RETT SYNDROME

INTRODUCTION — Rett syndrome (RS) is a neurodevelopmental disorder that occurs almost exclusively in females. It was described in 1966 by Andreas Rett, an Austrian neuropediatrician. Affected patients initially develop normally, then gradually lose speech and purposeful hand use. Deceleration of head growth, stereotypic hand movements, seizures, autistic features, ataxia, and breathing abnormalities subsequently develop. Most cases result from mutations in the MECP2 gene.

EPIDEMIOLOGY — In a report from a large population-based registry in Texas, the prevalence of classic RS was estimated as one per 22,800 females ages two through 18 years, or 0.44 per 10,000. Small geographic variations exist. The prevalence per 10,000 girls was 0.56 in France, 0.65 in Sweden and Scotland and 0.72 in Australia. RS occurs in all ethnic and racial groups, and at similar rates.

GENETICS — RS is caused by mutations in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2) [2]. Although MeCP2 is expressed in all tissues, it is most abundant in the brain, which may be more sensitive to abnormal MeCP2 than other tissues.

Three types of MECP2 mutations occur: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression. As examples, awake respiratory dysfunction and lower levels of CSF homovanillic acid (HVA) occurred more often with truncating mutations, while scoliosis was more common with missense mutations.

Most individuals with RS have random X-inactivation (also known as lyonization) so that the normal allele is expressed in some cells. The normal allele appears to enable affected females to survive but does not protect them from neurodevelopmental abnormalities. Random inactivation also contributes to the spectrum of phenotypes in RS. Except in special circumstances such as Klinefelter syndrome or mosaicism, similar mutations in brothers of affected girls result in severe neonatal encephalopathy and are lethal.

Some affected patients have nonrandom X-inactivation. In one series, this was associated with a milder phenotype or a mitigated classic RS caused by a rare early truncating mutation.

Mutations in MECP2 have been detected in 25 to 100 percent of classic sporadic RS cases, 33 to 50 percent of atypical RS, and 0 to 30 percent of familial cases. Variations in the rates of detected mutations may relate to clinical criteria and exclusion of variants, differences in testing methodology, and abnormalities in noncoding or promoter regions that have not been analyzed.

RS is sporadic in nearly all cases and is due to de novo mutations in the MECP2 gene. These mutations are almost exclusively of paternal origin. This may explain the high female to male ratio in RS and suggests another cause of male sparing besides lethality. In familial cases, the mother was either a carrier of the mutation, or a mosaic for the mutation. In one family with affected male children and a female child with classic RS, the MECP2 mutation was located on the mother's paternal X-chromosome.

Mutations of the MECP2 gene have been detected in other neurologic disorders. These include girls with non-Rett phenotypes such as autism, girls and boys with nonspecific X-linked mental retardation, and boys with progressive spasticity, congenital encephalopathy with respiratory arrest, or non-fatal neurodevelopmental disorders.

Mechanism — How MECP2 mutations lead to Rett syndrome is not yet established. MECP2 contains two functional domains, a methyl-CpG binding domain and a transcriptional repression domain. One possibility is that interaction between these two domains leads to transcriptional repression of some genes. However, transcriptional profiling analyses have failed to find consistent gene targets that are silenced by MECP2.

Another possibility is that MECP2 normally functions to repress transcription of some parentally imprinted genes. MECP2 mutations might then cause a loss of imprinting with subsequent target gene dysregulation. Earlier reports that tested well-established imprinted genes found no evidence for loss of imprinting related to MECP2 mutations. However, a later report found that MECP2 targeted the DLX5 gene, a maternally imprinted gene on chromosome 7q, and that MeCP2 was essential for the organization of a higher order chromatin loop at the DLX5-DLX6 locus that characterizes the silenced status of DLX5. Increased expression of DLX5 (by a factor of about two) was found in some brains of individuals with Rett syndrome as well as in MeCP2-null mice, supporting DLX5 dysregulation due to loss of MeCP mediated imprinting.

