Bone histomorphometry in three females with Rett syndrome.

The frequent occurrence of osteoporosis in Rett syndrome raises questions about the etiology of this finding. It is unknown whether there is any relationship between low bone mass and the underlying genetic disorder. We recently had an opportunity to study the status of bone remodeling by quantitative bone histomorphometry in three girls ages 9.75, 13.5, and 14 years, with typical Rett syndrome who required scoliosis surgery.Anterior iliac crest bone biopsies were performed 1-2 days after double labeling of the bone surfaces with tetracycline. Samples were processed for plastic embedding, sectioned, stained, and histomorphometry performed in the cancellous bone. The same observer performed all measurements. Bone volume was reduced, surface parameters of formation (osteoid surface) were normal while parameters of resorption (osteoclast surface and number) were decreased. The rate of bone formation was reduced in the first two girls but could not be measured in the third girl due to lack of double labeling. It may be that the slow rate of bone formation seen in each age group impedes the development and accumulation of peak bone mass and contributes to the decreased bone volume associated with Rett syndrome, although the data is limited. This is the first report to document decreased bone volume determined by quantitative bone histomorphometry in patients with Rett syndrome. With the recent identification of MECP2 mutations in Rett syndrome it is quite likely that genetic factors not only play a major role in brain development but may also influence other organ growth including bone formation.

Guidelines for reporting clinical features in cases with MECP2 mutations.

An international group recommends that papers relating phenotypes to genotypes involving mutations in the X chromosome gene MECP2 should provide a minimum data set reporting the range of disturbances frequently encountered in Rett Syndrome. A simple scoring system is suggested which will facilitate comparison among the various clinical profiles. Features are described which should prompt screening for MECP2 mutations.

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment.

Nine girls with Rett syndrome (mean age, 10.1 years) were monitored 24 hours a day over a period of 10 weeks using wrist actigraphy. Baseline sleep-wake patterns were assessed for 1 week. Subsequently, patients underwent a 4-week melatonin treatment period in a double-blind, placebo-controlled, crossover protocol that employed a 1-week washout between treatment trials. Melatonin doses ranged from 2.5 to 7.5 mg, based upon individual body weight. Baseline sleep quality was poor compared with healthy children. At baseline the group demonstrated a low sleep efficiency (mean [+/- SE], 68.0+/-3.9%), long sleep-onset latency (42.1+/-12.0 minutes), and a short and fragmented total sleep time (7.5+/-0.3 hours; 15+/-2 awakenings per night). Melatonin significantly decreased sleep-onset latency to (mean +/- SE) 19.1+/-5.3 minutes (P<0.05) during the first 3 weeks of treatment. While the variability of individual responsiveness was high, melatonin appeared to improve total sleep time and sleep efficiency in the patients with the worse baseline sleep quality. Finally, a 4-week administration of melatonin appears to be a safe treatment as no adverse side effects were detected, yet long-term effects of chronic melatonin use in pediatric patients are unknown at this time.

Is Rett syndrome caused by a triplet repeat expansion?

Rett syndrome is usually sporadic, but rare pedigrees with nonpenetrance in obligate carriers and possible anticipation suggest that it could be caused by a triplet repeat expansion (TRE). Rett probands and controls were systematically screened for expansions of any of the 10 possible triplet repeats by using a modified Repeat Expansion Detection (RED) assay that had been shown to detect expanded disease alleles in myotonic dystrophy and Huntington disease. No significant expansions were found in 26 sporadic and six familial Rett probands. Our results exclude the possibility that Rett syndrome is caused by a large TRE. We cannot exclude, however, causation by a small TRE that is masked by the background of longer polymorphic repeats in the normal population.

Rett syndrome: habilitation and management reviewed.

