of comparison. This study examined the effects of sedation on auditory brainstem response interpeak latency intervals (i.e., I-III, III-V, and I-V) in two groups: (1) a group with Rett syndrome who were positive for mutations in the MECP2 gene and (2) a group negative for mutations in the MECP2 gene but who were severely to profoundly delayed with other causes of mental retardation. To further assess the effects of sedation, a third group of sedated and nonsedated female participants, taken from an in-house normative auditory brainstem response database was also included. An analysis of variance indicated (1) longer I-V interpeak latency intervals in the sedated participants with Rett syndrome; (2) longer III-V interpeak latency intervals in the mutation-positive participants as compared to non-Rett syndrome, mutation-negative participants; and (3) no significant effects of sedation on the I-III, III-V, or I-V interpeak latency intervals among the normative group participants, according to t tests. The findings suggest a possible biological basis for the discrepancy in the literature on auditory brain stem responses in Rett syndrome, and warrant cautious interpretation of auditory brainstem responses findings in sedated subjects with Rett syndrome, as well as in those with mental retardation and seizures. Summering Undersökningen gav hållpunkter för att sedering vid Rett syndrom för, genomförande av hjärnstamsaudiometri, påverkade undersökningsresultaten. Detta talar för en biologisk orsak till diskrepansen i litteraturen vid hjärnstamsunersökning vid Rett syndrom.
Folatbrist J Inherit Metab Dis. 2010 Oct;33(5):563-70. Abstract Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the co ncentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis. Summering Folatbrist i hjärnan (CFD)definieras som ett neurologiskt syndrom med låg koncentration av 5-methyltetrahydrofolate (5MTHF) trots normalt perifert folatstatus. CFD har en stor variation av symtom som vanligen debuterar kring 4 månaders ålder med irritabilitet och sömnstörningar, som kan följas av utvecklingsförsening, , dyskinesi, ataxi och spastisk diplegi. Minskning av huvudomfångstillväxten ses liksom syn- och hörselförluster. CFD kan ofta behandlas med oral folinsyra. Tillägg av folsyra är däremot kontraindicerat och kan förvärra symtomen. CFD har rapporterats vid Aicardi-Goutieres och Rett syndrom och vid mitokondriesjukdomar.
Andning Respir Physiol Neurobiol. 2010 Sep 30;173(2):146-56. Abstract Rett syndrome is a neuro-developmental disease accompanied by breathing symptoms including breath-hold events, and is caused by mutation of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Males of Mecp2-deficient mice (Mecp2(-/y)) also develop breathing symptoms, with erratic rhythm and life-threatening apnoeas from postnatal day 30 (P30), leading to respiratory distress and premature death at around P60. We investigated the respiratory function of conscious Mecp2( -/y) mice at P40-P60 using conventional whole-body plethysmography, double-chamber plethysmography and chest EMG recordings. Double-chamber plethysmography revealed a persistent increase in respiratory work-load with enlarged chest movements, but no subsequent increase of tidal volume thus revealing a mismatch between airflow and muscle work-load. Apnoeas occurred with cessation of both chest movements and ventilation, but some (40%) developed with persisting rhythmic chest EMG discharges or chest movements without respiratory airflow, suggesting respiratory efforts against obstructed airways. Airway obstruction was maintained even when the respiratory drive increased significantly, triggering large chest EMG discharges and movements. Whole-body plethysmography of Mecp2(-/y) mice revealed significant increases of spirograms, reflecting forced chest movements against partially obstructed airways. The persisting chest EMG discharges and rhythmic chest movements without respiratory airflow suggest that Mecp2 inactivation alters neural circuits controlling the upper airway dilator muscles. The observed breath-hold events in Mecp2(-/y) mice might imply disturbance of neural circuits attached to voluntary control of breathing. Summering Andningsfunktionen studerades hos vakna Mecp2( -/y) möss vid postnatal ålder 40-60 dagar (P40-P60) med hjälp av konventionell helkroppspletysmografi, dubbelkammarpletysmografi och EMG-avledningar från bröstkorgen. Undersökningen visade kvarstående ökat andnigsarbete med förstorade andningsrörelser utan ökning av tidalvolymen, dvs en mismatch mellan luftflöde och andningsarbete. En del hade rytmiska EMG-urladdningar från andningsmusklerna utan luftflöde. Andra hade apneer utan vare sig rörelser i bröstkorgen eller luftflöde. En del hade kvarstående andningsarbete utan luftflöde vilket talade för obstruktion av luftvägarna. Kraftigt andnigsarbete triggades av detta och obstruktionen kvarstod även vid kraftigt ökat andnigsarbete. Man föreslår förklaringen att inaktivering av MeCP2 ändrar de neuronala kretsar som kontrollerar muskler som dilaterar övre luftvägarna.
