Background
Methods
Clinical assessment
Cardio-respiratory assessment
Genetic analysis and mutations classification
Description of the sample and of the different clinical RTT forms
Clinical forms | N. | % | Age at the evaluation Mean (SD) | Age at the diagnosis Mean (SD) |
---|---|---|---|---|
Classical | 98 | 64,9 | 12,5 (10,2) | 6,7 (8,5) |
Z-RTT | 19 | 12,6 | 12,5 (7,9) | 7,3 (5,6) |
Hanefeld | 13 | 8,6 | 6,1 (4,8) | 2,6 (1,7) |
Congenital | 1 | 0,7 | 2 | 1 |
ARTT-NOS | 20 | 13,2 | 13,5 (9,5) | 8,45 (4,8) |
Total | 151 | 100 | – | – |
Statistical analysis
Results
Evaluation with the International Scoring System (ISS)
ISS total | % Classical (n = 98) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) |
---|---|---|---|---|---|
Mean (SD) | 19.5 (5.9) | 11.7 (3.7) | 19.4 (4.8) | 26 | 21.4 (6) |
ISS (subscales and items) and clinical forms
ISS subscales with statistical significance and clinical forms
% Classical (n = 97) | % Z-RTT (n = 19) | % Hanefeld (n = 12) | % ARTT-NOS (n = 20) | |
---|---|---|---|---|
Height | ||||
<3rd centile | 39 | 5 | 17 | 60 |
3rd–40th centile | 48 | 47 | 58 | 15 |
>40th centile | 13 | 48 | 25 | 25 |
Weight | ||||
<3rd centile | 40 | 10 | 17 | 60 |
3rd–40th centile | 35 | 21 | 58 | 20 |
>40th centile | 25 | 69 | 25 | 20 |
OFC | ||||
<3rd centile | 46 | 5 | 8 | 55 |
3rd–40th centile | 39 | 27 | 50 | 30 |
>40th centile | 15 | 68 | 42 | 15 |
BMI | ||||
<3rd centile | 43 | 1 | 27 | 53 |
3rd–40th centile | 23 | 16 | 45 | 16 |
>40th centile | 34 | 79 | 27 | 31 |
Scoliosis | % Classical (n = 98) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) |
---|---|---|---|---|---|
No deviation | 36.7 | 63.1 | 75 | 100 | 35 |
Mild | 36.7 | 31.6 | 23.1 | – | 45 |
Severe | 26.5 | 5.26 | – | – | 20 |
Walking | % Classical (n = 97) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) |
Walks | 21.6 | 36.8 | 15.4 | – | 10 |
Walking impaired | 50.5 | 57.9 | 38.5 | – | 55 |
Not walking | 27.8 | 5.3 | 46.1 | 100 | 35 |
Use of hands | % Classical (n = 97) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) |
Normal | 2 | 15.8 | – | – | – |
Reduced | 54.6 | 78.9 | 61.5 | – | 65 |
No | 43.4 | 5.3 | 38.5 | 100 | 35 |
Stereotypies | % Classical (n = 95) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) |
Absent | 4.2 | 21.05 | 15.4 | – | 15 |
Mild | 46.3 | 42.1 | 61.5 | 100 | 50 |
Dominant or constant | 49.5 | 36.8 | 23.1 | – | 35 |
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Walking abilitySince the walking can start either before or after regression stage, and it can be lost in stage IV of the disease, we reported the status at the stage of evaluation.Among the 151 subjects, 32 (21.2 %) were able to walk without support, 76 (50.3 %) with support and 43 (28.5 %) were not able to walk. We found that females with Z-RTT variant were more able to walk without support if compared to females with classical and Hanefeld forms. Statistical analysis revealed that only 5 % of Z-RTT girls could not walk, while 45 % of Hanefeld cases could not walk (χ 2 test = 7.75; p = 0.021).In the subgroup of the RTT not walking, the scoliosis was severe in the 50 % of the sample.
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Use of handsThe evaluation of use of hands ability revealed that only the 3.3 % of the individuals were able to adequately manipulate an object; 59.3 % could grab and hold the object just for few seconds; 37.3 % of the cases did not have any purposeful use of the hands.The dyspraxia was more severe in the group of the classical RTT (43.4 %), ART-NOS (35 %) and Hanefeld variant (38.5 %) compared to Z-RTT (5.3 %), (χ 2 test, p = 0.01), in Table 5. Even considering the average across all the different groups (42 %) Z-RTT females showed lower impairment (5.3 %). Dispraxia was significantly different in females with Z-RTT (5.3 %) versus classic RTT (43 %) (χ2 test = 14.75, p = 0.001).