Experience over the past 10 years in the diagnosis and comprehensive management of females with Rett syndrome has given us a better understanding of the potential skills and abilities which need to be identified. This condition is unique in that after a period of early regression of development there appears to be stabilization with some improvement. The potential for these girls to achieve some functional skills and maintain them presents a challenge, but one that needs to be addressed. Medical management should include stabilization of uncontrolled seizures. Developing a comprehensive plan for feeding disorders is required so that resulting nutritional problems and constipation can be corrected. Recognition of gastroesophageal reflux and its proper management may prevent respiratory complications. Appropriate intervention strategies using different therapeutic techniques are described which have been effective in facilitating communication, maintaining hand function and ambulation, and preventing deformities. Progression of scoliosis can be managed with intensive physical therapy. Management encompasses a comprehensive medical, therapeutic, educational, and psychosocial approach, which is best provided by a team in collaboration with community agencies that serve children with special needs and their families.

Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome.

Immunocytochemical evaluations of the neocortex of three classical Rett syndrome (RS) individuals revealed a selective abnormality in the expression of microtubule-associated protein 2 (MAP-2). MAP-2 immunoreactivity (ir) was reduced throughout the neocortex of all three RS cases with a reversal of the normal pattern of more intense staining in deep cortical layers. This anomaly was selective for MAP-2 because nonphosphorylated neurofilament (SMI-32) labeling of deep pyramidal neurons and calbindin (CaBP)-stained GABAergic cells remained unchanged. Moreover, MAP-2 ir was virtually undetected in white matter while GABAergic and, particularly, peptidergic (neuropeptide Y: NPY) profiles were easily recognized. These results demonstrate a marked disruption of a major cytoskeletal component in neocortex in RS which seems to affect, predominantly, pyramidal projection and white matter neurons. MAP-2 expression appears early in neuronal maturation of the neocortex, particularly in the subplate region, the future superficial white matter, suggesting that these reported abnormalities in RS represent a developmental disturbance. Considering that MAP-2 expression is regulated by several neurotransmitter systems in adult cerebral cortex, particularly dopaminergic and cholinergic afferents that are deficient in RS, these neurochemical alterations could be related to this anomalous MAP-2 expression.

Management of Rett syndrome: a ten year experience.

Over the past 10 years (1983-1993) multidisciplinary team at the Child Development and Rehabilitation Center has diagnosed and evaluated 60 females with Rett syndrome aged 13 months to 43 years. Experience with comprehensive management is discussed with focus on feeding difficulties, communication needs, hand function, scoliosis, and deformities. Clinical and radiological assessment of feeding problems is important in deciding whether therapy will allay symptoms or a gastrostomy is indicated. Hand use can be facilitated with appropriate intervention, and a coordinated effort with a communication specialist can develop systems for environmental access. Aggressive physical therapy has been very effective in preventing progression of scoliosis and avoiding surgery. Asymmetrical function is commonly recognized in ambulatory females, and is of neurogenic origin. Psychosocial support and educational plan attempts to collaborate with community services and resources.

Women with cerebral palsy: obstetric experience and neonatal outcome.

The aim of the study was to provide a preliminary basis for advising women with cerebral palsy (CP) who choose to initiate pregnancy regarding the course of parturition and the outcomes for their newborn infants. The authors studied 22 women with CP who had 38 pregnancies at a mean age of 26 years. Eight pregnancies were electively terminated and two resulted in miscarriage. Of the 28 viable pregnancies, one resulted in a preterm stillborn infant and two in preterm liveborn infants. Delivery was vaginal in 18 cases and by cesarean section in nine (one pregnancy was lost to follow-up). Pregnancy outcomes were reassuringly normal in this small, select sample of women with relatively mild CP. Possible effects of pregnancy and childbirth on general adaptive skills or specific child-care skills of women with CP could not be assessed in this retrospective study.

Dominantly inherited megalencephaly, muscle weakness, and myoliposis: a carnitine-deficient myopathy within the spectrum of the Ruvalcaba-Myhre-Smith syndrome.

We report 27 children, aged 14 months to 9 years, who had megalencephaly, hypotonia, proximal muscle weakness, speech and motor delay, and increased intracellular lipid (myoliposis) in needle muscle biopsy specimens. The patients had many features of the Ruvalcaba-Myhre-Smith syndrome, and in 17 families we confirmed the autosomal dominant inheritance pattern previously suggested. Muscle carnitine content was low in all 11 patients and all 4 affected relatives tested. All 27 probands were treated with oral L-carnitine; a clinical response was noted in 17. We speculate that myoliposis may be found in other disorders with megalencephaly and muscle symptoms. In such cases, muscle carnitine deficiency should be considered. The reason for the reduced muscle carnitine content is not known.