DLX5 may function to induce expression of glutamic acid decarboxlyase (GAD) and the differentiation of gamma-amino butyric acid (GABA) producing neurons, suggesting that alterations in GABAergic neurons may be involved in the pathogenesis of Rett syndrome.

NEUROPATHOLOGY — Brain growth is differentially affected in RS. In a postmortem study of 39 patients 3 to 35 years old, most RS brains were smaller than normal and did not grow after age four years. In contrast, the heart, kidneys, liver, and spleen grew at a normal rate until 8 to 12 years of age. At that time, their growth rate decelerated, but continued so that organ weights were appropriate for height, which was also reduced. Adrenal organ weights were normal.

Deceleration of brain growth in RS begins after birth. The mechanism is uncertain but appear to reflect arrested development. This is supported by morphologic observations that include no evidence of brain degeneration, no alteration in brain weight with increasing age, lack of correlation of dendritic length with increasing age, and reduced neuromelanin in the substantia nigra.

In one study, the dendrites of pyramidal neurons were examined in six regions of the cerebral cortex in girls with RS, ages 2.9 to 35 years. The cortex was selectively involved. The apical and basilar dendritic branches in layers 3 and 5 of the frontal, motor, and inferior temporal cortex were shorter compared to brains in trisomy 21 or non-Rett neurologic disorders. These findings did not change with age.

In another report, the proteins that initiate cortical dendritic differentiation and expansion (Map2, adult form) and dendritic remodeling (cyclooxygenase) were defectively expressed in RS. This indicated marked disruption of a major cytoskeletal component in the cortex. The relationship of these findings with the MECP2 mutation is unknown.

CLINICAL FEATURES

Overview — The clinical picture of RS is unique. Affected patients initially develop normally, then gradually lose speech and purposeful hand use. Deceleration of head growth, seizures, autistic features, ataxia, stereotypic hand movements, and intermittent breathing abnormalities develop subsequently.

Girls with classic RS are typically born at term after an uneventful pregnancy and delivery. They usually appear developmentally normal for at least the first six months, although some are retrospectively characterized as placid or slightly floppy. Other nonspecific signs may be present during the first six months, as illustrated by a study in which videotapes of 22 Rett patients were retrospectively reviewed. Detailed analysis revealed abnormal quality of general movements, tongue protrusion, postural stiffness, asymmetric eye opening and closing, abnormal finger movements, stereotyped hand and body movements, bursts of abnormal facial expressions, and bizarre smile. These observations further support earlier observations that subtle developmental abnormalities are present early, before regression. However, the observations need to be confirmed by comparison to a control group, such as siblings without a MECP2 mutation.

Deceleration of head growth beginning as early as two to three months is usually the first sign of RS. At 12 to 18 months, loss of acquired fine motor, intellectual, and communicative abilities is seen. In some cases, this regression is rapid, with parents reporting "She woke up and was no longer speaking." In others, regression is slow and insidious, occurring over weeks to months with loss of interest in the surroundings and loss of purposeful hand use. During this phase, unprecipitated episodes of inconsolable screaming may occur during the day or at night, disrupting sleep. These begin abruptly and may last hours.

In the beginning of the regression phase, stereotypic hand movements may be subtle and interspersed with purposeful hand use. They typically consist of periodic hand-to-mouth licking or grasping of the hair or clothing. Each girl develops her own distinctive unique hand pattern. Some retain the ability to hold a cup or feed themselves in a messy, rudimentary manner.

Following the regression phase, there is a period of some recovery of nonverbal communication, with improved eye contact and nonverbal interactions with the environment. This is followed by a slow, insidious deterioration in gross motor function. Additional features that occur in the majority of patients include: 1.Growth. 2.failure Epilepsy. 3. Disorganized breathing pattern during wakefulness characterized by periods of apnea alternating with periods of hyperventilation. 4. Autonomic nervous system dysfunction, characterized by cold feet and peripheral vasomotor disturbances

Although cardiac abnormalities may predispose to sudden death, lifespan in patients with Rett syndrome appears to be unaffected. However, life tables have not yet been established. Based on our own experience of about 500 patients with Rett syndrome, survival well into adulthood is typical.

