Silent angel: A case report on Rett syndrome
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.153178
Rett syndrome is a disorder characterized by arrested neurodevelopment due to mutation of the MECP2 gene. We present one such case of a 2.5-year-old female with no prior diagnostic intervention. History revealed normal physical and mental development for the first 6-8 months of life, followed by a pattern of deceleration across all growth measurements, especially microcephaly. Characteristic midline hand stereotypical movement along with loss of purposeful hand movements was also observed. Rett syndrome provides us with a diagnostic challenge. Awareness of this disorder is important because early identification and timely intervention can help both the patient and their families. Keywords: ASD, hand wringing, MECP2 gene
Andreas Rett, an Austrian physician, first described Rett syndrome (RS) following his serendipitous discovery of two girls seated in his waiting room. They displayed strikingly similar handwringing mannerisms. Unable to find a known classification for the disorder, Rett published a report in German in 1966 describing a syndrome consisting of stereotypic hand movements, dementia, autistic behavior, ataxia, cortical atrophy and hyperammonemia. [1] Thereby, it was termed as cerebroatrophic hyperammonemia, a term that was later discarded. Meanwhile, unaware of Rett's work, Bengt Hagberg in Sweden reported patients displaying similar symptoms. In 1980, he presented a paper at the European Federation of Child Neurology Societies describing 16 girls. [2] Thence, Rett syndrome was recognized, characterized by developmental arrest, loss of communication, diminished play interest, deceleration of head growth from 6 to 18 months of age, stereotypical hand movements, severe dementia with autistic features, ataxic gait, hyperventilation and seizures. [3] Until 1999, only clinical features were used to diagnose RS. However, a major discovery in 1999 by Ruthie Amir showed the mutation of the MECP2 gene to be causative for RS. [4] Hence, it was concluded that RS was not a degenerative disease, as first suspected, but actually a disorder characterized by arrested neurodevelopment caused by mutation. Indian Scenario The first report of RS from India was in 1994. [5] The incidence in India is about 1/10,000-22,000 live births. [6] Paucity of literature in India may be attributed to underdiagnosis or misdiagnosis of RS as cerebral palsy. [7]
A 2.5-year-old female child presented to us with poor growth, gradual loss of speech and hand skills, poor social interaction and stereotyped movements of the hands since the last 1 year. The patient was born following an uncomplicated pregnancy and full-term normal delivery at a rural hospital. Her birth weight, height, APGAR score and head circumference (HC) were not available. The mother reported that the child was healthy, cried immediately and fed well. She was the third in the sibship of three, belonging to the low socio-economic strata with no family history suggestive of genetic, psychiatric or medical illnesses. All milestones were normal for the first 13 months - characterized by adequate social interaction, eye contact with parents, speaking double syllables by 7 months and walking with support by 13 months. However, since the last 1 year, the patient was noticed to not grow adequately for her age, interact with others or develop any further milestones. Movements - characteristic midline hand stereotypical movement - were observed. The patient repeatedly made fists with both her hands and touched them to her face. Gait was slightly clumsy. Usage of speech had regressed to mere babbling. There was no history of respiratory disturbances or seizures or ataxia. Her height and weight were below the 50 th percentile and the HC was 45 cm. There was no facial dysmorphia. Neurological examination was within normal limits. All basic laboratory investigations including serum ammonia levels were normal. Electroencephalography, Computerized tomography brain and audiometry were unremarkable. Formal IQ testing was not possible. Genetic studies could not be carried out due to unaffordability. Growth retardation was handled with a high protein diet. Regular follow-up with physiotherapy was suggested. Treatment focused on counseling the parents about the illness; no medications were prescribed. However, management could not be carried out in an effective and comprehensive manner as the case was lost to follow-up after assessment.
Initially thought to be strictly affecting females, the disease has also been identified in males. The incidence in males is unknown, partly owing to the low survival of male fetuses with the RS-associated MECP2 mutations, and partly due to differences between signs caused by MECP2 mutations and those caused by Rett's. There have been several cases of 46XY karyotype males with a MECP2 mutation carried to term who were affected by neonatal encephalopathy and died before the age of 2 years. [8] Clinical Features The course of RS, including the age of onset and the severity of symptoms, varies from child to child. Milestones-Pre-natal and perinatal histories are generally unremarkable. The parents report normal physical and mental development for the first 6-8 months of life, as evidenced by physical growth and psychomotor and verbal behavior. A pattern of deceleration across all growth measurements, especially microcephaly, following the first 6 months of life is witnessed in most persons with RS. Growth retardation may be suggestive of nutritional factors. Movement- Stereotyped hand movements represent one of the most distinguishing characteristics of the RS. Hand wringing, hand washing, hand tapping and hand-to-mouth movements are common. This results in the loss of purposeful hand function. [2] A loss of social interaction skills is frequently observed during the pre-school years, but social interest often increases later. Seizures - Although most girls with RS demonstrate abnormal EEG tracings, seizure activity is not universal. Our case did not manifest a seizure disorder and the EEG profile showed no abnormality. This is in contrast to the literature, where EEG has been shown to be significantly abnormal, except in the earliest stages of RS. By adolescence, approximately 75% of patients are in wheelchairs or bedridden. Other common concomitant features are breathing problems (hyperventilation, breath holding and air or saliva expulsion), bruxism and scoliosis. [2] Genetics The MECP2 gene contains instructions for the synthesis of methyl cytosine binding protein 2, which is needed for neural development. In less than 10% of cases of RS, mutations in the gene cyclin-dependent kinase, like 5 (CDKL5) or FOXG1, have been found. Sporadic mutation is seen in at least 95% of RS cases and the cause is a de novo mutation that is not inherited from either parent. Inheritance may be from phenotypically normal mothers who have a germline mutation in the gene encoding MECP2. [4] Management An integrated, multidisciplinary approach comprising of symptomatic, supportive medical management, therapy and supportive services is needed. Pharmacotherapy, in the form of bromocriptine, magnesium citrate, L-carnitine (may help improve language skills, muscle mass, alertness, energy and quality of life while decreasing constipation and daytime sleepiness), naltrexone (to stabilize breathing irregularities) and levodopa (to alleviate muscle stiffness) have been tried for symptom control without reasonable success. [9] Patients with scoliosis may need surgery. Feeding problems may benefit with changing the food texture. Haas and his associates have reported improved weight gain in conjunction with diminished stereotyped behavior and better seizure control with the implementation of a high-calorie, high-fat ketogenic diet. Currently, there is no cure, but studies have shown that restoring MECP2 function may lead to a cure. One area of research is in the use of insulin-like growth factor 1 (IGF-1), which has been shown to partially reverse signs in MeCP2 mutant mice. [10]
Researchers have learnt much about this disorder over the past two decades; however, plenty remains yet to be discovered. All female children with low intelligence and autistic symptoms following a normal period of development should be suspected of having RS until proven otherwise.
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