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Neurology India, Vol. 50, No. 3, Sept, 2002, pp. 330-333 Rett's Syndrome - A Neurodevelopmental Disorder : Report of Two Cases S. Malhotra, D. Kumar, N. Gupta Department of Psychiatry,
Postgraduate Institute of Medical Education and Research,
Chandigarh - 160 012, India. Accepted for publication : 5th January, 2001. Code Number: ni02094 Summary Rett's syndrome (RS), a pervasive neurodevelopmental disorder, is being increasingly recognized all over the world, but there is paucity of reports from India. Due to its manifestations at any stage of development, it is important to arrive at a correct diagnosis. Two cases are presented, highlighting the need to recognize this relatively uncommon disorder and to differentiate it from various other neurodegenerative disorders. Key words : Rett's syndrome, Pervasive developmental disorder, Neurodevelopmental disorder. Introduction Rett's syndrome (RS), a progressive developmental disorder, was first described in 22 girls presenting with stereotyped hand movements, autistic behavior, dementia, ataxia, cortical atrophy, and hyperammonemia.1 This condition has been exclusively described in females with a characteristic pattern of cognitive and functional stagnation and subsequent deterioration. RS has an onset after 5 months of apparently normal psychomotor development but it can have its onset even in late adolescence.2,3 The clinical presentation can, therefore, differ considerably depending on the age of observation/presentation.3 To facilitate characterization of the patterns of this disorder, a four-stage system was proposed by Hagberg and Witt- Engerstrom4 and adopted by the Rett syndrome diagnostic criteria work group.5 However, due to different stage and age of presentation, RS gets frequently misdiagnosed most commonly as neurological illnesses. Lack of awareness of this disorder amongst physicians3 along with the initial, but misleading, emphasis on hyperammonemia6 has also contributed to its low rate of diagnosis all over the world. We present two such cases identified from a patient population attending the child and adolescent psychiatry clinic at the Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh from 1989-1999. Case Report Case 1: GK, a 4 ½ year old female child presented with loss of acquired speech and motor hand skills and presence of abnormal behavior. Developmental history revealed presence of delayed cry and birth asphyxia. However, she had normal developmental milestones till the age of one year, when she showed a regression in her milestones and abnormal behavior (would beat her chest with her fist or clap her hands repeatedly). She showed lack of attachment with family members, would walk aimlessly, remain self absorbed, preferred solitary play, and would speak only a few words. Her sleep was disturbed and mood irritable. By the age of 2 years, there was gradual and complete loss of expressive language. At the aged of 3 years, motor clumsiness was noticed e.g. not being able to grasp or hold onto objects, required support while walking. She would no longer indicate toilet needs, would smile or cry without apparent reason, developed bruxism and flapping movements of hands. Her social aloofness worsened with absence of meaningful expressive and receptive communication. There was no evidence of seizure disorder, scoliosis, breathing difficulties like hyperventilation or breath holding spells. At the time of examination, head circumference was 46.5 cm, upper limbs showed spasticity and absence of grasp reflex. Neurological examination of lower limbs was normal. Investigations i.e. CT Head, EEG, audiometry were unremarkable. I.Q. assessment revealed presence of severe degree of mental retardation (IQ=20). Treatment focused on counseling the parents about the illness; no medications were prescribed. Case 2 : P, a 3½ year old girl child was brought by her parents with complaints of gradual and progressive loss of speech and previously acquired skills. She was born of a full term normal delivery; had attained normal milestone till 18 months of age with ageappropriate social and communication skills. She was noticed to have become quiet, lethargic with diminished social and emotional reciprocity to her mother and other people following an exanthematous illness at the age of 1½ years. She would indulge in repetitive, stereotyped and solitary play and activities e.g. banging toys on floor repeatedly, moving about in a circle etc. She lost bowel and bladder control, spat repeatedly, indulged in aggressive and self-injurious behavior, laughed without reason and gradually became mute. The above features worsened, with presence of aimless overactivity, tendency to fall, irritability, and disturbed sleep in the next one year. Low dose haloperidol did not improve her symptomatology. There was no history of seizures, hearing or visual problems, and respiratory difficulties. On examination, her head circumference was 46.5 cm with no other abnormality. Investigation viz. audiometry, EEG, CT scan were normal. I.Q. revealed presence of moderate degree of mental retardation (IQ=42). Patient was continued on low dose antipsychotics (0.25 mg/day of haloperidol). Discussion Due to absence of a specific laboratory marker, diagnosis of RS rests on a careful exploration of clinical manifestations and specific pattern of symptom progression.3 Both the cases described above were diagnosed using ICD-10 diagnostic criteria.2 The clinic prevalence rate for RS was 0.7 per 1000 children, which is in contrast to a prevalence rate of 3.5 per 1000 children reported by Kerr and Stephenson.7 The high prevalence rate of RS reported by Kerr and Stephenson could possibly be due to RS being studied in a pediatric neurology set-up. There was an apparently normal development for the initial period (12 months and 18 months respectively) in both girls followed by progressive and rapid loss of speech and hand function with appearance of stereotypies. In case 1, history of birth asphyxia and delayed cry at birth can only be taken as an associated finding as complications in prenatal and perinatal period of development are not considered as exclusion criteria for RS, nor is it a diagnostic criteria.2,3 Both children did not manifest a seizure disorder and EEG profile showed no abnormality. This is in contrast to literature where EEG has been shown to be significantly abnormal, except in the earliest stages of