Diagnostic categories — The clinical phenotype of RS is quite broad. Three diagnostic categories have been proposed.

Classic Rett syndrome — This group includes individuals who meet all specific diagnostic criteria.

Provisional Rett syndrome — This group includes girls, typically one to three years old, who have some clinical evidence of RS, but not enough to meet all the specific diagnostic criteria.

Atypical Rett syndrome — This group includes girls with mental retardation of unknown etiology who have at least three of six main criteria and five of 11 supportive criteria and have none of the exclusion criteria for classic RS. This category is intended to account for the heterogeneous phenotypes seen with MECP2 mutations, as well as atypical or variant cases without the genetic abnormality.

STAGING — A staging system is helpful to track the clinical course of RS. It can be used as a tool to anticipate potential clinical problems and provide anticipatory guidance to parents. However, it is often difficult to discern precisely transitions between stages. In addition, this system should not be used to predict life expectancy.

Stage I — Stage I consists of developmental arrest. The onset is between 6 to 18 months and it may last for many months. During this time there is less eye contact, reduced play, gross motor delays, nonspecific hand wringing, and decelerating head growth. Infants seem placid and not cuddly compared to healthy infants.

Stage II — Stage II consists of rapid deterioration or regression. The onset is typically between one to four years. It may be so acute that parents can give a specific date after which their child was no longer normal. In other cases, the onset may be insidious. The duration is usually weeks to months.

Stage II is characterized by the loss of purposeful hand use and spoken language, and the onset during wakefulness of hand stereotypes and periodic breathing irregularities. Hand stereotypes are most frequently midline and hand wringing or hand washing in character, occur incessantly during wakefulness but cease during sleep, and continue into adulthood. During this stage, many affected girls exhibit autistic-like behavior. Many experience variable periods of unprovoked inconsolable crying or irritability and a disturbed sleep pattern.

Stage III — Stage III is the pseudostationary stage. It begins at 2 to 10 years of age, following the period of rapid deterioration. This stage lasts many years and is characterized by behavioral improvement and some improvement in hand use and communication skills, particularly by using eye-pointing. Motor dysfunction and seizures are more prominent during this stage.

Stage IV — Stage IV consists of late motor deterioration and usually begins after 10 years of age. It is characterized by increased rigidity and reduced mobility, dystonia, hypomimia, and bradykinesia. Stage IV is further divided into stage IVA (previously ambulant) and Stage IVB (never ambulant). Cognitive function is stable and interpersonal communication may continue to improve. However, spoken communication is not regained. Seizures also often improve. Quadriparesis, scoliosis, and staring may be features of this stage.

Differential diagnosis — Depending upon the stage of presentation, alternative disorders should be considered. The differential diagnosis for each stage includes the following conditions: Stage I — Benign congenital hypotonia, Prader-Willi syndrome, and cerebral palsy Stage II — Autism, hearing/visual disturbance, encephalitis, and metabolic or degenerative disorders such as neuronal-ceroid lipofuscinosis, phenylketonuria, and urea cycle disorders. Stage III — Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, Lennox-Gastaut syndrome, and Angelman syndrome Stage IV — Unknown degenerative disorder

DIAGNOSIS — The diagnosis of RS is based upon clinical characteristics. Affected children should meet all necessary criteria, demonstrate some or many of the supportive criteria, and have none of the criteria for exclusion. Detection of mutations in the MECP2 gene may be helpful. However, this abnormality is not present in all cases.

Diagnosis of RS in middle childhood is usually straightforward because of the distinctive presentation. However, diagnosis in early infancy may be more difficult. In the absence of the MECP2 mutation, the diagnosis cannot be made definitively in the young child with decreasing head growth and delayed gross motor skills until she reaches the regression phase and shows other characteristic features of RS. The diagnosis can usually be made in an adult mentally retarded woman with typical signs, including the prominence of motor problems with progression from a hyperkinetic to a bradykinetic state, and lower motor neuron features.

History — A thorough history should be obtained from the parents. Special attention should be paid to the timing of developmental milestones and the presence of abnormal hand movements.