J Child Neurol. 2010 Oct 4. Abstract Loss of hand function is a core feature of Rett syndrome. This article describes longitudinal hand function at 3 time points for 72 subjects participating in the Australian Rett Syndrome Database. Approximately 40% of subjects with some grasping abilities lost skill over the 3- to 4-year period between video assessments. In these subjects, a decrease in hand function was seen less frequently in girls 13 to 19 years old than in those younger than 8 years, in subjects with some mobility compared with those who were wheelchair bound, and in those who had previously been able to finger feed. Relationships with the magnitude of change reflected these findings. Change in hand function did not vary with clinical severity. The results for all subjects were similar to results obtained when analysis was restricted to those with a pathogenic mutation. Variability in the longitudinal course of hand function in Rett syndrome was observed. Summering Förändring i handfunktion varierade inte med hur allvarlig funktionsnedsättningen i övrigt var. Variationer i handfunktion kunde ses på lång sikt vid Rett syndrom.
MeCP2-genens roll Curr Psychiatry Rep. 2010 Apr;12(2):127-34. Abstract Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Rett syndrome, the primary disorder caused by mutations in the X-linked MECP2 gene, is characterized by a period of cognitive decline and development of hand stereotypies and seizures following an apparently normal early infancy. In addition, MECP2 mutations and duplications are observed in a spectrum of neurodevelopmental disorders, including severe neonatal encephalopathy, X-linked mental retardation, and autism, implicating MeCP2 as an essential regulator of postnatal brain development. In this review, we compare the mutation types and inheritance patterns of the human disorders associated with MECP2. In addition, we summarize the current understanding of MeCP2 as a central epigenetic regulator of activity-dependent synaptic maturation. As MeCP2 occupies a central role in the pathogenesis of multiple neurodevelopmental disorders, continued investigation into MeCP2 function and regulatory pathways may show promise for developing broad-spectrum therapies.
BMC Neurosci. 2010 Apr 26;11:53. Abstract BACKGROUND: The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. RESULTS: Using microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1) or are involved in synaptic vesicle cycling (dynamin 1). RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP) analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression. CONCLUSIONS: This study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implica ted in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited.
Pediatr Neurol. 2010 Jul;43(1):35-40. Abstract Rett syndrome is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 gene (MECP2). The MECP2 protein is expressed primarily in neurons, and mutations in the gene lead to the clinical features of Rett syndrome in human patients and neurologic deficits in murine models. Visual function is relatively preserved in Rett syndrome patients, but the cause is unknown. The eyes of two Rett syndrome patients who died of the disease were analyzed; no gross or microscopic changes were found. MECP2 expression was examined using immunohistochemistry; nuclear protein expression was largely limited to ganglion cells and the portion of the inner nuclear layer populated by amacrine cells. No significant differences in MECP2 protein level or distribution were identified in the two eyes from the Rett syndrome patients, compared with 11 controls. The findings were compared with MECP2 expression in the brain of these two subjects and in MECP2-deficient mice. The findings suggest that the normally limited expression of MECP2 in visual pathway neurons may underlie the intact vision ob served in Rett syndrome.
CDKL5 Twin Res Hum Genet. 2010 Apr;13(2):168-78. Abstract Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n=102), males with X-linked mental retardation (n=9), patients with West syndrome (n=52), patients with autism (n=59), patients with epileptic encephalopathy (n=33), patients with Aicardi syndrome (n=7) and other patients with intellectual disability with or without seizures (n=54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1-3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.
FOXG1 Eur J Hum Genet. 2010 Aug 25. Abstract Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.European Journal of Human Genetics advance online publication, 25 August 2010; doi:10.1038/ejhg.2010.142.