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StereotypiesThe presence of stereotypies is particularly important in the diagnosis of RTT syndrome. Initially stereotypies are limited to bringing the hand to the mouth, and later appear typical bimanual stereotypies different from those observed in autism.Hand stereotypies were present in 135/148 RTT subjects and had a higher occurrence in the RTT classical forms than in all the variant forms: in particular stereotypies were absent in only 4 % of Classic RTT individuals, while 21 % of Z-RTT females failed to show stereotypies (χ 2 test = 6.87, p = 0.032).
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Other movement disorders (tremors, dystonia and similar)The 50.3 % of the RTT cases showed some movement disorders, often tremor. In the 23.2 % this tremor was mild, in the 0.7 % instead it was sub-continuous and disabling. No significant statistically differences were observed among the groups.
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SpeechSince the first description of Andreas Rett one of the key symptoms was the absence or loss of speech. At the onset of the disease some children had already developed a vocabulary of a few words or even sentences with two words. To this stage usually follows a stop phase and then regression, however 12.6 % of females in our sample recovered and amplified the vocabulary, using more than 10 words at age of 5; they constitute the Zappella variant. In this form we recognized the presence of moderate speech consisting of a few words, and eventually the construction of complex sentences, sometimes echolalic, sometimes purposeful, with an extensive vocabulary. In some the language skills extended to the understanding of writing.
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Intellectual impairmentThe disorder involves a significant cognitive impairment, very difficult to quantify in standard tests: the lack of speech and the eminent dyspraxia implies that many assessments should be done with eye tracking technology or other techniques of augmentative and alternative communication (AAC). These methods are incompatible with short assessments, carried out in our sample. ISS discriminates between profound cognitive impairment (IQ <20) and cognitive impairment present but not profound (Q.I. between 20 and 70), because by definition there are no cases with normal cognitive levels.The distinction that we have arbitrarily used is the acquisition of object consistency and attention to language and images. According to this criteria we distinguished a profound cognitive delay for individuals with IQ <20, and a mild cognitive delay in individuals with IQ between 20 and 70.Z-RTT females showed minor globally impairment that others groups (F test = 21.12; p < 0.001).
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EpilepsyWe analysed epilepsy distribution and onset across the clinical forms.In the whole sample, epilepsy was present in 64.2 % of cases. Epilepsy was present in the 58.2 % of classical RTT cases and in all the cases with the Hanefeld variant (100 %). Drug resistant (completely or partial) epilepsy was present in 17.2 % of cases.Furthermore, we observed that the drug resistant epilepsies had progressively higher percentages in the following order subgroups: Z-RTT variant 5.3 %; ARTT-NOS 15 % Classical RTT 17.4 % and Hanefeld variant 38.5 %. Severe epilepsy was present with major frequency in Hanefeld variant if compared to the other clinical forms (15.3 %) with χ 2 test = 15.7; p < 0.05 (Table 6).Table 6Epilepsy and clinical formsEpilepsy% Classical (n = 98)% Z-RTT (n = 19)% Hanefeld (n = 13)% Congenital (n = 1)% ARTT-NOS (n = 20)Absent41.836.8–10025Controlled by therapy40.857.961.5–60Barely or not controlled by therapy17.45.338.5–15The median age of onset of epilepsy in the entire sample was 50 months with a range between 1 and 216 months. An earlier onset epilepsy was present peculiarly in the Hanefeld variant compared to the other forms (F test = 9.38, p < 0.001) (Table 7).Table 7Epilepsy distribution and onset (in months) and clinical formsEpilepsy onsetClassical(n = 51)Z-RTT(n = 11)Hanefeld(n = 13)Congenital(n = 0)ARTT-NOS(n = 13)Mean (SD)62.6 (43)49.4 (11.7)2.2 (1.6)–49 (39.9)Range1–21636–721–7–2–108
% Classical (n = 96) | % Z-RTT (n = 19) | % Hanefeld (n = 13) | % Congenital (n = 1) | % ARTT-NOS (n = 20) | |
---|---|---|---|---|---|
Dysphagia | |||||
None | 35.4 | 58 | 38.5 | – | 40 |
Mild | 47.9 | 42 | 31 | 100 | 50 |
