Rett Syndrome: Long-Term Clinical Follow-Up Experiences Over Four Decades

Discussion

This presentation focuses on the long-term course of Rett syndrome, exemplified by three middle-aged women with Rett syndrome. Decelerating head-growth curves, particularly through the very first years of life, have been shown to give the best clinical indication of the future development of gross and fine motor dysfunction associated with a diagnosis of Rett syndrome.^[10] The deceleration of head growth appearing at an early stage, together with its magnitude, could be shown to be associated with increased motor disability and with the appearance of intractable epilepsy.^[10,11] There was a continuum ranging from almost normal head growth with well-preserved gross motor functions and relatively good fine motor abilities to a markedly decelerated head growth curve followed by maximum gross and fine motor disabilities. The difference in outcome between our first case (S-1) and the other two presented here is illustrative.

In most cases, the very first remarkable abnormalities to be noted by parents are the often sudden, early syndrome-essential loss of acquired ability to grasp in addition to the changes in contact and personality. The loss of acquired manipulative hand skill, particularly when combined with the appearance of the stereotypic but nonspecific hand-wringing and circulating hand-mouth movements, constitutes the single most informative and early signal of Rett syndrome, as shown by systematic follow-up studies.^[12,13] The age at onset and the degree of inability to use the acquired skill of pincer grasping-or to use grasping functions of any kind-definitely appear to correlate with severely impaired long-term development. The well-known hand stereotypies so obvious from early childhood, however, have little prognostic value in relation to the severity of the long-term course. Sometimes they change in adult middle age toward frozen and stiff malpositions (Figure 4).

(Enlarge Image)

The rigid, stiff, and distorted hand position of an elderly woman with Rett syndrome.

Even if the loss of active grasping, learned single words, and general emotional contact are usually the first areas of focus for worried parents, the more slow and successive disappearance of acquired gross motor skills tends to take place in parallel but is less dramatic. For parents, the most worrying thing is that their "child has changed." Nevertheless, gross motor functions are lost at an early stage and dysequilibrium signs appear in parallel. In addition, generalized neuromuscular weakness with side-asymmetric patterns is already present in the early years and is subsequently covered by dystonic-rigid stiffness. Through childhood into young adulthood, some gross motor functions appear to slightly improve, with a temporary recovery and compensation, in contrast to the loss of fine motor abilities. In the long term, middle-aged women with Rett syndrome lose a great deal of muscle volume, strength, and power and present with general premature neuromuscular aging.^[14,15] Some also exhibit marked atrophy owing to the degeneration and loss of spinal ganglion cells and gliosis of white and gray matter.^[16] Overall, this results in a massive muscle loss combined with general rigidity that increases toward frozen stiffness.

The early general growth deceleration not only affects body and skull growth (ie, brain growth), it also involves the overly thin, small, cold, sweaty feet; the wringing "baby hands"; and the insufficient, compressed, and curved spine. The latter is usually manifested as a double-curved thoracolumbar deformity, in which the convexity of the greater upper curve is right sided in families with dominant right-handedness.^[17] Single women with Rett syndrome can live well into their late seventies.^[17]

Epilepsy occurs in more than 90% of girls who have Rett syndrome.^[11] For many parents, the frequent, irregular occurrence of repeated fits over a number of days is the dominant and most worrying problem. Characteristically, the onset of clinical seizures first occurs around 3 to 5 years of age, reaches its peak frequency in adolescence into young adulthood, successively tapers in early middle age, and finally presents only rare and minor problems after the age of 40 years. The EEG is, however, invariably abnormal after about 2 years of age.^[18] Rett syndrome childhood epilepsy is mainly characterized by partial seizures occurring in showers over a series of days and then stopping for a week or longer.

The therapeutic response to traditionally used antiepileptic drugs is, not surprisingly, unsatisfactory. The antiepileptic treatment regimen has to be individualized, and an open-minded approach must therefore be applied. After 40 years of age, an attempt should be made to withdraw antiepileptic drugs completely; otherwise, there is a risk of unnecessary negative side effects in the all-too-premature aging process associated with Rett syndrome. With regard to epileptic seizures, the paroxysmal vacant spells described by Kerr and Witt Engerström should be mentioned.^[19] These spells, which are nonepileptic in their pathophysiologic background, need to be more extensively studied to find a satisfactory therapeutic approach.

In contrast to the severe motor disability associated with Rett syndrome, parents frequently emphasize their child's well-preserved long-term memory and preference for adhering to previous childish routines. The easily missed yet preserved abilities of eye contact, awareness, and memory, certainly on a fairly limited and "hidden" developmental level, are too often overlooked. Many otherwise prematurely aged and severely disabled adult women with Rett syndrome apparently have a persistent memory (eg, the need to have small favorite toys from their early childhood hanging over their beds). They also frequently want to have the same childish music played repeatedly for extended periods while rejecting alternative choices. In addition, some parents say that their daughters directly react to sudden changes in "geographic routines" (eg, daily car transportation routes to day centers.) This difference over time between memory and gross motor capabilities was made particularly obvious to us in a female patient with an odd mild variant of Rett syndrome and a mutation in MECP2.^[15] At age 8 years, she was able hyperactively and skillfully to ride on a tricycle, whereas at age 25 years, she was dysplastic, kyphotic, neuromuscularly prematurely aged, and disabled in motor terms. In contrast, she had retained an impressive memory, even for complicated details. These reported examples are only a few of many similar experiences, indicating limited yet nevertheless surprisingly well-preserved detailed long-term memory functions.

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We are grateful to the parents and caregivers of the patients with Rett syndrome for their time and cooperation.

J Child Neurol. 2005;20(9):722-726. © 2005 BC Decker, Inc.

Cite this: Rett Syndrome: Long-Term Clinical Follow-Up Experiences Over Four Decades - Medscape - Sep 01, 2005.