Physical examination — Physical examination should identify the characteristic findings of RS. Measurements typically show impaired growth, especially of head circumference. A variety of neurologic manifestations may be seen, including mental retardation or developmental delay, loss of or poor communication skills, and stereotypic hand movements.

DNA analysis — A blood sample should be obtained for DNA analysis to identify mutations of MECP2 in a female with characteristic signs. Testing should also be considered in male infants with severe encephalopathy. The diagnosis of RS (MECP2 positive) is made if the MECP2 mutation is found and clinical criteria are met.

To avoid unnecessary and expensive DNA testing, a screening checklist for RS has been proposed. The checklist is based upon the necessary criteria for the diagnosis of RS and assigns points for individual items. A total score 8 had a specificity of 100 percent and eliminated from genetic testing nearly one-half of the girls without mutations. Use of this checklist may be appropriate in girls over two years old. However, because the full profile of RS may not be developed in younger girls, screening with the checklist may delay diagnosis. For example, we have identified girls at one year of age with MECP2 mutations who presented with mild developmental delay and deceleration of head growth without other criteria for RS.

Other studies — If no mutations of MECP2 are identified, other inborn errors of metabolism and neurodegenerative disorders should be considered. The following studies should be performed: 1. Brain MRI. 2.Serum amino acids. 3.Urine organic acids. 4.Chromosome analysis, with specific attention to Chromosome 15, and FISH for Angelman Syndrome. 5.Hearing test. 6.Ophthalmologic evaluation

If these studies are nondiagnostic and clinical criteria are met for RS, the patient is considered to have RS without the MECP2 mutation.

Electroencephalogram — The electroencephalogram (EEG) may be helpful in the evaluation of RS, although it is not used for diagnosis. The EEG is always abnormal and shows characteristic changes. The epileptiform abnormalities typically begin at approximately two years of age. The EEG subsequently deteriorates, with loss of expected developmental features and the appearance of abnormal patterns. These include focal, multifocal, and generalized epileptiform abnormalities, and the occurrence of rhythmic slow (theta) activity primarily in the frontal-central regions.

Evoked potentials typically demonstrate intact peripheral auditory and visual pathways and suggest dysfunction of central or higher cortical pathways. Somatosensory evoked potentials may be characterized by "giant" responses suggesting cortical hyperexcitability.

ASSOCIATED CONDITIONS — Patients with RS often have serious medical conditions associated with the disorder. These include growth failure, seizures, cardiac abnormalities that may lead to sudden death, motor dysfunction, scoliosis, breathing dysfunction, and sleep disturbance.

Growth failure — The characteristic growth pattern of RS consists of early deceleration of head growth, followed by deceleration of weight and height measurements. This pattern deviates from growth aberrations associated with chronic disease or central nervous system or chromosomal disorders and is similar to patterns seen with acute and chronic malnutrition. It may provide the earliest clinical indicator for the diagnosis of RS.

Characteristic patterns were identified in a longitudinal study of growth in 96 affected girls. The following findings were noted: Median head circumference followed the 50th percentile from birth to three months. The rate of head growth then decelerated and head circumference fell below the 2nd percentile by four years. Median length approximated the NCHS 50th percentile until 16 months, then gradually deviated to the 5th percentile by seven years. Median weight deviated from the NCHS 50th percentile after age four months and crossed the 5th percentile at age four years. Deviation below the 5th percentile increased with advancing age for both weight and height. The mean height-for-age Z score was -4.0 SDs by age 16 years, and the mean weight-for-age Z score was -4.0 SDs at age 18 years. In another study, girls with RS had slower rates of hand and foot growth than normals. Relative to height, the rate of decelerated growth was greater for feet than hands.

Nutrition — Although multiple factors are likely responsible for the growth aberration in RS, inadequate nutrition appears to play an important role. This may result from inadequate dietary intake, increased energy expenditure, and/or feeding difficulties.

