Table 1.
Patient’s clinical features grouped according to Neul classification, the pathogenic variants and the Next generation sequencing (NGS) approach.
| Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
|---|---|---|---|---|---|---|---|---|---|
| Sex, Current Age (years) | F (18 y) | F (11 y) | F (19 y) | F (29 y) | F (7y) | F (9 y) | F (38 y) | F (42 y) | |
| Molecular Approach | NGS-pediatric epilepsy | WES-RTT | WES-RTT | NGS -pediatric epilepsy | NGS-diagnostic | NGS-diagnostic | NGS -pediatric epilepsy | WES-RTT | |
| Mutation/Inheritance Pattern | STXBP1 NC_000009.11: g.130423471 C>T, NM_003165.3: c.416C>T: p.(Pro139Leu), de novo | STXBP1 NC_000009.11: g.130435529 C>T, NM_003165.3: c.1099C>T: p.(Arg367Ter), de novo | STXBP1 NC_000009.11: g.130416077 T>C, (NM_003165.3): c.169+2T>C, r.([169_170 ins [gc;169+3_169+1168]; 169_170ins [gc; 169+3_169+1334]]),p.(Ile57Serfs7*) de novo | STXBP1 NC_000009.11: g.130428548 T>C, NM_003165.3: c.767T>C, p.(Leu256Pro), de novo | STXBP1 NC_000009.11: g.130444840 G>A, (NM_003165.3) c.1702+1G>A, r. [1585_1702del117] p.(Glu530_Gly 568del) de novo | STXBP1 NC_000009.11: g.130438188 C>T, NM_003165.3: c.1216 C>T, p.(Arg406Cys), de novo | GABRG2 NC_000005.9: g.161576128_161576129 delinsGG, NM_000816.3: c.937_938 delinsGG, p.(Leu313Gly), de novo mosaic | GABRB2 NC_000005.9: g.160758063 C>T, NM_021911.2: c.904G>A p.(Val302Met), de novo | |
| Regression (age indicated) Followed by Recovery or Stabilization | No cdv | No cdv | No cdv | No cdv | No | Yes (6 months) | Yes (12 months) | Yes (9 months) | |
| Main Criteria | Partial or Complete Loss of Acquired Purposeful Hand Skills | No: not lost, but NevAcq (grabs food and takes it to her mouth) | No: not lost, but NevAcq (grasping and manipulation disturbed by involuntary movements) | No: not lost, but NevAcq (grasping disturbed by tremors and stereotypies) | No | No: very limited hand skills | No: not lost, but Nev completely Acq | Yes: very limited hand skills | Yes: (since 2 years leaves behind and drops things) |
| Partial or Complete loss of Acquired Spoken Language | No: not lost, but NevAcq | No: not lost, vocalisms and only ten words | No: not lost, but NevAcq | No: not lost, only a few words | No: not lost, but Nev Acq, only vocalisms | No: not lost, but NevAcq(vocalism) | No: not lost, but NevAcq | Yes (only “Mum” and “Dad”, then lost) | |
| Gait Abnormalities: Impaired or Absence of Ability | Yes (ataxic-dyspraxic, unstable and only for short distances: since 4 years) | Yes (ataxic with axillary support: since 4 years) | Yes absent (only standing with axillary support) | Yes ataxic (walking with enlarged base and out of rotation of feet: since 3 years) | Yes (walking with enlarged base/ not apraxic: since 3 years) | Yes (Nev Acq) | Yes (ataxic: since 6 years) | Yes (apraxic, slow but autonomous, since 16 months, climbs the stairs) | |
| Stereotypic Hand Movements (type) | Yes frequent (brings her hands to mouth and bites fingers) | Yes (not typical for RTT, beats her head: since 3 years) | Yes (hand washing) | Yes (hand rocking) | Yes (hand washing, clapping, tapping right hand on table/books, tapping the forehead with the right upper limb, upper limb flickering) | Yes (upper limbs tremors, upper limb flickering, and dyskinesias) | Yes (tapping her right hand on her teeth: since 18 months), | Yes (upper limbs flickering) | |
| Exclusion Criteria | Brain Injury: Peri or Postnatal Trauma, Neurometabolic Disease or Severe Infection | No | No | No | No | No | No | No | No |
| Grossly Abnormal Psychomotor Development in First 6 Months of Life: Exam at the Birth | hypotonia | normal | normal | hypotonia, hyperexcitability, inconsolable crying | normal | normal | normal | normal | |
| Supportive Criteria | Breathing Disturbances | No | Yes | No | No | No | No | Yes (mild cyanosis and apneas) | Yes (hyperventilation) |
| Bruxism when Awake | No | No | Yes | No | Yes | Yes | Yes | Yes (significant) | |
| Impaired Sleep Pattern | Yes (sleeplessness and nocturnal agitation) | Yes (seizures) | Yes (nocturnal bruxism) | No | Yes (several and prolonged nocturnal awakenings) | No | Yes | No | |
| Abnormal Muscle Tone | Yes (proximal hypotonia) | Yes | Yes | No | No | Yes (axial hypotonia, hypertonus of the limbs) | Yes mild hypertonus (hypotonia in the first years of life) | No | |
| Peripheral Vasomotor Disturbances | No | No | Yes | No | No | No | cold and bluish hands and feet without trophic changes | No | |
| Scoliosis/Kyphosis | Yes (lumbar hyperlordosis) | Yes (mild) | Yes | No | No | No | Yes (mild kyphosis) | No (only scoliotic attitude) | |
| Growth Retardation | No | No | No | hypostaturism and obesity | No | Yes | Yes mild | No | |
| Small Cold Hands/Feet | Yes | No | Yes | No (but short and stubby fingers) | No | Yes (small, not cold) | Yes | Yes (cold feet) | |
| Inappropriate Laughing /Screaming Spells | Yes | No | Yes (screams) | No | Yes | nd | Yes frequent | Yes rare | |
| Diminished Response to Pain | Yes | No | No | nd | Yes | nd | nd | No | |
| Intense Eye Communication | No | Yes | No | No | Yes | No | Yes | Yes | |
| Microcephaly: if Yes Indicate if Acquired | Yes acquired | No | No | No | No | Yes acquired | No | Yes acquired | |
| Clinical Diagnosis at Referral | RTT atypical | RTT atypical Hanefeld | RTT atypical congenital | RTT-like-EOEE (West>Lennox-Gastaut) | RTT atypical | RTT-like (myoclonic epileptic encephalopathy) | RTT atypical | RTT classic | |
WES-RTT= Whole Exome Sequencing on Rett Syndrome; RTT = Rett Syndrome; NGS = Next generation Sequencing; WES = Whole Exome sequencing; cdv = Congenital Developmental Delay; nd = not done; Nev Acq = Never Acquired.