Table 2 Case summaries
From: Psychiatric illness and regression in individuals with Phelan-McDermid syndrome
Case # Gender Age at time of study | Genetic defect | Level of functioning prior to onset psychiatric illness 1 | Reported possible triggering stressors | Age onset psychiatric illness; psychiatric diagnoses by DM-ID-2 criteria; associated features; number of episodes | Age and areas of regression after onset psychiatric illness 2, 3 | Years since last psychiatric episode and regression; degree of recovery in that time and skills regained |
|---|---|---|---|---|---|---|
Case 1 Female 18 years 9 months | Terminal deletion [89 kb] arr[hg19] 22q13.33(51,122,483-51,211,392)x1 | Phrase speech Toilet trained Dressed self Fed self Independent for hygiene Read sight words Counted to 100 | None noted | Age 14 First episode depressed with new tics, fecal smearing Then, OCD, new pica, manic episode and catatonia Three episodes | Age 14 Decreased speech Decreased eye contact New onset incontinence Unable to dress self Lost all academic skills | Mood episode in past year Four years since regression Minimal recovery Occasional meaningful speech and singing Intermittent feeding self with utensil |
Case 2 Female 29 years 6 months | Mosaic terminal deletion and interstitial duplication [4.4 Mb] 46,XX; arr[hg19] 22q13.2q13.31(43,675,642-46,807,366)x3[0.65], 22q13.31q13.33(46,808,071-51,197,838)x1[0.65] | Single words Toilet trained Pretend play with dolls | Program transition | Age 27 First episode depressed with catatonia Then new generalized anxiety disorder (GAD) One mood episode Ongoing GAD | Age 27 Decreased speech Incontinent Decreased independence in ADLs Decreased pretend play | Two years since mood episode Two years since regression No recovery |
Case 3 Female 18 years 0 month | Terminal deletion–unbalanced translocation [207 kb] 46,XX; arr[hg19] 3p26.3(180,509-2,097,153)x3,22q13.33(50,990,475-51,197,838)x1 | Spoke in full sentences Toilet trained Wrote simple text Used iPad | URI Beginning new school | Age 12 First episode OCD dx PANDAS Then depressed with new tics, tremors and posturing, Then mixed manic and depressed symptoms with new aggression, new anxiety at leaving house Four episodes (three mood) | Age 15 Decreased speech clarity Frequent urinary incontinence Decreased independence in ADLs | Mood episode in past year Three years since regression Moderate recovery Still unpredictably incontinent Speech improved, still dysfluent |
Case 4 Female 22 years 3 months | Terminal deletion – ring 22 | Phrase speech Never toilet trained Dressed self with prompts Read some sight words Did puzzles | URI | Age 16 First episode depressive symptoms5 Then manic symptoms with hand posturing and gait disturbance Three mood episodes | Age 16 Decreased speech Decreased response to environment Decreased orientation | Mood episode in past year Six years since regression Skills continue to deteriorate |
Case 5 Male 36 years 1 month | Terminal deletion [106 kb] 46,XY; arr[hg18] 22q13.33(49,474,771-49,581,309)x1 | Full sentences Toilet trained Dressed self Did all self-care Independent with own routines Able to return home from day program unassisted and to be home alone safely | Program transition | Age 28 First episode depressed Then new aggression which worsened to require two hospitalizations and placement in nursing care facility Three mood episodes | Age 30 Slowly regressed over several years Lost speech Decreased continence Lost ability to dress and shower Needs help with eating Moved slowly No longer can be left alone | No episode in past 3 years Six years since regression Moderate recovery Remains largely mute and uses single words or grunts Dependent for ADLs Regained some self-care skills Improved mood Incontinent at night |
Case 6 Female 28 years 11 months | Terminal deletion [54 kb] arr[hg19] 22q13.33(51,123,491-51,178,264)x1 | Spoke in full sentences Toilet trained Dressed self Made snacks Read simple books Wrote simple text | Pneumonia | Age 14 First episode depressed Then mania with complete insomnia for 12 days, catatonia, neuroleptic malignant syndrome and seizures Now ECT dependent 10+ mood episodes | Age 26 Sporadic incontinence Confused Couldn’t read or write Decreased hand skills Poor memory | Mood episode in past year Two years since regression No recovery |