The contribution of increased energy expenditure due to involuntary repetitive movements is uncertain. In one study, total daily energy expenditure (TDEE) adjusted for differences in body weight was similar in RS and healthy girls. In another study from the same group, metabolic rates while sleeping and quietly awake were 23 percent lower in RS girls than controls; rates while actively awake were similar. Although TDEE was similar in the two groups, energy balance was less positive in the RS girls than controls. If sustained, these small deficits in energy balance may account for growth failure.

Aggressive nutritional support improves growth in RS, confirming the importance of dietary energy intake. In a preliminary report, an aggressive nutritional intervention was made in RS girls using gastrostomy feedings in amounts that approximated an energy intake of 85 kcal/kg per day. During one year, the velocity for height and weight increased by 33 percent and tenfold, respectively. However, the weight gain consisted of 63 percent fat and only 37 percent lean body mass. This deficit in lean body mass deposition may be explained by a defect in body protein metabolism. In another preliminary report, rates of amino acid loss were significantly greater in RS than controls, indicating failure to suppress endogenous body protein degradation.

Feeding impairment — Feeding impairment, characterized as chewing or swallowing difficulties, choking, and nasal regurgitation, frequently complicates RS. In addition to oromotor dysfunction, the upper gastrointestinal (UGI) tract may be affected. In a study of 34 RS females age 2.3 to 40.1 years, oropharyngeal dysfunction and UGI dysmotility occurred in 95 and 68 percent, respectively. Abnormalities of oropharyngeal function included poor tongue mobility, reduced oropharyngeal clearance, and laryngeal penetration of liquids and solid foods during swallowing. Esophageal dysmotility, characterized by the absence of primary or secondary waves, delayed emptying, atony, the presence of tertiary waves, or spasm was found in 11 patients (39 percent). Gastroesophageal reflux (GER) was present in 11 patients (35 percent), including one with nasopharyngeal reflux. Six patients (20 percent) had gastric dysmotility, characterized as decreased peristalsis or atony, and one had duodenal dysmotility. In another study, decreased dietary energy intake was associated with poor chewing and persistence of liquid and solid food residue in the pyriform sinuses and valleculae, as well as decreased body fat.

Bone mineral deficit — Bone density frequently appears diminished on conventional radiographs in RS girls, although the cause is unknown. This is seen in affected children (age two to five years) and adults, whether or not they are ambulatory. RS girls have abnormally low regional bone mineral density and whole-body bone mineral content. In one study, bone mineral content was measured by dual-energy X-ray absorptiometry in six RS girls (age 7 to 12 years); children with cystic fibrosis, juvenile dermatomyositis, liver disease, and human immunodeficiency virus; and healthy controls. Bone mineral deficit was greatest in the RS patients, who all had severe abnormalities (osteoporosis).

Seizures — Seizures occur in the majority of RS patients. In a series of affected females in West Sweden diagnosed between 1971 and 1998, 50 of 54 (94 percent) had epilepsy. Only five patients were seizure-free for more than five consecutive years and three never had seizures. Two of the nine deaths that occurred were associated with seizures (aspiration and status epilepticus). Patients in the Swedish series had all seizure types except for typical absences and clonic seizures. The most common types were complex partial, tonic-clonic, tonic, and myoclonic seizures. Seizures were controlled with antiepileptic medication in 46 percent, while the remainder of patients had intractable epilepsy. The latter was associated with smaller head circumference. Status epilepticus occurred in 19 of 50 patients-38 percent.

The median age at seizure onset was four years, with a range of 0.2 to 27.6 years. Onset before one year of age was associated with more severe epilepsy, including more seizure types, more frequent intractable epilepsy, and status epilepticus. Early seizure onset was more likely to be associated with an atypical or variant form of RS. In another report, 6 of 94 RS females had onset of epilepsy in infancy. In all, intractable seizures preceded the appearance of classic RS features. The occurrence of epilepsy may be overestimated because affected patients have a variety of abnormal behaviors that may be reported as seizure manifestations. These include breath holding, hyperventilation, incessant hand wringing, "vacant" episodes with sudden-absence-like freezing of activity, inappropriate screaming or laughter, and motor abnormalities (dystonia, tremulousness, and limpness). However, these events may not have associated EEG changes. This was illustrated by a study of video/polygraphic/EEG monitoring in 82 RS females age 2 to 30 years, all of whom had epileptiform abnormalities on EEG. During monitoring, 51 percent of the parents identified events that they thought represented their child's typical seizure, such as twitching, jerking, head turning, falling forward, and trembling, as well as episodes of staring, laughing, pupil dilatation, breath holding and hyperventilation. However, only 18 percent of these clinical episodes correlated with an EEG seizure discharge. In addition, some actual seizures were unrecognized by parents or occurred during sleep.

