Elsevier

Brain and Development

Volume 23, Supplement 1, December 2001, Pages S38-S43
Brain and Development

Review article
Importance of Rett syndrome in child neurology

https://doi.org/10.1016/S0387-7604(01)00335-7Get rights and content

Abstract

The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723–726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471–479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 11/2 years, the rapid destructive stage at 1–3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15–30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.

Introduction

Andreas Rett, an Austrian pediatrician in Vienna [1], first described a peculiar syndrome of brain atrophy in childhood in 1966, but the condition was not brought to the attention of the English-speaking world until 1983, when Hagberg and his co-authors [2] published a report on 35 cases in the Annals of Neurology as a progressive syndrome of autism, dementia, ataxia and loss of purposeful hand use in girls: Rett's syndrome. Further studies confirmed that the disease was practically confined to girls, and in 1986 Hagberg and Witt-Engerström [3] suggested a staging system for describing the impairment profile with increasing age. This remains useful for the description of the classical form of the disease.

The first is the early onset stagnation stage at 6 months to 11/2 years which includes developmental arrest, decelerating head growth, reduced communication and eye contact, and diminishing interest in play.

The second is the rapid destructive stage, which encompasses developmental deterioration, autistic features and stereotypes, severe dementia with loss of speech, loss of hand skills with frequent hand wringing, better preservation of gross than fine motor skills, apraxia and ataxia and also irregular breathing while awake, with hyperventilation. Seizures may begin in this stage.

The third or pseudo-stationary stage lasts from pre-school to school years and contains some stabilization, so that autism is no longer a big problem. However, profound mental retardation persists, with marked motor dysfunction and jerky truncal ataxia.

In the fourth and late motor deterioration stage the girls have decreased mobility at the age of 15 to more than 25 years and are often wheelchair-bound. There is persistent growth retardation, and there is frequently a paraparesis with tense heelcords. Scoliosis is also very common, and the feet may be trophic and cyanotic. Emotional contact tends to be improved, and epilepsy becomes less common and more easily controlled.

In the past it had been considered that Rett girls are usually normal at birth. However, recent Australian studies [4] have shown that their mean birth weight and head circumference are slightly below the average for normal control infants of the same gestational age. Like others we [5] have also noted an increased frequency of minor neonatal problems like difficulty in sucking and hypotonia. Nonetheless, these infants are usually considered normal on discharge and during the first 6 months, but in the Australian group [4] nearly half the parents reported that their daughter's development or behaviour had been unusual in the first 6 months. In this connection it may be noted that some pathological features like hypopigmentation of the zona compacta of the substantia nigra and absence of retrograde cell loss in the inferior olivary nuclei suggest an onset of the syndrome during prenatal development [6], [7], [8].

Atypical Rett variants at the age of 10 or more years were defined by Hagberg and Skjeldal [9] in 1994. It was postulated that these atypical girls should have mental retardation of unexplained origin and at least three of six primary criteria like loss of acquired fine finger skills in early childhood, stereotypes like wringing of hands, and deceleration of head growth. In addition, these girls were expected to have at least five out of eleven Rett syndrome (RS) supportive criteria, like breathing irregularities, grinding of teeth and intensive eye communication.

Prevalence studies from Sweden and Scotland [10], [11], [12] showed that RS occurred about once in 10,000–15,000 girls, i.e. more commonly than phenylketonuria, and thus represents one of the more frequent causes of more than mild mental retardation in girls.

Section snippets

Genetics

Most of the cases of RS are isolated in their families, apart from identical twins being affected. However, in Sweden it was noted [13] that affected children tended to cluster in certain areas and frequently had some common ancestry. Often milder ‘forme fruste’ cases came from the same ‘Rett areas’ as classical RS girls. Akesson et al. [14] suspected that transmission might start with a premutation which over generations could result in a full mutation with greater clinical severity. Similar

Neuropathological studies

Neuropathological studies have shown no consistent site of gross neuronal degeneration and no evidence of abnormal neuronal migration. However, slowing of head growth usually becomes definite from the age of about 3 months. Jellinger et al. [32] found that in nine Rett girls aged 3–17 years brain weight was decreased to 66–88% of expected values for the age. Bauman et al. [33] observed a global decrease in the size of individual neurons in RS, associated with increased packing density. In 1994

Electrophysiology

The electroencephalogram (EEG) in RS is usually clearly abnormal except in the initial stage. Glaze et al. [37] correlated the EEG with clinical staging. In Stage II the EEG frequently shows slowing of background rhythms, rare focal spike or sharp wave discharges while awake, and progressive loss of sleep characteristics like spindles and vertex transients (Fig. 2) [38]. Focal spike and sharp wave discharges occurred typically in the central-parietal regions. In Stage III, further slowing is

Autonomic function

Japanese workers have long suspected a deficiency of noradrenaline as one of the abnormalities in infants with Rett syndrome. Nomura and her colleagues [45] also noted abnormal twitching movements during REM sleep bursts, atonia during NREM sleep, and akinesia on attempted walking which could be attributed to hypofunction of noradrenaline, e.g. in the brainstem (?locus ceruleus). Recently Nomura et al. [46] also studied sympathetic skin responses in Rett girls on electrical stimulation and

Differential diagnosis

As pointed out by Budden [49] and Naidu [50] the remarkable feature setting the Rett syndrome apart from most other neurodegenerative diseases is that it shows rapid clinical deterioration during active brain growth, after which there is relative stability for decades. Presumably the crowding of neurons and inadequate formation of synapses, axons and dendrites in Rett girls are due to lack of a suitable biochemical environment, particularly in the relevant layers of the cerebral cortex, in the

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