Neurogenetics. 2010 Aug 24. Abstract Mutations in the FOXG1 gene have been shown to cause congenital variant of Rett syndrome. To date, point mutations have been reported only in female patients. We screened the entire coding region of the gene for mutations in 50 boys with congenital encephalopathy, postnatal microcephaly, and complex movement disorders, a clinical picture very similar to that described in girls with FOXG1 mutations. We found one boy carrying the de novo c.256_257dupC frameshift mutation. He presented the association of postnatal microcephaly, severe axial dystonia with severe feeding difficulties with protruding tongue movements during the first year of life that subsequently evolved into dyskinetic movement disorders with hand stereotypies. In contrast to his severe motor impairment, he developed nonverbal communication skills and relative good eye contact. Brain MRI showed frontal gyral simplification with dramatic myelination delay most prominent in both frontal lobes. Altogether the presentation in this male patient is highly reminiscent of that observed in FOXG1-mutated females with the congenital variant of Rett syndrome. This new case confirms the prediction that congenital variant of Rett syndrome should be found also in males, with the characteristic hallmarks consisting of postnatal microcephaly, dyskinetic movement disorder with Rett-like features, i.e., hand stereotypies, and frontal gyral simplification with myelination delay. FOXG1 screening should be considered in individuals with these clinical features. Summering Sammanfattningsvis återger denne pojke bilden av den som ses hos FOXG1-muterade flickor med kongenital variant av Rett syndrom. Han konfirmerar prediktionen att congenital variant of Rett syndrom ska finnas också hos pojkar, med de karaktäristiska tecknen postnatal mikrocephali, dyskinesi, sjukdom i rörelseapparaten med Rett-liknande drag såsom handstereotypier och förändringar i hjärnans frontallober. FOXG1 screening skall övervägas vid dessa kliniska drag.
J Dev Behav Pediatr. 2010 Sep;31(7):564-81. Abstract A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult a nimals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man. Summering Farmakoterapier mot utvecklingsneurologiska störningar är under utveckling. Särskilt intresse riktas mot de åkommor där man känner till en genetisk bakgrund. Man vill undersöka mekanismerna bakom störningarna och testa effektiva behandlingsstrategier på djur och om möjligt senare på människa. Så kallad translational research, ”översättningsforskning”, baserad på djurmodeller av genetiska utvecklingsneurologiska störningar, liksom farmacokerapeutiska strategier under utveckling riktade mot defekter i hjärnans funktion vi Down syndrome, fragile X syndromet, Rett syndrom, neurofibromatosis-1, tuberous sclerosis, och autism. Trots de stora skillnaderna i bakgrund och kliniska symtom har man funnit gemensama passager och mekanismer för dysfunktionen. Dessa inkluderar abnorma gendoser, imbalans mellan neurotransmittorsystem, and defekter i utveckling, underhåll och plasticitet i nervcellskretsar. Ett mål för ”översättningsforskning” är att ersättsk symptomatic ochtödjande drogbehandling med farmaotherapier baserade på förståelse av orsakerna till funktionsstörningarna. Baserade på denna princip erbjuder många nyligen utvecklade terapeutiska strategier klara löften om klinisk utveckling hos människa.
Juni 2010KommunikationJ Dev Phys Disabil. 2010 Apr;22(2):105-118. In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77-86, 2000a). Informants completed the IPCA and the results were analysed to provide a systematic inventory and objective description of the communicative forms and functions present in each individual’s repertoire. Results show that respondents reported a wide variety of communicative forms and functions. By far most girls used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Exploratory analyses revealed that several communicative forms and functions were related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of girls who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young. Kommunikation hos individer med Rett Syndrom: en bedömning av former och funktioner. I den här studien undersökte vi former och funktioner av prelingvistiskt kommunikativt beteende hos 120 barn och vuxna med Rett syndrom med hjälp av ”Förteckningen över Potentiella Kommunikativa Handlingar” (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77-86, 2000a). Uppgiftslämnarna fyllde i Förteckningen (IPCA) och resultatet analyserades för att skapa en systematisk förteckning och objektiv beskrivning av de kommunikativa former och funktioner som fanns i varje individs repertoar. Resultatet visar att varje respondent rapporterade en stor variation av kommunikativa former och funktioner. De allra flesta flickorna använde prelingvistiska kommunikativa beteenden, av dessa var ögon-/blickkontakt den allra vanligaste formen. De mest noterade kommunikativa funktionerna var socialt umgänge, kommentarer, svar, att fråga efter och att välja. Problemskapande (såsom självskador, skrikande, bristande samverkan) användes som kommunikation av 10-41 %. Forskningsanalyser visade att många kommunikationsformer och funktioner var relaterade till den miljö de levde i, förekomst eller frånvaro av epilepsi, samt ålder. Det vill säga, en större procent flickor som visade former/funktioner sågs bland dem som bodde hemma, inte hade epilepsi och var relativt unga.