Cardiac abnormalities — The incidence of sudden, unexpected death is higher in RS than the general population (22 to 26 versus 2.3 percent). The mechanism is thought to be cardiac electrical instability due to abnormal autonomic nervous system regulation. Increased sympathetic activity is suggested by the increased incidence of prolonged QTc in RS. In several reports, the incidence of prolonged QTc (>0.45 msec) was higher and heart rate variability was lower in girls with RS than age-matched healthy girls. An increased proportion of QTc interval prolongations with advancing RS clinical stage has been shown by some studies but not by others.

Abnormal autonomic regulation was also suggested by a study of cardiac vagal tone, cardiac response to baroreflex, and beat-to-beat heart rate measured during rest, hyperventilation, and immediately after hyperventilation in RS girls. A deficiency in substance P in the central nervous system identified in RS girls may contribute to impairment of autonomic nervous system dysfunction, resulting in cardiac dysautonomia.

Approximately 50 to 70 percent of RS patients have clinical features that indicate autonomic nervous system dysfunction with increased sympathetic tone. These include the presence of cold, blue feet and/or hands, drooling, and breathing irregularities. A report of the relief of the vasomotor instability in the ipsilateral foot after an inadvertent unilateral sympathectomy during scoliosis surgery in an RS patient also suggests that sympathetic tone was increased.

Motor dysfunction — Extrapyramidal motor dysfunction with stereotypic hand movements and gait disturbance affects all RS patients. Stereotypic hand movements include opposition of hands, finger kneading and rubbing, hand clapping and washing, wringing, squeezing, twisting, and pill rolling. The gait typically is broadbased, clumsy, and ataxic/apraxic. Patients often have retropulsion and rock to and fro while standing or sitting. Many have difficulty crossing from one floor surface or color to another and will stop and refuse to take another step.

Extrapyramidal motor disturbances were characterized in a series of 32 affected patients, age 30 months to 28 years. Abnormalities identified in addition to stereotypic movements and gait disturbance included: Bruxism — 97 percent. Oculogyric crises — 63 percent. Dystonia — 59 percent. Proximal myoclonus — 34 percent. Excessive drooling — 75 percent. Rigidity — 44 percent. Bradykinesia — 41 percent. Hypomimia — 63 percent.

The underlying mechanism for these extrapyramidal disturbances is not known.

Scoliosis — Scoliosis that is neurogenic develops in 50 to 70 percent of RS patients. Factors influencing the onset of spinal curvature include postural alignment, gradual loss of equilibrium responses, loss of spatial perceptual orientation, loss of transitional motor skills, and onset of rigidity.

Scoliosis typically presents between 8 to 11 years of age and may progress rapidly. In a Swedish series of 106 patients age 1 to 54 years, scoliosis was identified before 11 years in 40 percent, with 14 percent before five years. The range of curvature was wide and progressed with age in the majority. However, curvature remained unchanged in 17 percent. The likelihood of progression and worsening appears to be greater in patients with early hypotonia, dystonia, or loss of ambulation. Kyphosis occurs in some RS patients and may require surgical intervention.

Breathing dysfunction — A characteristic pattern of disordered breathing during wakefulness occurs in 60 to 77 percent of RS patients. This pattern consists of episodes of hyperventilation with concomitant hypocapnia alternating with hypoventilation and/or apnea. The periods of hypoventilation and/or apnea may last as long as 20 to 120 seconds and result in hypoxemia. Breathing usually is normal between these episodes.