Severe | 16.7 | – | 30.5 | – | 10 |
Constipation | |||||
None | 23.9 | 47.4 | 23.1 | – | 20 |
Mild | 59.4 | 36.8 | 53.8 | 100 | 55 |
Severe | 16.7 | 15.8 | 23.1 | – | 25 |
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Gastro-enteric disordersRTT syndrome is often associated with nutritional intake and growth problems. In general, feeding difficulties are complex and involve oromotor, behavioral, nutritional and medical components. Oromotor problems may include: oropharyngeal dysfunction, sensory defects, reduced mobility of the tongue. One or all phases of the deglutition function can be compromised.Furthermore, breath disorders could disturb the swallowing ability; drug used to control epilepsy can induce lack of appetite, sedation and increase of drooling. Severe not treated constipation can influence in a bad way the appetite too. In our cohort use of PEG was rare (2 %).The 38.9 % of the individuals did not present dysphagia, 46.3 % presented dysphagia for solid foods but not for liquid ones, while only the 14.7 % presented dysphagia for both. Among Z-RTT females, nobody presented severe dysfagia and in 58 % disfagia was absent. Sixty-two percent individuals with Hanefeld variant presented functional dysfunction with half individuals with severe dysfunctions and half with mild dysfunctions. There was a significant difference between groups (χ2 test = 6.69; <0.035).In our sample more than a half of the cases (55.7 %) presented a mild irregular intestinal rhythm and 18.1 % of individuals presented severe constipation; many of these individuals needed drug based approach. The Z-RTT females presented constipation more rarely than the other groups.
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SleepThere is high prevalence of sleep problems in Rett syndrome (80–94 % across different age groups). Sleep problems were identified most frequently in the younger age group. Daytime napping, night-time laughter, teeth grinding, night screaming and seizures were the problems most frequently reported. Some specific sleep problems did appear to vary with age with night laughing decreasing with age and daytime napping increasing with age. Sleep dysfunction had consequence on the whole family, hence in our cohort we considered only the most severe cases with sleep difficulties and early awakenings.Sixty-one point seven percent of the individuals did not present sleep disorders, the 24.8 % presented occasional difficulties and only the 13.4 % of the cases needed drugs to treat them. There was a significant statistical difference (χ 2 test = 17.7; p < 0.02, Table 9) in Z-RTT females the sleep abnormalities were less severe.Table 9Sleep and clinical formsSleep% Classical(n = 96)% Z-RTT(n = 19)% Hanefeld(n = 13)% Congenital(n = 1)% ARTT-NOS(n = 20)None66.778.938.5–40Mild17.721.146.110045Severe15.6–15.4–15The 69 % with Classical forms and Z-RTT did not show any alteration in the sleep-awake rythm compared to other subgroups (38 %).We report cardio-respiratory abnormalities later, since they are often misinterpreted by caregivers.
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ISS areas and clinical formsThe results of the ISS components in the different forms are reported below. The table was realized with the individuals with reported scores for ISS (Table 10).Table 10ISS areas and clinical formsISS areasClassicalZ-RTTHanefeldCongenitalARTT-NOSDevelopment(n = 144)Mean (SD)4.2 (2.6)1.4 (1.4)4.4 (2.6)9 (−)5.5 (2.8)Range0–80–52–8–0–9M_SKEL(n = 146)Mean (SD)2.6 (1.8)1.2 (1.1)1.5 (0.9)2 (−)2.4 (1.7)Range0–60–50–3–0–5Movement(n = 147)Mean (SD)4.6 (1.4)3.4 (1.3)4.5 (1.1)6 (−)4.5 (1.5)Range0–81–63–6–2–8Cortical(n = 146)Mean (SD)3.8 (1.1)2.5 (0.8)5.1 (1)4 (−)3.9 (0.9)Range1–61–53–6–3–6Brain(n = 146)Mean (SD)4.3 (2)3.3 (1.8)4.5 (1.8)5 (−)5.1 (2.4)Range1–90–72–8–1–10Growth and development: Z-RTT showed a minor deficit than all the other RTT form (F test = 8.18; p < 0.005). Musculoskeletal appearance: Z-RTT group was less affected than the Classical RTT group (F test = 3.29; p < 0.05). Movement: the motricity area was less compromised in the Z-RTT if compared to the classical forms (F test = 3.5; p < 0.005). Cortical: minor impairement was observed for the group of Z-RTT if compared to the ARTT-NOS, Hanefeld, (F test = 12.21; p < 0.001). Autonomic system: no significant differences among the single RTT clinical forms. Altogether we confirmed that Z-RTT females have lower scores as they have a milder clinical presentation.