SkolioserPediatr Res. 2010 Apr;67(4):435-9. To understand scoliosis, related comorbidities, and phenotype-genotype correlations in individuals with Rett syndrome (RTT), the Rare Disease Clinical Research Network database for RTT was probed. Clinical evaluations included a detailed history and physical examination, comprehensive anthropometric measurements, and two quantitative measures of clinical status, Clinical Severity Scale (CSS) and motor-behavioral analysis (MBA). All data were exported to the Data Technology Coordinating Center (DTCC) at the University of South Florida. Scoliosis assessment was based on direct examination and curvature measurements by radiography (Cobb angle). Statistical analyses included univariate and multiple logistic regression models, adjusting for age at enrollment or mutation type. Scoliosis data were available from 554 classic RTT participants, mean age = 10 y (0-57 y). Scoliosis was noted in 292 (53%); mean age = 15 y with scoliosis and 6 y without. Using multiple regression analysis, MBA severity score, later acquisition, loss or absent walking, and constipation were associated with scoliosis. Two common methyl-CpG-binding protein 2 (MECP2) mutations, R294X and R306C, had reduced risk for scoliosis. These findings corroborated previous reports on scoliosis and extended understanding of comorbidities, clinical severity, and relative risk reduction for specific mutations. Clinical trial design should account for scoliosis and related factors judiciously. En översikt över skolioser vid Rett syndrom. För att förstå skolios, relaterad ko-morbiditet och fenotyp-genotyp-korrelation hos personer med Rett syndrom (RTT), användes databasen för RTT, Rare Disease Clinical Research Network. De kliniska bedömningarna inkluderade detaljerad anamnes och fysisk undersökning, omfattande antropometriska mätningar och två kvantitativa mått på kliniskt status, Clinical Severety Scale (CSS) och Analys av motoriskt beteende (MBA). Alla data exporterades till Data Technology Coordinating Center (DTCC) vid South Florida Universitet. Skoliosbedömningarna baserades på direkt bedömning och röntgenundersökning av kurvaturen (Cobbs vinkel). Statistiska analyser inkluderade modeller för univariat och multipel logistisk regression med anpassning för ålder då de kom in i studien och för mutationstyp. Skoliosdata fanns för 554 deltagare med klassiskt RTT, medelålder 10 år (0-57 år). Skolios hade noterats hos 292 (53%); medelålder 15 år med skolios och 6 år utan. Vid användande av regressionsanalys var motoriskt beteende (MBA), severity score, senare uppnående, förlust eller frånvaro av gående och förstoppning, associerade med skolios. Två vanliga MECP2-mutationer, R294X och R306C, visade minskad risk för skolios. Dessa fynd bekräftade tidigare rapporter om skolioser och ökade förståelsen av ko-morbiditet, klinisk svårighetsgrad och relativ riskreduktion vid specifika mutationer. Kliniska prövningar måste utformas så att skolioser och relaterade faktorer redovisas omdömesgillt.
