Laboratory Studies
Females who meet the clinical diagnostic criteria for Rett syndrome (RS) should undergo genetic testing. Several laboratories provide diagnostic sequencing of the MECP2 gene; details on how to order this testing are available from the International Rett Syndrome Foundation (IRSF). Patients with positive MECP2 mutational gene analysis need no further diagnostic testing.
Mutations in the MECP2 gene have been identified in a wide spectrum of clinical phenotypes, including girls with classic RS, girls with atypical or variant forms of RS, girls with autism spectrum disorder, healthy females (carriers), males with severe infantile encephalopathies, males with classic RS, and males with X-linked neurologic problems (eg, motor deficits or communication deficits). [35, 36]
Patients in whom no MECP2 mutation is found should undergo other diagnostic tests aimed at identifying other possible causes of their signs and symptoms. Such tests may include the following:
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Serum lactate, ammonia, pyruvate, and amino acids
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Urinary organic acids
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Chromosomal studies, including specific tests for Angelman syndrome (chromosome 15)
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Urinary tests for uroporphobilinogen to rule out intermittent porphyria (rarely helpful)
Barium Swallow or Overnight pH Probe Study
A barium swallow study or an overnight pH probe study may be performed to document gastroesophageal reflux (GER), which is present in approximately 15% of patients with RS. GER may cause weight loss, discomfort with meals, vomiting after eating, obstructive apnea, or recurrent respiratory congestion and problems. Swallowing studies frequently document poor oral motor skills and risk of aspiration.
Neuroimaging
Neuroimaging may be useful. Magnetic resonance imaging (MRI) may help include or exclude other causes of a patient’s signs and symptoms. Although RS is associated with a significant decrease in cerebral cortex size, cerebellar atrophy, and a brain weight that is approximately 70-90% of normal, these findings are not specific for the diagnosis of RS. Changes may also be observed in the corticospinal tracts, with reduced myelin and some gliosis.
Electrocardiography
Findings on electrocardiography (ECG) may include an inverted T wave and a prolonged QT interval. [37] Studies have demonstrated that the incidence of sudden death in persons with RS is greater than that in the general population. Patients with RS may also have significantly lower heart rate variability. These cardiac abnormalities may increase through the successive stages of the syndrome.
Electroencephalography
Abnormal results on electroencephalography (EEG) are common. [38] Seizures are reported in 60-90% of patients with RS. Differentiation from Landau-Kleffner syndrome (acquired epileptic aphasia) should be made clinically and secondary to response to therapy. Patients also frequently have epileptiform abnormalities that appear to be age-related and to occur most frequently during clinical stage III, as well as with abnormalities that can be noted earlier during nonrapid eye movement (NREM) sleep.
Video-EEG polygraphic monitoring may be required to determine whether antiepileptic therapy is indicated. Many reported seizure episodes are nonepileptic behavioral events, whereas actual seizures may be underrecognized because they occur during sleep.
Neurophysiologic Testing
Auditory brainstem-evoked response testing generally demonstrates normal hearing with a delayed conduction time. Somatosensory-evoked responses demonstrate spinal cord and brainstem conduction abnormalities. Electromyographic (EMG) studies are typically normal and need not be completed, except for the purpose of excluding other conditions.
Electroretinography
Electroretinography (ERG), in conjunction with EEG and the continued decline observed children with infantile neuronal ceroid lipofuscinosis, can help differentiate RS from infantile neuronal ceroid lipofuscinosis. Both disorders cause rapid regression of psychomotor development and the development of hand and finger stereotypes in children aged 1-2 years.
Polygraphic Respiratory Recordings
Polygraphic respiratory recordings may demonstrate a pattern of disorganized breathing characterized by periods of apnea or hyperventilation and significant oxygen desaturation and clinical cyanosis.
Normal breathing occurs during sleep in persons with RS. Total sleep time may be decreased. Patients may demonstrate prolonged periods (≥18 h) of wakefulness or sleep. Nighttime awakenings with frequent laughing are reported. Screaming episodes may also occur at night; however, the possibility of other medical problems (eg, GER) must also be considered.
Psychometric Testing
Generally, the results of psychometric testing in patients with RS are indicative of profound intellectual disability. However, standard instruments that depend on the use of hands and oral language may be inadequate for full assessment of these individuals. Specialized tests, such as the Gilliam Autism Rating Scale or the Children’s Autism Rating Scale, can be helpful for detailing autisticlike symptomatology.
Histologic Findings
Morphologic features in individuals with RS include reduced brain weight (including reduced volume of the frontal cortex and caudate), reduced neuronal size, and dendritic arborizations in certain areas (frontal correlates, motor correlates, and limbic correlates), with preservation in the visual cortex and decreased organ weights proportional to height and weight.
Neurochemical findings include the following:
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Reduced levels of catecholamines in the substantia nigra
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Reduced dopamine D2 receptors and dopamine reuptake in the caudate nucleus
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Reduced choline acetyltransferase in the hippocampus, caudate, and thalamus
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Reduced acetylcholine vesicles or transporters in the putamen and thalamus
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Reduced benzodiazepine receptor binding in the frontal and temporal cortex
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Reduced beta-endorphins in the thalamus and cerebellum but increased beta-endorphins in the cerebrospinal fluid (CSF)
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Increased glutamate in the CSF
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Reduced melanin in the substantia nigra
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Decreased substance P levels in the CSF