Comparison of the 15q deletions in Prader-Willi and Angelman syndromes: specific regions, extent of deletions, parental origin, and clinical consequences.

It has recently been shown that apparently similar deletions of chromosome 15q occur commonly in the Prader-Willi and Angelman syndromes. The distinctness of the syndromes suggests that the deletions are not identical. To address this possibility, the specific bands involved and the sizes of the deletions were compared in seven patients with Prader-Willi syndrome and 10 patients with Angelman syndrome using high-resolution G-, Q-, and fluorescent R-banding techniques. The parental origin of the nine cases of Angelman syndrome for which parents were available for study was determined. The same proximal band was deleted (q11.2) in both syndromes. In general, the deletion in patients with Angelman syndrome was larger, though variable, and included bands q12 and part of q13. All of the studied deletions in patients with Angelman syndrome were of maternal origin. This contrasts with the predominant paternal origin of the deletion in patients with Prader-Willi syndrome. Two possible reasons for these observations are postulated: 1) the deleted regions are different at the cytologic and/or molecular level because of different exchange points in meiosis in males and females or to different mechanisms of breakage in males and females, resulting in differing breakpoints; 2) the deleted regions are essentially the same, but differential expression of the genes in the homologous chromosome 15 has occurred (imprinting).

Communication and oral-motor function in Rett syndrome.

The communication skills, oral-motor function and respiration patterns of 20 girls with Rett syndrome were studied. Loss of communication has been previously recognized as a sign of the onset of Rett syndrome, but oral-motor dysfunction has not been reported. All the girls showed a regression in speech and language function by the onset of stage II Rett syndrome. Changes in oral-motor function and respiration correlated with the progression of the disease from stages II to IV.

Cerebrospinal fluid studies in the Rett syndrome: biogenic amines and beta-endorphins.

The etiology of the Rett syndrome (RS) is unknown. Reduced function of biogenic amines has been described. Symptoms of central apnea, hyperventilation, hypothermia, peripheral analgesia, muscle rigidity, myoclonic jerks, hand stereotypy and seizures occur in RS and have been suggested as a result of elevated central beta-endorphins. It was hypothesized that a dysfunctional modulation of endogenous opiate systems and biogenic amines may be present. Cerebrospinal fluid (CSF) from 12 girls with RS was studied for beta-endorphin immunoreactivity, and biogenic amines. Lactates and pyruvate levels were measured. Eleven of the 12 girls had elevated beta-endorphin immunoreactivity in CSF, 4 girls had reduced biogenic amines and 6 girls had elevated pyruvate and lactate levels. Whether the elevated beta-endorphin immunoreactivity is a primary disorder or is a result of secondary feedback mechanisms is unknown. Naltrexone, an antiopioid drug, may reduce symptoms.

Is Angelman syndrome an alternate result of del(15)(q11q13)?

Two unrelated females, age 15 and 5 years respectively, were studied cytogenetically because of severe mental retardation, seizures and ataxia-like incoordination. A similar deletion of the proximal long arm of chromosome 15 was found in both patients. Re-evaluation showed no voracious appetite or obesity; normal size of hands and feet, minimal to no hypotonia by history or examination and facial features not typical of the Prader-Willi syndrome. However, the facial appearance of the girls was similar to each other with mild hypertelorism. The similarity of these girls and dissimilarity to Prader-Willi syndrome suggest a different syndrome, perhaps the result of deletion of a different segment of 15q. The findings of ataxic-like movements, frequent, unprovoked and prolonged bouts of laughter and facial appearance are more compatible with the diagnosis of Angelman syndrome.

Auditory brainstem response findings in Rett syndrome.

The ABR findings for 11 subjects with Rett syndrome were compared with two normal control groups, one female and the other male. Measurements were made for ipsilateral and contralateral recorded responses. Significant findings were noted for the latency of Wave V and for the III-V interval between the Rett subjects and the normal female controls on ipsilateral recording and between the Rett group and both control groups for the difference obtained between ipsilateral and contralateral recorded III-V intervals. While the basis for these observations is not clear, the findings provide evidence for some degree of involvement within the auditory brainstem pathway of this group and further support for the rather diffuse nature of the CNS pathology within the syndrome. Suggestions are made for further ABR study of this clinical entity.