Magsäck och tarmarBrain Dev. 2010 Feb 8. Introduction: Rett syndrome is a neurologically disorder that affects approximately one in 10,000 females. Case report: A 21-year-old girl with Rett syndrome was hospitalized for abdominal distention and pain. Physical examination revealed abdominal tenderness. Radiology investigation revealed bilateral free air in subdiaphragmatic area. Gastric perforation observed at laparotomy. Primary suturing and omentoplasty were performed. In the follow-up, the symptoms of intestinal obstruction occurred. Conservative treatment failed and second intervention was performed. At laparotomy severe gastric and intestinal dilatation and bowel adhesions were detected. Adhesiolysis, tube gastrostomy, and feeding jejunostomy performed. Discussion: Rett syndrome and associated gastric complications are uncommon. These pathologic disorders may cause gastric, intestinal necrosis, intestinal obstructions. Because of the late occurring of physical findings and insidious presentation of the gastrointestinal perforations in Rett syndrome, physicians should keep in mind this rare entity to reduce morbidity and mortality. Behandling av perforation av magsäcken hos en flicka med Rett syndrom: En fallbeskrivning. Introduktion: Rett syndrom är en neurologisk sjukdom som förekommer hos ungefär 1:10 000 flickor/kvinnor. Fallbeskrivning: En 21-årig flicka med Rett syndrom lades in på sjukhus på grund av utspänd buk och smärtor. Kroppsundersökningen avslöjade ömhet över buken. Röntgenundersökning visade fri gas i buken, bilateralt under diafragma. Vid laparatomi (då man öppnade buken) fann man perforation av magsäcken. Primär suturering och omentum-täckning gjordes. Vid uppföljning sågs tecken till obstruktion (hinder) i tunntarmarna. Konservativ behandling misslyckades och en andra operation företogs. Då buken öppnades upptäcktes allvarlig dilatation (utspänning) av magsäck och tunntarmar och sammanväxningar vid tjocktarmen. Sammanväxningarna löstes, gastrostomi och jejunostomi anlades. Diskussion: Rett syndrom och associerade komplikationer från magsäcken är ovanliga. Dessa patologiska tillstånd kan orsaka nekros (vävnadsdöd) i magsäcken och tunntarmarna och obstruktion i tarmarna. Eftersom kliniska tecken kommer sent och tecknen till perforation av magsäcken är smygande vid Rett syndrom, bör läkare ha detta ovanliga tillstånd i åtanke för att reducera sjukdom och död. Fem personer med MECP2-mutationer i samma familj – olika kliniska bilderJ Neurodev Disord. 2009 Dec;1(4):313. We report a three generation family in which five members, three females and two males, demonstrate a 44 bp deletion (1164-1207del44) in the MECP2 gene associated with Rett syndrome, leading to a truncation of the C-terminus of the protein. Two of the three females and both males do not meet RTT criteria whereas the youngest female has classic RTT. Both males demonstrated a clear pattern of progressive involvement including dystonia. The transmitting females do not demonstrate features of RTT as a result of unbalanced X chromosome inactivation (XCI) and were only identified as carriers following the evaluation of the affected males and the girl with classic RTT. As such, accurate assessment of the precise frequency of MECP2 mutations in carrier females with mild cognitive impairment or borderline cognitive function will be under-represented unless an affected offspring is recognized. Strategies for accurate diagnosis in such instances should be considered carefully. Variabelt fenotypiskt uttryck av en MECP2-mutation i en familj. Vi rapporterar en 3-generationers familj där 5 medlemmar, 3 kvinnliga och 2 manliga, har en 44 baspars deletion (1164-1207del44) i MECP2-genen, associerad med Rett syndrom (RTT), vilket lett till att C-terminalen av proteinet skurits bort. Varken männen eller två av de tre kvinnorna fyller kriterierna för RTT, medan den yngsta kvinnan har klassiskt RTT. Bägge männen visade klart progredierande symtom inkluderande dystoni. De båda kvinnorna visade inga drag av RTT på grund av obalanserad X-kromosom-inaktivering (XCI) och identifierades som bärare först efter undersökning av männen och flickan med klassiskt RTT. Adekvat bedömning den exakta frekvensen av MECP2-mutationer hos kvinnliga bärare med endast lätt störd eller något svag inlärningsförmåga kommer att vara underrepresenterad, om inte en påverkad ättling diagnostiseras. Strategier för tillförlitlig diagnos under sådana omständigheter måste övervägas noga. Nymutationer vid Rett syndrom – från vilken förälder härstammar de?J Child Neurol. 