Evaluation with Pbz scoring system
PBZ and clinical forms
PBZ score | Classical | Z-RTT | Hanefeld | Congenital | ARTT-NOS | |
---|---|---|---|---|---|---|
Motor area | Mean (SD) | 13.3 (4.6) | 6.4 (3.8) | 16.3 (4.5) | 0 (−) | 11.8 (2.3) |
Range | 5–24 | 0–15 | 12–22 | – | 8–14 | |
S-C | Mean (SD) | 12.2 (4.6) | 8 (4.1) | 21.5 (5.7) | – | 14.2 (5.9) |
Range | 3–23 | 1–15 | 16–32 | – | 8–25 | |
Daily living | Mean (SD) | 10.2 8 (3.4) | 5.4 (3.4) | 11.8 (2.7) | – | 7.7 (2.8) |
Range | 1–17 | 0–11 | 7–15 | – | 4–13 | |
Total | Mean (SD) | 35.7 (9.8) | 19.8 (10.3) | 49.7 (11.2) | – | 33.7 (6) |
Range | 13–62 | 2–41 | 40–69 | – | 27–44 |
PBZ areas | Severity scale | Classical | Z-RTT | Hanefeld | ARTT-NOS |
---|---|---|---|---|---|
Motor (0–36) | Mild | 3.8 | 50 | – | – |
Medium | 40.4 | 42.9 | – | 40 | |
Severe | 40.4 | 7.1 | 50 | 60 | |
Extreme | 15.4 | – | 50 | – | |
S-C (0–48) | Mild | 17.3 | 50 | – | – |
Medium | 40.4 | 35.7 | – | 50 | |
Severe | 34.6 | 14.3 | 50 | 30 | |
Extreme | 7.7 | – | 50 | 20 | |
Daily living (0–20) | Mild | 7.7 | 42.9 | – | 20 |
Medium | 30.8 | 42.9 | 16.7 | 60 | |
Severe | 44.02 | 14.3 | 33.3 | 10 | |
Extreme | 17.3 | – | 50 | 10 | |
Total (0–104) | Mild | 9.6 | 71,4 | – | – |
Medium | 82.7 | 28.6 | 66.7 | 100 | |
Severe | 7.7 | – | 33.3 | – | |
Extreme | – | – | – | – |
Cardiorespiratory evaluation
Respiratory abnormalities and cardiorespiratory phenotypes
% Breath abnomal | Classical (n = 86) | Z-RTT (n = 19) | Hanefeld (n = 12) | Congenital (n = 1) | ARTT-NOS (n = 17) |
---|---|---|---|---|---|
Mean (SD) | 50.8 (21.4) | 41.7 (17.7) | 57.1 (23.1) | 37.4 | 42.5 (24.4) |
Range | 0–100 | 3–71.5 | 17.2–84.4 | – | 0–77 |
BMI | Apneustic (n = 14) | Feeble (n = 50) | Forceful (n = 63) |
---|---|---|---|
<3rd centile | 30 % | 34 % | 42 % |
3rd centile–40th centile | 35 % | 22 % | 14 % |
>40th centile | 35 % | 44 % | 23 % |
Cardiorespiratory phenotype and clinical forms
Phenotype | Classical (n = 86) | Z-RTT (n = 19) | Hanefeld RTT (n = 10) | Congenital (n = 1) | ARTT-NOS (n = 18) |
---|---|---|---|---|---|
Feeble | 37 % | 53 % | – | – | 50 % |
Forceful | 49 % | 42 % | 80 % | 100 % | 39 % |
Apneustic | 13 % | 5 % | 20 % | – | – |
Normal | 1 % | – | – | – | 11 % |
Valsalva | Classical (n = 86) | Z-RTT (n = 19) | Hanefeld (n = 12) | Congenital (n = 1) | ARTT-NOS (n = 17) |
---|---|---|---|---|---|
Mean (SD) | 5.5 (9.8) | 0.6 (0.7) | 1.3 (1.9) | 0.2 (−) | 3 (7.8) |
Range | 0–53.2 | 0–2.1 | 0–6.8 | – | 0–32.8 |
HR | Apneustic (n = 13) | Feeble (n = 50) | Forceful (n = 61) | Normal (n = 1) |
---|---|---|---|---|
Mean (SD) | 98.9 (15.8) | 91.3 (15.7) | 101.2 (17.4) | 90 |
Range | 74–137.4 | 55–130 | 54–148 | – |
HR | Classical (n = 80) | Z-RTT (n = 18) | Hanefeld (n = 12) | Congenital (n = 1) | ARTT-NOS (n = 16) |