RS.3 Researchers have reported abnormal sleep patterns, most prominent around middle third of the head, and short spikes or waves as a common feature.3 These EEG changes generally appear at the beginning of Stage 2 and then follow a stepwise progression, with slowing, loss of normal sleep characteristics, multifocal abnormalities, and finally, generalized slow spike and wave activity.8 Cases of PDD including RS are expected to have normal hearing. Therefore, a normal audiometry in these cases was helpful in ruling out presence of hearing loss as the underlying cause of the loss in language skills.3 Neuroimaging was normal in both cases. Some recent studies using quantitative MRI have shown caudate nucleus reduction, explaining the significant motor and cognitivedevelopmental symptoms of RS.9 Post-mortem studies have reported various findings viz. abnormal dendritic connections in frontal cortex-caudate region (leading to microcephaly), reduced melatonin in substantia nigra (leading to movement disorder), reduced nerve growth factor (leading to stagnation of brain growth), dendritic regression and reduced gangliosides in frontal cortex etc.3 Biogenic amine abnormalities, though contradictory, have been reported, without specific clinical correlates. However, a detailed neurochemical or quantitative neuroanatomical study could not be undertaken in these cases. Also, no genetic analysis was carried out. Genetic analysis is a promising area for validation of RS. Recent research has reported on the presence of random X-chromosome inactivation, autosomal modifying gene, translocations on X-chromosome, and presence of either OCT or Fragile X locus, or dislocation of X chromosome xq28 locus in RS. However, further research is necessary to validate any of the above hypothesis.3 Severe degree of mental retardation (MR) was evident in both cases.We cannot comment about declaration of head growth with confidence, as the head circumference measurement at birth was not available. However, the head circumference measurement was definitely less for age in both cases. The natural history of RS is characterized by rapid development of a full blown syndromal presentation by 3-4 years of age, followed by developmental regression. On approaching adolescence, motor difficulties, apnoea, seizures etc. develop. In later stages, motor deterioration and reduced mobility predominate; possibly contributing to the lowered age expectancy.4 Both cases, in terms of age of onset, fall under Stage 2;5 also termed as 'rapid destructive stage'.4 The developmental regressions in this stage often suggest neurodegenerative diseases. It is important for a physician to differentiate between neurodevelopmental and neurodegenerative disorders as the modalities of management, course and outcome of either type differ significantly. RS was initially thought to be a neurodegenerative disorder but considerable research in this area has established, beyond doubt, that it is a disorder characterized by arrested neurodevelopment of unknown cause.3 Management could not be carried out in an effective and comprehensive manner, as both cases were lost to follow-up after assessment. Case 2 was started on low dose typical antipsychotics, which were partially helpful. Necessity of a multimodality, multidisciplinary approach in the management of RS has been emphasized. Pharmacotherapy, in the form of bromocriptine, magnesium citrate, L-carnitine, naltrexone etc., has been tried for symptom control without reasonable success.10 Growth retardation and constipation are managed with high-energy, high fibre diet and laxatives. Impaired communication is handled through programmed, augmentative techniques and the use of musical instruments.11 Physical and occupational therapy is a key aspect of management of RS in terms of reducing deformities, improving mobility, and maintaining environmental contact.12 Some important differential diagnosis to be considered, apart from childhood (infantile) autism, include Landau-Kleffner syndrome, tuberous sclerosis, encephalitis, infantile neuronal ceroid lipofucinosis (INCL) etc. Although infantile autism (IA) is the most common differential diagnosis for RS, yet the behavioral patterns, progression, and prognosis vary significantly. A basic distinction between RS and IA is the presence of a normal development for initial few months followed by regression in the former, while the onset is from early infancy in the latter (i.e. developmental delay rather than regression). Another important aspect is based on motor behavioral analysis wherein there is delayed development of only verbal skills in IA, while regression of motor and verbal skills is seen in RS. Children with RS also differ from IA with respect to the respiratory pattern they display (breath holding, hyperventilation, and air or saliva expulsion); presence of ataxia, apraxia, bruxism, hypoactivity and a general slowness of movements; absence of purposeful hand movements; and less complex stereotypic behavior occurring in a patterned fashion.5,13 It has also been mentioned that IA is uncommon in females, meaning thereby that the mere presence of severe autistic symptomatology in a girl under 2 years of age should prompt the consideration of RS in the differential diagnosis.3 Absence of seizures ruled out the first two diagnostic possibilities; additional evidence against the latter being absence of adenoma sebaceum and a normal neuroimaging study.13 A normal neurological examination and EEG ruled out encephalitis. INCL is similar to RS in initial stages; both being characterized by rapid psychomotor developmental regression and hand stereotypies. However, absence of seizures and visual disturbances (as the illness progresses) refute the diagnosis of INCL, as was seen in our cases. Progressive brain disorders and metabolic diseases constitute a significant minority of etiologies in persons with severe or profound MR.3 Hagberg14 mentioned that RS could be responsible for one-fourth to one-third of progressive developmental disabilities among females. Hence, it is important for neurologists, pediatricians and psychiatrists alike to be aware about RS, to recognize it and be able to differentiate this neurodevelopmental disorder from other potentially fatal neurodegenerative and infective disorders. References
Copyright 2002 - Neurology India. Also available online at http://www.neurologyindia.com |
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