2010 Mar 5. Rett syndrome is an X-linked neurodevelopmental disorder that predominantly affects females. It is caused by mutations in methyl-CpG-binding protein 2 gene. Due to the sex-limited expression, it has been suggested that de novo X-linked mutations may exclusively occur in male germ cells and thus only females are affected. In this study, the authors have analyzed the parental origin of mutations and the X-chromosome inactivation status in 24 sporadic patients with identified methyl-CpG-binding protein2 gene mutations. The results showed that 22 of 24 patients have a paternal origin. Only 2 patients have a maternal origin. Except for 2 cases which were homozygotic at the androgen receptor gene locus, of the remaining 22 cases, 16 cases have a random X-chromosome inactivation pattern; the other 6 cases have a skewed X-chromosome inactivation and they favor expression of the wild allele. The relationship between X-chromosome inactivation and phenotype may need more cases to explore. Analys av föräldraursprung av de novo MECP2-mutationer och X-kromosominaktivativering hos 24 patienter med Rett syndrom i Kina. Rett syndrome är en X-bunden utvecklingsneurologisk sjukdom som huvudsakligen förekommer hos flickor/kvinnor. Den orsakas av mutationer i MECP2-genen. På grund av den könsbundna förekomsten har man trott att X-bundna de novo-mutationer endast uppkommer hos manliga ”germ cells” och att därför endast kvinnor drabbas. I den här studien har författarna analyserat föräldraursprunget till mutationerna samt X-kromosom-inaktiveringen hos 24 patienter med identifierade sporadiska mutationer i methyl-CpG-binding protein 2. Resultaten visade att 22 av 24 patienter hade paternellt ursprung. Endast 2 patienter hade maternellt ursprung. Utom 2 fall som var homozygoter vid androgenreceptor-locus, av de återstående 22, hade 16 slumpartat X-kromosom-inaktivativeringsmönster; de övriga 6 hade förskjuten X-inaktivering och det favoriserade användning av den friska allelen. Relationen mellan X-kromosominaktivering och fenotyp behöver undersökas på fler fall. Första flickan med dubblerad MECP2-genClin Genet. 2010 Jan 5. Loss-of-function mutations of MECP2 are responsible for Rett syndrome (RTT), an X-linked neurodevelopmental disorder affecting mainly girls. The availability of MECP2 testing has led to the identification of such mutations in girls with atypical RTT features and the recognition of milder forms. Furthermore, duplication of the entire gene has recently been described in boys with mental retardation and recurrent infections. We describe a girl with a heterozygous de novo MECP2 duplication. The patient, at the age of 19, has mental retardation with no autistic features. She is friendly but gets frequently anxious. She has neither dysmorphic features nor malformations. Her motor development was delayed with walking at 20 months. Speech is fluid with good pronunciation but is simple and repetitive. Diagnosis was made after single-strand conformation analysis (SSCA) and multiplex ligation-dependent probe amplification (MLPA) analysis of MECP2. Array comparative genomic hybridization (aCGH) analysis showed a duplication of 29 kb including MECP2 and part of IRAK1. Fluorescent in situ hybridization (FISH) has revealed that the duplicated region is inserted near the telomere of the short arm of chromosome 10. X-chromosome inactivation in leukocyte DNA was not skewed. We conclude that it is likely that this MECP2 duplication is responsible for the mental retardation in this patient. This case broadens the phenotypic spectrum of MECP2 abnormalities with consequent implication in diagnosis and genetic counselling of girls with non-syndromic mental retardation. De novo-duplikation av MECP2 hos en flicka med mental retardation men utan avvikande drag. Mutationer med funktionsförlust hos MECP2 orsakar Rett syndrom (RTT), en X-bunden utvecklingsneurologisk sjukdom som huvudsakligen ses hos flickor. Möjligheten till MECP2-undersökning har medfört identifiering av sådana mutationer hos flickor med