Episodes of hyperventilation tend to occur when the child is excited or agitated, and are frequently associated with other stereotypic movements. Apnea that occurs during wakefulness is typically central, although it may be obstructive. These events may be isolated, or precede or follow hyperventilation. During apneic episodes, the child may stare quietly ahead or smile and appear happy with no evidence of distress, despite severe cyanosis. Apnea may occur in inspiration or expiration. In one study using fiber optic endoscopy significant oxygen desaturation occurred in expiration but not inspiration.

Breathing abnormalities may cause severe hypoxemia. In studies recording EEG and breathing in our laboratory, hypoxemia led to electrographic seizures only when it was associated with apnea. Seizures did not occur with disorganized breathing alone, even when oxygen saturation was as low as 30 to 50 percent. The awake breathing abnormalities are not associated with bradycardia.

The breathing pattern during wakefulness does not appear to be related to the RS stage. The most severe desaturations typically appear in Stage III; these may decrease in frequency and severity during Stage IV. The underlying pathophysiology and relationship to the MECP2 mutation are unknown. It has been suggested that the disordered breathing may be due to an abnormality of cortical influences on ventilation or awake control of breathing, rather than brain stem control of ventilation.

Breathing typically is normal during sleep. However, some reports note increased periodic breathing during sleep or central apnea of 20 seconds or greater during REM sleep.

Sleep disturbance — Sleep disturbances affect approximately 57 to 80 percent of RS patients and are a problem for both the patient and her caregivers. The symptoms most commonly reported by caregivers are irregular sleep times, including prolonged periods of wakefulness or sleep, periodic nighttime awakenings with disruptive behavior (such as crying, screaming, laughing), and abbreviated total nighttime sleep with increased amounts of daytime sleep. Sleep architecture is abnormal in RS. In one report, the amount of REM sleep was less than age-matched healthy controls.

MANAGEMENT — No specific therapy is available for RS. Management consists of treating the associated conditions. A multidisciplinary approach is optimal.

The first important step in management is confirming the diagnosis of RS. This is often a relief to families who have searched for an explanation of their child's problems. It may also be the beginning of the grief process for the loss of a normal child. At the time of diagnosis, anticipatory guidance should be provided regarding the spectrum of clinical problems. All parents should be taught cardiopulmonary resuscitation.

C Genetic testing — DNA analysis should be offered to the female siblings of RS patients with a mutation in MECP2 and to the mother if future pregnancies are planned. Male siblings with neurologic or developmental disorders should also be tested. Prenatal testing is available.

Nutrition — Somatic growth should be closely monitored. A high calorie, well-balanced diet should be provided with vitamins and minerals at the recommended dietary allowance. If needed to maintain adequate growth, energy intake should be increased with high-calorie supplements either orally or by gastrostomy feeding.

GI dysfunction — Oromotor function should be assessed by videofluoroscopy in children who have choking, decreased control of secretions, frequent upper or lower respiratory infections, or weight loss. An individualized treatment plan should be developed including appropriate food and beverage consistencies, positioning, and the use of selected feeding utensils. Patients with a history of eating difficulty, eructation, emesis, or irritability should be evaluated for possible GER.

Constipation can be a severe and chronic problem for many patients. One approach is a program of daily prophylaxis. Options include Miralax 1 cap (3 tsp) dissolved in 4 to 6 oz of water, juice, or milk daily with titration up or down by 0.5 tsp, or Milk of Magnesia 0.5 to 1.0 cc/kg per day as a single dose daily with titration up or down by 2.5 cc.

Bone mineral deficit — Severe bone mineral deficit (osteoporosis) is common and may lead to fractures. Affected patients with crying and/or screaming episodes of unknown etiology should be evaluated for fractures.

Seizures — Seizures may occur during sleep or not be recognized by caregivers. Conversely, many behavioral events identified by parents as seizures are nonepileptic. Thus, video-EEG monitoring may be necessary to differentiate nonepileptic behavioral events from actual seizures and to identify unrecognized seizures.

