Japanese monozygotic twins with Rett syndrome

We present a study of 28-year-old Japanese monozygotic female twins with Rett syndrome (RS). To our knowledge, this is the first report of monozygotic twins with RS from Japanese family. There are some differences between twins about seizures, scoliosis and stereotypical hand movements during adolescence. Monozygosity was confirmed by both blood typing and HLA titers.     

Respiration patterns during feeding in Rett syndrome

Pollen allergy--one of the most frequent allergies in people is diagnosed by combined data, derived from patient's history together with in vitro and in vivo examinations. Basic in vivo examinations consist of skin prick tests with chosen allergens, functional tests of upper and lower respiratory tract, specific as well as non-specific nasal and bronchial challenge tests. The major role among in vitro examinations is played by those tests, which confirm atopic background of the disease (total and specific IgE). Other tests, like those for T-cell function and tests for effector cells activation, have secondary importance. Patients who are asymptomatic but endangered by the possibility of symptoms occurrence, are treated by primary prevention. Complex therapeutical approach consists of causal treatment (identification of allergens, specific immunotherapy), secondary prevention and symptomatic pharmacology.     

Insulin-dependent diabetes mellitus presenting with ketoalkalosis in Rett syndrome

A 9-year-old girl with Rett syndrome presented with typical symptoms of insulin-dependent diabetes mellitus. Upon investigation she was found to have a primary respiratory alkalosis associated with diabetes ketoacidaemia. Once non-ketotic normoglycaemia was achieved her respiratory alkalosis persisted. This was felt to be due to an abnormal breathing pattern of hyperventilation punctuated by apnoeas which is associated with Rett syndrome.     

Scoliosis in Rett syndrome. Clinical and biological aspects

STUDY DESIGN: The natural history of progression of scoliosis was studied. The authors included a wide range of ages and correlated progression and progression rate to both age of the patient and the neurobiologic staging of the disease. OBJECTIVES: The authors studied information compiled by Hagberg and coworkers regarding Rett syndrome. The total number of patients was 78, with age ranging from 1 to 34 years. Standing or sitting anteroposterior roentgenograms were collected and measured. METHOD: The material was studied initially separately regarding orthopedic and radiologic analysis on one hand and neurobiologic staging on the other. Radiographic films were measured both retrospectively and prospectively, and scoliosis angle and progression and progression rate was calculated. Staging of patients with Rett syndrome was done according to Hagberg. RESULTS: When correlating curve magnitude and progression, the authors found that patients progressing > 15 degrees/year were classified as IV-A or IV-B stages. In the 0-5 year group, of the patients already having a curve of 15 degrees or more, all but one rapidly progressed to stage IV. The ten worst cases were characterized by early hypotonia, weakness, and gross motor disturbance. CONCLUSIONS: The scoliosis in Rett syndrome is of a neurogenic type, and it develops earlier than idiopathic scoliosis. The development of scoliosis is dependent more on stage of disease than on age. Curve progression is usually more rapid than in idiopathic scoliosis and in most other types of neurogenic scoliosis in childhood and occurs in a broader age span. Early hypotonia, weakness, and muscular insufficiency, and an early clinical referral to disease stages IV-A or IV-B are ominous factors. Clinical follow-up should begin early and be repeated regularly and frequently.     

Diagnosis of Rett syndrome: can a radiograph help?

Rett syndrome (RS), a neurodevelopmental disorder almost exclusively affecting girls, is associated with severe intellectual and motor disability. In the absence of biological markers, diagnosis is determined by a set of clinical criteria. In a previous study in Scotland, shortening of the fourth metatarsal was reported clinically in 20% of classical RS cases aged 5 years or older. The Australian Rett Syndrome Study database has facilitated a population-based radiological study of the hands and feet of girls with RS. Straight radiographs of hands and feet were available from 94 cases, representing 70.1% of the known RS population in Australia. Control radiographs were matched for age, sex, and laterality. Relative shortening of the fourth metacarpal/metatarsal was assessed using the sign method. A short ulna (negative ulna variance) was defined as the distal articular surface of the ulna being at least 5mm proximal to the distal articular surface of the radius. A positive metacarpal sign was twice as common in verified cases of RS than in controls in the right but not the left hand. A short ulna was more common in subjects with RS than in controls. A short fourth metatarsal was also more common among subjects with RS. More than half (56.6%) the girls with RS over the age of 4 years had a negative ulnar variance in either wrist or a metatarsal sign in either foot. These findings will assist with the diagnosis of RS and may help direct research towards the location of the molecular defect.     