atypiska RTT-drag och mildare former. Dessutom har duplikation av hela genen nyligen beskrivits hos pojkar med utvecklingsstörning och återkommande infektioner. Vi beskriver en flicka med en heterozygot de novo MECP2-duplikation. Vid 19 års ålder har patienten mental retardation utan autistiska drag. Hon är vänlig men blir ofta ångestfylld. Hon har varken avvikande drag eller missbildningar. Hennes motoriska utveckling var försenad, hon gick vid 20 månaders ålder. Talet är flytande med tydligt uttal men enkelt och repetitivt. Diagnosen ställdes efter SSCA (single-strand conformation analysis ) och MLPA (multiplex ligation-dependent probe amplification) (MLPA) avMECP2. aCGH /Array comparative genomic hybridization) analys visade duplikation av 29 kb inkluderande MECP2 och del av IRAK1. FISH (Fluorescent in situ hybridization) visade att den duplicerade regionen är instucken nära telomeren på den korta armen av kromosom 10. X-kromosominaktivering i DNA var inte förskjuten. Vi sammanfattar att det är troligt att denna MECP2-duplikation är ansvarig för den mentala retardationen hos patienten. Detta fall breddar det fenotypiska spektrat för MECP2-abnormaliteter med åtföljande implikationer för diagnos och genetisk rådgivning för flickor med mental retardation utan tecken till något syndrom. Beskrivning av fyra pojkar med MECP2-mutationer, varav två bröderPediatr Res. 2010 Jan 21. The MECP2 gene mutations cause Rett syndrome (RTT) (OMIM: 312750), an X-linked dominant disorder primarily affecting girls. Until recently RTT was considered lethal in males, although now approximately 60 cases have been reported. Males with MECP2 mutations present with a broad spectrum of phenotypes ranging from neonatal encephalopathy to non-syndromic mental retardation (MR). Four boys (aged 3-11 years) were evaluated for MR. Patient 1 had autistic features. Patients 2 and 3, were brothers both presenting with psychomotor delay. Patient 4, showed dysmorphic features and behavioral problems reminiscent of Fragile X Syndrome (FXS). All patients had a normal 46, XY karyotype and three were tested for FXS with negative results. MECP2 gene analysis of exons 3 and 4 was performed using methods based on the Polymerase Chain Reaction (PCR), including Enzymatic Cleavage Mismatched Analysis (ECMA) and direct sequencing. Patient 1 presented somatic mosaicism for the classic RTT p.R106W mutation and patient 4 carried the p.T203M polymorphism. Analysis of the mothers in both cases revealed normal DNA sequences. Patients 2 and 3 had a novel deletion (c.1140del86) inherited from their unaffected mother. MECP2 gene mutations may be considered a rare cause of MR in males although great phenotypic variation hinders genotype-phenotype correlation. Fenotypisk och genotypisk variabilitet hos fyra pojkar/män med MECP2-gensekvens-avvikelser inkluderande en ny deletion. MECP2 mutationer orsakar Rett syndrome (RTT) (OMIM: 312750), en X-bunden dominant sjukdom som framför allt ses hos flickor. Tills nyligen ansågs RTT letalt hos pojkar, men nu har omkring 60 fall rapporterats. Män med MECP2-mutationer visar ett brett spectrum av fenotyper som sträcker sig från neonatal encefalopati (hjärnsjukdom) till mental retardation utan tecken till syndrom (MR). Fyra pojkar (3-11 år) bedömdes för MR. Patient 1 hade autistiska drag. Patienterna 2 och 3 var bröder, båda debuterade med psykomotorisk försening. Patient 4 visade dysmorfa drag och beteendeproblem som påminde om Fragile X Syndrome (FXS). Alla patienter hade normal 46 XY karyotyp och tre testades för FXS med negativa resultat. MECP2 genanalyser av exon 3 och 4 gjordes med metoder baserade på PCR (Polymerase Chain Reaction) inkluderande ECMA (Enzymatic Cleavage Mismatched Analysis) och direkt sekvensering. Patient 1 hade somatisk mosaicism för den klassiska RTT-mutationen p.R106W och patient 4 hade p.T203M polymorfism. Analys av mödrarna avslöjade i båda fallen normala DNA-sekvenser. Patient 2 och 3 hade en ny deletion (c.1140del86) ärvd från deras symtomfria mamma. MECP2-mutationer är en ovanlig orsak till mental MR hos pojkar även om stor fenotypisk variation hindrar genotyp-fenotypkorrelation. Hur kommer det sig att mutationer i CDKL5-genen kan ge samma symptom som mutationer i MECP2-genen?Neurobiol Dis. 2010 Mar 6. Rett syndrome and its ”early-onset