The role of the physician in the care of the child with Rett syndrome.

In caring for a child with Rett syndrome, the physician as an advocate for the child can provide, access and facilitate medical, therapeutic, psychosocial and community services. A coordinated effort in the management of children with multiple medical and psychosocial problems is best provided by an interdisciplinary team.

Effects of fenfluramine on eight outpatients with the syndrome of autism.

Fenfluramine was administered to eight autistic outpatients in a double-blind study to determine its effects on symptomatic behavior, developmental scores, blood serotonin levels and platelet counts. Two children benefited substantially according to academic and cognitive tests, parental and teacher reports and the principal investigator's clinical impressions. They also manifested behavioral and mood swings. The remaining six children showed varying degrees of response; one was withdrawn during the study by his parents. The greatest improvement occurred in children with an IQ above 40; the more severely retarded improved little, and primarily in the motor sphere.

Rett syndrome: studies of 13 affected girls.

This is a presentation and discussion of clinical and laboratory data obtained on 13 girls with Rett syndrome, a progressive neurological disorder. The condition is thought to be far more prevalent than earlier reported. Family history in one patient showed presence of abnormal hand movements, increasing spasticity and psychomotor retardation in a paternal great grandaunt who died at 7 years. In the absence of chromosomal or biochemical markers, the characteristic disorder of hand movements can be used to distinguish this entity from other mental retardation, cerebral palsy and autism conditions. This report addresses the uniformity of clinical expression and highlights the differences between autism and Rett syndrome. Precocious puberty and respiratory alkalosis were not found in our patients. Feeding disorders were commonly present, and are often difficult to manage. The importance of diagnosis is emphasized as it influences long term management.

Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia: studies in four children.

We describe a relatively new syndrome in four children with characteristic facial dysmorphism, sensorineural hearing loss, severe visual impairment with retinitis pigmentosa, hypotonia, hepatomegaly, and severe developmental delay. Two patients had intracranial hemorrhage secondary to a vitamin K-responsive clotting defect; both had steatorrhea. Liver biopsy specimens in two children showed an accentuated lobular architecture with prominent fibrous bands in the portal area. In one, the ultrastructure showed accumulation of abnormal substances and occasional trilaminar structures in hepatocytes and other cells. All four patients had elevated serum phytanic acid concentrations (0.3 to 2.7 mg/dl, normal less than 0.2 mg/dl) and deficient fibroblast phytanic acid oxidase activity (0.1 to 6.7 pmol/mg protein/hr, normal 23 to 87 pmol/mg protein/hr). Serum pipecolic acid was 7 to 55 times normal, and the ratio of C26/C22 very long chain fatty acids was increased (0.10 to 0.22; normal less than 0.03). This characteristic syndrome has been described in several children and called infantile Refsum disease or phytanic acid storage disease. Its relationship to neonatal adrenoleukodystrophy, hyperpipecolic acidemia, and Zellweger syndrome is discussed.

Ophthalmic manifestations of infantile phytanic acid storage disease.

Two patients had infantile phytanic acid storage disease. Patient 1 had nystagmus from early infancy, epicanthal folds, esotropia, and a pigmentary retinopathy. The second case had similar manifestations; however, no nystagmus was present. Both patients were hypotonic as infants, had a severe hearing impairment, and were moderately severely developmentally delayed. Serum phytanic acid levels in both cases were clearly elevated. The fundus and fluorescein angiogram showed macular and diffuse retinal pigment epithelial defects, vascular attenuation, and pigmentary dispersion. The electroretinogram demonstrated severely subnormal rod- and cone-mediated responses, with greater involvement evident for responses generated by middle and inner retinal neurons compared with responses mediated by photoreceptors. The ophthalmologist may be the first to recognize the characteristic features of this disorder. Early diagnosis may be important because this disorder may be ameliorated by dietary restriction of phytanic acid.