Case 7 Female 34 years 6 months | Terminal deletion – ring 22 46,XX,r [22](q13.3) with deletion of terminal 22q | Simple repetitive speech Toilet trained Dressed self with prompts Some sight words Some computer skills | None noted | Age 30 First episode depressed Then both manic and depressed episodes 10+ mood episodes | Age 30 Decreased vocalizations Frequent incontinence Decreased independence with dressing | Mood episode in past year Four years since regression Moderate recovery Vocalizes more Remains incontinent Feeds self but needs supervision for choking Needs help with dressing |
Case 8 Female 36 years 3 months | Terminal deletion [106 kb] arr[hg18] 22q13.33 (49,475,238-49,581,309)×1 | Phrase speech Toilet trained Dressed self with supervision Read simple words Played with dolls | None noted | Age 11 First episode manic symptoms Then mixed mood episodes 10+ mood episodes | Age 11 Steady developmental decline from age 11 Lost almost all language Incontinent Lost use of utensils No longer dresses self No play interests | No episode in past year 25 years since regression No recovery |
Case 9 Female 43 years 1 month | Terminal deletion – ring 22 [2.1 Mb] 46,XX,r [22](p13q11.2); arr[hg19] 22q13.32q13.33(49,056,457-51,179,671)x1 | Spoke in full sentences Toilet trained Dressed self Independent for hygiene Active in programs | None noted | Age 32 Abrupt onset of stuporous catatonia with food phobia Then multiple manic and depressed episodes 10+ mood episodes | Age 32 Decreased speech Incontinent No longer able to dress self or bathe self | Mood episode in past year 12 years since regression Minimal recovery Decreased speech Intermittent incontinence Needs supervision for self-care |
Case 10 Female 17 years 11 months | Sequence variant – Frameshift NM_033517.1:c.3424_3425delCT, p.Leu1142Valfs*153 | Spoke in full sentences Toilet trained Dressed self and did most hygiene Read sight words Wrote name, familiar words, copied text | Menses Started at new school | Age 14 First had three peri-menstrual manic episodes followed by paranoia Then prolonged severe depression with catatonic features Then acute OCD with tics, posturing and choreiform movements Then mania with first seizure and catatonia, dx seronegative autoimmune encephalitis Six episodes (five mood episodes) | No lasting loss of skills | Mood episode in past year No regression |
Case 11 Male 14 years 11 months | Sequence variant – Frameshift NM_033517.1:c.3679dupG, p.Ala1227Glyfs*69 | Phrase speech Social and interactive Toilet trained Read sight words Typed from a model | Gastro-enteritis | Age 12 First episode manic with agitation, new pica, new incontinence, destructive behavior, mutism, and catatonia Then OCD with agitation and aggression Five+ mood episodes | Age 12 Lost most language Less social and interactive Incontinent Lost all academic skills New obsessional and repetitive behaviors | Mood episode in past year Two years since regression Minimal recovery Rare speech and interaction now Still incontinent |
Case 12 Female 43 years 8 months | Sequence variant – Frameshift NM_033517.1:c.4906_4921dup16, p.Pro1641Leufs*58 dn | Spoke in full sentences Toilet trained Dressed and washed Read at 3rd grade level Math grade level through 9th grade Worked at supported job in library and in town hospital Balanced own checkbook | Menses Viral infections | Age 11 First episode mixed, with agitation, insomnia, cognitive dulling, posturing Then multiple mood episodes with catatonia 20+ mood episodes | Age 11 Gradual, with each episode lost skills, twice lost ability to walk, would regain some skills with therapies, still working and verbal to age 28; after a severe cold lost all speech, continence, self-care and many motor skills, cannot use hands (dystonic posturing at wrists) | No episode in past year 15 years since most severe regression No recovery |
Case 13 Female 14 years 1 month | Terminal deletion [123 kb] 46,XX; arr[hg18] 22q13.33(49,468,254-49,591,415)x1 | Spoke in full sentences Toilet trained Pulled on clothes Needed help with ADLs Read at 1st grade level Wrote and typed Used iPad | Strep infection Menses | Age 9 First episode complex tics and choreiform movements w/ high strep titers, dx PANDAS and resolved with antibiotics Then rage outbursts and peri-menstrual aggression Then depressive episode with severe anxiety and new generalized anxiety disorder 3+ mood episodes | No lasting loss of skills | No episode in past year No regression |