---|---|---|---|---|---|
Mean (SD) | 95.6 (16) | 94.2 (14.4) | 105.2 (24.6) | 148 (−) | 97.6 (13.6) |
Range | 55–130 | 65–115 | 54–137,4 | – | 78–126 |
CVT | Classical (n = 83) | Z-RTT (n = 19) | Hanefeld (n = 12) | Congenital (n = 1) | ARTT-NOS (n = 17) |
---|---|---|---|---|---|
Mean (SD) | 5.6 (3.5) | 5.9 (2.4) | 6.1 (7.7) | 0.7 (−) | 6.4 (3.4) |
Range | 1.2–20 | 3–13.1 | 0.9–28.9 | – | 1.9–15 |
CVT | Apneustic (n = 13) | Feeble (n = 51) | Forceful (n = 64) | Normal (n = 2) |
---|---|---|---|---|
Mean (SD) | 5.5 (2.1) | 5.6 (2.4) | 9.2 (8.1) | 9,2 (8,1) |
Range | 0.9–9.4 | 1.2–116 | 3.5–15 | 3.5–15 |
Genetics
Classical | Atypical | Total | ||||
---|---|---|---|---|---|---|
Hanefeld | Congenital | Z-RTT | ARTT-NOS | |||
RTT male MECP2 + | – | – | – | – | 2/20 (10 %) | 2 |
RTT females MECP2 + | 94/98 (96 %) | – | – | 18/19 (95 %) | 4/20 (20 %) | 116 |
RTT females MECP2- | 4/98 (4 %) | – | – | 1/19 (5 %) | 13/20 (65 %) | 18 |
CDKL5 + | – | 12 | – | – | – | 12 |
CDKL5-e MECP2- | 1 | 1 | ||||
FOXG1 + | – | – | 1 | – | – | 1 |
MEF2C + | – | – | – | – | 1/20 (5 %) | 1 |
TOTAL | 98 (100 %) | 13 (100 %) | 1 | 19 (100 %) | 20 (100 %) | 151 |
Mutations | Classical | Atypical | Tot | % | |
---|---|---|---|---|---|
Z-RTT | ARTT-NOS | ||||
Substitutions | |||||
Non sense | 29 | 1 | 1 | 31 | 26 % |
Early truncating | 22 | – | 1 | 23 | |
Late truncating | 7 | 1 | – | 8 | |
Missense | 29 | 9 | 4 | 42 | 36 % |
Large Deletions | 17 | – | – | 17 | 14 % |
Frameshift | 19 | 8 | 1 | 28 | 24 |
C terminal deletions
|
12
|
7
| – |
19
| |
94 | 18 | 6 | 118 | 100 % |
ISS total | Early truncating (n = 22) | Late truncating (n = 8) | Large deletion (n = 18) | Frameshift (n = 9) | Missense (n = 39) | C ter del (n = 18) |
---|---|---|---|---|---|---|
Mean (SD) | 21.3 (6.2) | 16.7 (4.7) | 19.2 (5.9) | 20.3 (7) | 18.4 (5.7) | 14.2 (6) |
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Development: 77 % of the mutations terminals C had a mild severity (ISS) for domain DEV (development and growth) while all other mutations were mild only in 33 % of cases (test χ2 = 7.63; p < 0.05).
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Autonomic system: 72 % of cases C term were mild compared to 33 % of other (χ2 test = 9.78; p < 0.01).
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Total: 78 % of cases the term C had a mild form versus 24 % of other forms (χ2 test = 3.20; p < 0.001).
PBZ total | Early truncating (n = 9) | Late truncating (n = 5) | Deletions (n = 13) | Frameshift (n = 3) | Missense (n = 24) | C terminal del (n = 14) |
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Mean (SD) | 34.4 (13.5) | 33.4 (9.3) | 38.2 (8.8) | 42.7 (11.6) | 32.6 (9.9) | 23.4 (12) |