Neuroanatomy in Rett syndrome: cerebral cortex and posterior fossa

Rett syndrome (RS), a neurodevelopmental disorder of unknown etiology occurring almost exclusively in females, is characterized by autistic-like behavior, motor dysfunction, loss of language skills, dementia, and microcephaly. This study is a follow-up and extension of a previously reported neuroimaging study of patients with RS. We replicated previously reported findings with a larger patient population, and the volumetric MRI analysis was extended to include an analysis of neuroanatomy of the posterior fossa. Twenty girls with RS were compared with individually age- and gender-matched normal controls. Patients with RS showed global reduction in gray- and white-matter volumes. The prefrontal, posterior-frontal, and anterior-temporal regions showed the largest bilateral decrease in gray-matter volume, whereas white-matter volume was uniformly reduced throughout the brain. We found confirmation for the preferential reduction in caudate nucleus volume. However, we observed no preferential reduction in midbrain volume despite a preferential reduction in the midsagittal area of this region. We also present an individual case comparison between monozygotic twins discordant for RS.     

Is Rett syndrome caused by a triplet repeat expansion?

One of the strategies used by Gram-negative bacteria to secrete proteins across the two membranes which delimit the cells, is sec independent and dedicated to proteins lacking an N-terminal signal peptide. It depends on ABC protein-mediated exporters, which consist of three cell envelope proteins: two inner membrane proteins: an ATPase (the ABC protein), a membrane fusion protein (MFP) and an outer membrane polypeptide. Erwinia chrysanthemi metalloproteinases B and C, and Serratia marcescens hemoprotein HasA are secreted by such homologous pathways and interact with the ABC protein. Interaction between the ABC protein and its substrate has also been evidenced by studies on proteinase and HasA hybrid transporters obtained by combining components from each system. Association between hemoprotein HasA and the three exporter/secretion proteins was demonstrated by affinity chromatography on hemin agarose on which the substrate remained bound with the three secretion proteins. The three component association was ordered and substrate binding was required for the formation of this multiprotein complex.     

Cytogenetic and molecular genetic diagnostics of Rett syndrome in children]

Rett syndrome in 32 children (31 girls and 1 boy) was diagnosed according to International association on Rett syndrome. The phenomenon of the presence of special type of late-replicating chromosome X (type C) was revealed. This phenomenon may be recommended as a diagnostic test for both preclinical periods of development of the disease and in atypical cases of Rett syndrome.     

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome: analysis of 31 cases

Rett syndrome (RS) is a progressive encephalopathy restricted to the female sex. In the present study we investigated 30 females and one male with RS by cytogenetic and molecular-cytogenetic methods. We failed to identify any chromosomal rearrangements within the female groups and no correlation between fra(X)(p22) and RS in either the female group or the male. The boy with RS has karyotype 46,XY/47,XXY with abnormal cell clone (47,XXY) in 6-12% of his lymphocytes (revealed by fluorescence in situ hybridization analysis (FISH) of interphase cells with chromosome X-specific DNA probe). Our results indicated a possible connection between RS and X-chromosome replication disturbance. A late-replicating X-chromosome with a specific banding pattern (type 'C') has been observed in RS patients only. We propose to analyse the X-chromosome replication pattern as a test for confirmation of RS at preclinical diagnosis.     