Case 14 Male 16 years 6 months | Sequence variant – Nonsense NM_033517.1:c.5008A > T, p.Lys1670* (this individual also has a likely benign missense variant in SHANK3, c.3872C > T, p.Ser1291Leu) | No speech, used PECS Toilet trained Fed self Used iPad Navigated internet Liked music | None noted | Age 15 First episode manic Then monthly manic episodes Then severe aggression requiring hospitalization and residential care 20+ manic episodes | Age 15 Lost toilet training Averse to touch Lost computer skills Lost social interest | No episode in past year 18 months since regression Moderate recovery of toileting, self-feeding, some computer skills |
Case 15 Female 28 years 11 months | Terminal deletion [43 kb] arr[hg18] 22q13.33(49,479,705-49,522,868)x1 | Single words Never toilet-trained Could change own pull-up Dress self Drink from cup | School re-entry Possible URIs | Age 9 First episode manic Then manic spells with OCD behaviors Then depressed periods with new aggression 10+ mood episodes | Age 24 Lost ability to: Dress self Change pull-up Drink from cup | Three years since last episode Four years since regression No recovery |
Case 16 Female 15 years 1 month | Sequence variant – Frameshift arr[hg19] 22q13.33(51,121,452-51,197,838)x1 | Spoke in full sentences Toilet trained Dressed self Read Pretend play Wrote in cursive Karate | Menses | Age 13 First episode manic with paranoia Then depressive episode with catatonia requiring ICU care and ECT Then recurrent manic episodes Five+ mood episodes | No lasting loss of skills | Mood episode in past year No regression |
Case 17 Female 13 years 10 months | Terminal deletion [4.3 Mb] arr[hg19] 22q13.31q13.33(46,928,208-51,224,252)x1 dn | Single words or short phrases Toilet trained Dressed self Fed self Rode scooter | Menses | Age 13 First episode depressed with catatonia Then mania with urinary frequency and occasional incontinence, changes in gait and posture Four mood episodes | No lasting loss of skills | Mood episode in past year No regression |
Case 18 Male 20 years 10 months | Terminal deletion [76 kb] arr[hg19] 22q13.33(51,121,452-51,197,838)x1 | Spoke in full sentences Toilet trained Dressed self Showered self Read at 3rd grade level Wrote sentences Used calculator Used iPhone to call/text friends | Possibly his increased awareness of deficits | Age 16 First episode mixed mood disturbance with sleepiness and irritability Then mania alternating with depression and severe aggression Three+ mood episodes | Age 16 Confused Needs constant supervision Cannot dry self Puts clothes on while still wet Decreased academic skills Urinary incontinence Lost interest in usual activities | Mood episode in past year Four years since regression No recovery |
Case 19 Male 26 years 5 months | Sequence variant – Nonsense NM_033517.1:c.1572C>A, p.Cys524* | Spoke in full sentences Toilet trained Independent for ADLs and travel with school groups Reading at 3rd grade level Attended community college Competitive tennis Marathoner | School transition | Age 17 First episode manic with irritability, confusion, catatonia and new aggression Then multiple manic and depressed episodes Psychotic features occurring between mood episodes 20+ mood episodes | Age 17 Gradual, lost most speech Often incontinent Lost ability to perform ADLs Requires constant 1:1 supervision | Mood episode in past year 12 years since regression No recovery |
Case 20 Female 17 years 1 month | Sequence variant – Frameshift NM_033517.1:c.4065_4066delTG, p.Val1357Glyfs*4 dn | Phrase speech Asked for needs Toilet trained Fed self | Strep infection | Age 14 First episode OCD with enuresis at night, aggression and sub-threshold manic symptoms Then similar episodes of OCD with manic symptoms Later diagnosis of autoimmune encephalitis Three+ mood and OCD episodes | Age 15 Decreased intelligibility Decreased toileting Decreased communication Decreased feeding self | Mood episode in past year Two years since regression Moderate recovery of speech clarity and toileting skills |
Case 21 Female (twin of case 20) 17 years 1 month | Sequence variant – Frameshift NM_033517.1:c.4065_4066delTG, p.Val1357Glyfs*4 dn | Phrase speech Toilet trained Fed self Dressed self Read a few sight words Basic writing | Strep infection | Age 14 First episode anxiety/OCD, transient inability to speak, then developed mania Then diagnosed with PANDAS, Then catatonia Five+ mood episodes | Age 14 Slow onset Decreased toileting Decreased communication Decreased orientation Decreased feeding self No longer writes name | Mood episode in past year Two years since regression Moderate recovery of communication and self-care skills Less improvement with academics |