Most seizures are easily controlled and respond to standard antiepileptic drugs. A ketogenic diet or vagus nerve stimulator may improve intractable seizures. However, in view of the frequent occurrence of growth failure, a ketogenic diet should be used with caution. Hormonal therapy may be helpful in patients with infantile spasms.

Breathing dysfunction — There is no known treatment for apnea during wakefulness. In our experience, treatment with supplemental oxygen or rebreathing has not resulted in improvement; rebreathing has occasionally worsened the apnea. Naltrexone and magnesium citrate have been reported to lessen the severity of disordered breathing. In our experience, these have been beneficial to a small number of girls. A preliminary report suggested that parenteral naloxone might be helpful for disordered breathing. However, a controlled trial of oral naltrexone failed to show benefit.

Apnea during sleep is not characteristic of RS. It should be evaluated as in any patient with sleep apnea.

Cardiac abnormalities — An ECG should be obtained when the diagnosis of RS is made. If the QTc > 0.45, a cardiologist should be consulted. The ECG should be monitored annually. The family history should be reviewed for sudden unexpected death. In some cases, it may be appropriate to obtain an ECG on the parents.

Medications associated with prolongation of the QT interval (eg, tricyclic antidepressants, erythromycin) should be avoided. Beta blockers such as propranolol may be appropriate in some cases.

Scoliosis — Scoliosis should be identified as early as possible with serial examinations at yearly intervals, or more often if rapidly changing. Optimal treatment for scoliosis in RS is not certain. Bracing to control progression of the curvature does not appear to be helpful. Early referral to an orthopedic surgeon and aggressive surgical management are recommended.

Sleep disturbance — Evaluation of sleep disturbance should include characterization of night and daytime routines, time of occurrence and related factors, and impact on the family as a whole. Specific disorders that disturb sleep should be considered, such as sleep apnea secondary to tonsillar and/or adenoidal hypertrophy, gastroesophageal reflux, and seizures.

Behavioral intervention should be attempted to treat dysfunctional sleep patterns. Good sleep habits should be encouraged, including the maintenance of regular day and night routines and allowing the child only to sleep in bed. This approach includes establishing a bedtime conducive to rapid sleep onset, removing the child from the bed if she does not fall asleep within one hour, and avoiding daytime sleep except for scheduled naps. Other measures that may be helpful are taking a warm bath one to two hours before sleep, avoiding caffeine, exercising no later than three to four hours before bedtime, and following a routine bedtime ritual. Bright light exposure in the early morning promotes early sleep time, while evening exposure promotes later sleep time and should be avoided.

Pharmacological agents are not consistently successful at correcting sleep disorders. Many disrupt the normal sleep architecture and/or have persistent effects on the following day. Alternative therapies may include short-acting, non-benzodiazepine receptor agonists (such as zaleplon or zolpidem). Melatonin has improved sleep disturbances in some RS patients, but further studies are needed before it can be recommended.

Motor dysfunction — A program of physical, occupational, and communication therapy should be provided. Physical therapy is thought to promote ambulation and balance, prevent or retard the development of contractures, and control deformities.

The goal of occupational therapy is to promote purposeful use of the hands. Hand stereotypies can often be diminished by providing elbow or hand restraints. It may only be necessary to restrain the non-dominant hand or elbow. In several small series, splinting to inhibit repetitive hand activity was associated with improvements such as increased socialization and interaction with the environment.

Therapy should be provided to enhance communication skills. The majority of girls with RS lose expressive language, although some may retain one-word expressions. They usually communicate via eye gaze, body language, and facial expressions. Parents and educators must attune themselves to their child's communicative behavior and respond consistently to these signals. A computer-based requesting system may be an effective communication tool.

Other types of therapy may be helpful, although little data are available to support their use. Music therapy may facilitate sustained focus, attention, and improve interaction. Hydrotherapy may promote movement and balance. Horseback riding may promote balance and protective responses that help maintain mobility and avert falls.

Reproductive issues — Girls with RS go through puberty, menstruate, and may become pregnant. Issues and options concerning birth control and hygiene should be discussed with parents or guardians of women with RS.