Rett syndrome. An update and review for the primary pediatrician

Rett syndrome is a common developmental-neurologic disorder that has been reported almost exclusively in females. Recent work has improved recognition of this condition and helped to clarify the management of this disorder for affected individuals. The primary-care physician can become a major source of support and advocacy for the family of a girl with Rett syndrome. Many other resources are available to the primary care giver and the families of children with Rett syndrome; these may help to provide early diagnosis, psychological support, and preventive medical care for these individuals. The current state of knowledge regarding Rett syndrome is reviewed and a framework is provided for medical and developmental interventions.     

Carnitine deficiency and carnitine therapy in a patient with Rett syndrome

The aim of the present study was to establish an alternative methodology for testing the antibacterial effects of different amalgams. The vitality of mutans streptococci grown in vitro on various amalgam surfaces was monitored with a vital fluorescence staining technique using fluorescein diacetate and ethidium bromide. The in vivo effect of amalgam-non-gamma 2 fillings on the vitality of dental plaque was assessed with the same method and compared with samples originating from enamel. The median in vitro vitality of mutans streptococci was estimated as 70% on glass, 50% on Amalcapnon-gamma 2 and Sybraloy, 20% on Amalcap F and 10% on Neo-Silbrin. In vivo plaque vitality on enamel varied from 60 to 70%. In contrast, plaque sampled from non-gamma 2-amalgam surfaces revealed significant reductions in vitality with a minimum value of 25% of one day old supragingival plaque. The vital fluorescence technique was shown as an easy and quick method to assess the bactericidal effect against biofilm bacteria of dental materials in vitro as well as in vivo.     

Neurotrophic factors in cerebrospinal fluid and serum of patients with Rett syndrome

Rett syndrome is now considered to be a neurodevelopmental disease. Its cause is unknown, but it has been suggested that neuronal growth factors and neurotransmitters play important roles. We measured levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid, and nerve growth factor and brain-derived neurotrophic factor in serum in child and adolescent patients with Rett syndrome. Levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid were below the limit of sensitivity of the methods used. Serum levels of nerve growth factor and brain-derived neurotrophic factor did not differ from control values. In Rett syndrome, the normal serum levels of nerve growth factor together and previously reported low levels of the factor in cerebrospinal fluid indicate that the latter may reflect low levels of nerve growth factor in the central nervous system.     

Rett syndrome, classical and atypical: genealogical support for common origin

AIMS OF THE STUDY: By using genealogical methods in atypical females with Rett syndrome (RS) we looked for support for the assumption that atypical RS cases are true variants of classical RS. SUBJECTS: We selected from the Swedish national RS series the "milder" RS cases, 10 years of age and older, fulfilling the criteria for the "forme fruste" (FF) type of RS. For 32 FF cases we were able to carry out complete genealogical analyses on 61 parental lines. The pedigrees contained details of about 3200 ancestors. COMMON GEOGRAPHICAL ORIGINS: Eleven (34%) of the FF females could be traced to a previously defined "Rett area" and no fewer than six females had their origin in the same homestead as another previously examined classical RS patient. ANCESTRY: In four pedigrees, two each contained one FF and two classical RS and two each contained one FF and one classical RS, all 10 being descendants of the same four couples who lived several generations ago. CONSANGUINITY: Consanguinity in four grandparents (6.6% (SD 3.2%)) is probably a higher frequency than in the average Swedish population and supported our findings from a series of classical RS. TRANSMISSION: The data indicate that transmission starts with a premutation that over generations can result in a full mutation giving rise to RS. Both the X chromosomes and a pair of autosomes may be involved. CONCLUSION: Many, or most, atypical FF cases are true variants of RS.     

A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map

Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map.     

Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21

Although some of the susceptibility to Graves' disease is conferred by genes in the human leucocyte antigen (HLA) region on the short arm of chromosome 6, other genetic factors must also predispose. Among the cytokines involved in thyroid autoimmunity interferon-gamma (IFN-gamma) plays a key role in the pathogenesis of Graves' disease. We therefore analyzed the first intron of the IFN-gamma gene for a dinucleotide (CA) repeat polymorphism on chromosome 12q. Two hundred two Caucasian patients with Graves' disease and 214 Caucasian controls were analyzed by polymerase chain reaction (PCR) and subsequent polyacrylamide gel electrophoresis technique: eight different alleles designated as IFN-gamma*1 to IFN-gamma*8 could be differentiated. Among Graves' disease patients IFN-gamma*5 (12.9% vs. 6.8%, p < 0.04) was significantly more frequent whereas IFN-gamma*2 (2.5% vs. 9.8%, p < 0.002) was significantly less frequent. Patients positive for the genetic susceptibility marker HLA DQA1*0501 had significantly more IFN-gamma*3 alleles (13.6% vs. 2.6%, p < 0.009) and IFN-gamma*5 alleles (22.1% vs. 7.6%, p < 0.03) compared with DQA1*0501 positive controls. Also, among patients with endocrine ophthalmopathy IFN-gamma*3 (17.9% vs. 4.2%, p < 8 x 10(-6)) and IFN-gamma*5 (18.9% vs. 7.0%, p < 0.003) were significantly more frequent compared with controls. Although a significant association of IFN-gamma microsatellite polymorphism was observed, only a small proportion of Graves' disease patients have these markers. Thus, it is likely that the detected microsatellite polymorphisms play only a minor role in the susceptibility to Graves' disease.     

Coffin-Siris syndrome. Review of the literature

A great deal of new information has become available in the field of hypertension since the JNC report of 1988. The JNC V report has changed the categorization of blood pressure, modified suggested drugs for initial therapy, and recommended that diuretics or beta blockers be considered the first-line drugs of choice. Information concerning the J curve and end-stage renal disease has made therapeutic goals more challenging. One of the most important additions to this report is the new information on treating elderly patients, which had been lacking until last year. The report calls on pharmacists to assist with detecting, evaluating, and referring hypertensive patients. Pharmacists must take a leadership role in promoting compliance with antihypertensive therapy and can assist other health-care professionals by suggesting therapeutic alternatives to improve efficacy, reduce the frequency of administration, and lower costs. The complete JNC V report is an essential reference for the files of any pharmacist who is responsible for the care of hypertensive patients.     

Identification and molecular characterization of a small 11q23.3 de novo duplication in a patient with Rett syndrome manifestations

BACKGROUND AND STUDY AIMS: Modern fine-caliber endoscopes enable clinicians to directly visualize the pancreatic duct. They allow intraductal manipulation under optical control. We tried to evaluate the additional diagnostic potential of pancreatoscopy in assessing inconclusive intraductal pancreatic changes. PATIENTS AND METHODS: We prospectively performed 20 pancreatoscopies in 18 patients with inconclusive ductal abnormalities that had been previously investigated by computed tomography (CT) scan, abdominal ultrasound and endoscopic retrograde cholangiopancreatography (ERCP). The CHF-BP 30 (Olympus Optical Co., Japan) endoscope with an outer diameter of 3.1 mm and an instrumentation channel of 1.2 mm was used. Biopsies, cytological brushing and fluid collection were carried out, and the site of ductal abnormality was visualized. Endoscopic sphincterotomy (EST) was carried out in every patient prior to insertion of the pancreatoscope. RESULTS: Seven intraductal tumors were histologically confirmed, i.e. five intraductal papillary mucinous tumors and two adenocarcinomas. Benign appearance of the intraductal lesion plus negative histopathological examinations were confirmed by a follow-up of two years in eight patients. Five had chronic pancreatitis, and a further three had pancreatitis with strictures, blood clot obstruction, and idiopathic benign stricture, respectively. There were no complications with the exception of one bleeding episode after EST; no pancreatitis occurred. CONCLUSIONS: Pancreatoscopy is of diagnostic value in addition to CT, transabdominal ultrasound and ERCP in the differential diagnosis of poorly defined pancreatic lesions, particularly when assessing alterations of the ductal caliber without parenchymatous lesions.