seizure” variant are severe neurodevelopmental disorders associated with mutations within the MECP2 and the CDKL5 genes. Antidepressants and drugs of abuse induce the expression of the epigenetic factor MeCP2, thereby influencing chromatin remodeling. We show that increased MeCP2 levels resulted in the repression of Cdkl5 in rat brain structures in response to cocaine, as well as in cells exposed to serotonin, or overexpressing MeCP2. In contrast, Cdkl5 was induced by siRNA-mediated knockdown of Mecp2 and by DNA-methyltransferase inhibitors, demonstrating its regulation by MeCP2 and by DNA methylation. Cdkl5 gene methylation and its methylation-dependent binding to MeCP2 were increased in the striatum of cocaine-treated rats. Our data demonstrate that Cdkl5 is a MeCP2-repressed target gene providing a link between genes the mutation of which generates overlapping symptoms. They highlight DNA methylation changes as a potential mechanism participating in the long-term plasticity triggered by pharmacological agents. CDKL5 är en målgen för MeCP2 i hjärnan och regleras av DNA-metylering. Rett syndrom och dess variant med tidigt debuterande kramper är allvarliga utvecklingsneurologiska sjukdomar associerade med mutationer i MECP2- och CDKL5-generna. Antidepressiva och missbruksdroger inducerar uttryck för den epigena MeCP2-faktorn och påverkar då ombyggnaden av kromatin. Vi visar att ökade MeCP2-nivåer resulterade i undertryckande av Cdkl5 i råtthjärnstrukturer som svar på kokain, liksom i celler exponerade för serotonin eller överexpression av MeCP2. I kontrast till detta inducerades Cdkl5 av siRNA-medierad utslagning av Mecp2 och av DNA-metyltransferas-inhibitorer och demonstrerade därigenom sin reglering med MeCP2 och med DNA-metylering. Cdkl5-metylering och dess metyleringsberoende bindning till MeCP2 ökade i striatum hos kokainbehandlade råttor. Våra data visar att Cdkl5 är en MeCP2-hämmad målgen som förbinder gener vars mutationer ger symtom som överlappar varandra. De belyser DNA-metyleringsförändringar som en potentiell mekanism i den långtidsplasticitet som triggas farmakologiskt.
November 2009J Child Neurol. 2009 Jan;24(1):115-27. Från rashygienisk eutanasi till habilitering av ”funktionshindrade’’ barn: Andreas Retts insats.
J Pediatr Gastroenterol Nutr. 2009 Jun 9. Anläggande av gastrostomi förbättrar längd- och viktutveckling hos flickor med Rett Syndrom. BAKGRUND: Tillväxthämning och bristande nutrition komplicerar det kliniska förloppet hos flickor med Rett syndrom (RTT). Dessa avvikelser är till en del konsekvenser av oralmotorisk dysfunktion och inadekvat näringsintag.
An Pediatr (Barc). 2009 May 5. [Nutrition och gastrointestinala störningar vid Rett syndrom: Betydelsen av tidig intervention.]
Respir Physiol Neurobiol. 2009 Jun 10. Tidiga andningsstörningar efter moderat hypoxi eller hyperkapni hos en musmodell av Rett Syndrom. Rett syndrom (RTT) är en sällsynt utvecklingsneurologisk sjukdom som orsakas av mutationer i transcriptions-repressor metyl-CpG-bindande protein 2 (MeCP2) och åtföljs av komplexa symptom, inkluderande störd andning och livshotande apnéer. Hos manliga möss med Mecp2-brist (Mecp2(-/y)) är andningen normal vid födelsen, men förändras efter dag 30 (P30), till störd rytm och apnéer som förvärras tills de dör omkring dag 60 (P60). Med hjälp av pletysmografi analyserade vi andningen hos normala möss och Mecp2(-/y) vid P15, P25 och P30, i luft och vid kortvarig exponering för måttlig hypoxi (syrebrist) eller hyperkapni (koldioxidstegring). Hos Mecp2(-/y) med normal viloandning, rapporterar vi försämrat andningssvar på hypoxi vid P30 och övergående apnéer med störd rytm efter hypoxi och hyperkapni vid P30, P25 och i enstaka fall vid P15. Då skulle omgivningsfaktorer kunna inducera andningsstörningar mycket tidigare än väntat hos Mecp2(-/y) och eventuellt hos människor med RTT. Vi föreslår därför att man undviker exposition av unga RTT-patienter för omgivning eller situationer där de kan utsättas för måttlig hypoxi eller hyperkapni.
J Pediatr Orthop. 2009 Jun;29(4):369-74. Effekt av skolioskirurgi på aktiviteter i det dagliga livet hos kvinnor med Rett syndrom.
Neuropediatrics. 2008 Aug;39(4):205-10. Grovmotorisk profil vid Rett syndrom enligt videoanalys.
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