Case 22 Female 15 years 0 month | Terminal deletion [62 kb] arr[hg18] 22q13.33(49,406,251-49,468,408)x1 | Few single words Not toilet trained Needed help for dressing Fed self with utensils | None noted | Age 8 First episode manic, then depressive episodes 10+ episodes | No lasting loss of skills | Mood episode in past year No regression |
Case 23 Female 39 years 5 months | Terminal deletion [2.5 Mb] arr[hg18] 22q13.32q13.33(47,003,473-49,515,911)x1 | Phrase speech with poor articulation Toilet trained Intact ADLs Read simple books Memory games Jigsaw puzzles Dot-to-dot coloring | None noted | Age 32 First episode depressed Then recurrent depressed episodes with severe anxiety, SIB Then mania with catatonia 10+ mood episodes | No lasting loss of skills | Mood episode in past year No regression |
Case 24 Female 36 years 7 months | Terminal deletion [69 kb] arr[hg19] 22q13.33(51,128,324-51,197,766)x1 | Phrase speech Toilet trained Dressed self Fed self Read simple text Wrote at a second grade level | Puberty | Age 15 First episode agitation, OCD Then catatonia and depression Then manic episodes 10+ mood episodes | Age 18 Decreased urinary continence Decreased independence for ADLs Lost all academic skills | No episodes in past year 18 years since regression No recovery |
Case 25 Female 24 years 1 month | Terminal deletion – unbalanced translocation [6.0 Mb] 46,XX,der(22)t(22;acro)(q13.33;p12); arr[hg19] 22q13.31q13.33(45,156,254-51,197,725)x1 | Single words Toilet trained Fed self Did chores | Multiple family health stressors High strep titers | Age 21 First episode depressed with agitation, photophobia, then catatonia, diagnosed PANDAS One episode | No loss of skills | No episode in 3 years No regression |
Case 26 Male 18 years 1 month | Sequence variant–Frameshift NM_033517.1:c.4649_4653dupGCAGC, p.Pro1552Alafs*14 dn (based on the results of his monozygotic twin brother) | Spoke in full sentences Toilet trained Dressed with assistance Fed self Read fluently Acted out plays Used computer with sophistication (e.g., booked travel) | Strep infection | Age 13 First episode manic with acute onset insomnia, tics, anorexia diagnosed PANDAS Then new pica, catatonia Then mutism and aggression associated with recurrence of manic symptoms 10+ mood episodes | Age 13 Lost language Decreased fine motor skills Decreased toileting Decreased utensil use Decreased interest in people and hobbies Destructive Sleep disrupted | Mood episode in past year Five years since regression Minimal recovery Slightly improved language and toileting Remains socially withdrawn Has not regained fine motor skills |
Case 27 Male (twin of case 26) 18 years 1 month | Sequence variant – Frameshift NM_033517.1:c.4649_4653dupGCAGC, p.Pro1552Alafs*14 dn | Phrase speech Toilet trained Needed help with dressing Fed self with fingers Used computer Few sight words | Strep infection | Age 13 First episode manic with acute onset insomnia, tics, anorexia diagnosed PANDAS Then depression and catatonia 10+ manic and depressed episodes | Age 13 Lost most language Incontinent Decreased feeding self Decreased interest in people, activities | Mood episode in past year Five years since regression Moderate recovery Has regained some fine motor skills and social interests, but not language and full continence |
Case 28 Female 26 years 3 months | Terminal deletion [70 kb] arr[hg19] 22q13.33(51,127,898-51,197,838)×1 | Spoke in full sentences Toilet trained Independent with dressing and care Took own meds Black belt in karate | Menses | Age 16 Gradual onset aggression Then manic episodes with unsafe behaviors 10+ manic episodes | Age 18 Became confused about daily tasks and had trouble with self-care Language deteriorated Episodes of running away | Manic episode in past year Six years since regression Has recovered all skills |
Case 29 Female 16 years 7 months | Sequence variant – Frameshift NM_033517.1:c.3679dupG, p.Ala1227Glyfs*69 dn | Spoke in full sentences Toilet trained Dressed self Independent for hygiene Fed self Read at 2nd grade level | Menses Hashimoto’s encephalopathy | Age 12 Gradual onset confusion and choking spells unrelated to food Then episodes of mania and OCD with catatonia and disorganized behavior and new behavior posing risk of accidental injury 10+ mood episodes | Age 12 Lost all adaptive skills, including continence and speech Lost all academic skills | Manic episode in past year Four years since regression Minimal recovery of relatedness and communication No recovery of academic skills Dependent for ADLs Requires constant supervision Appears to understand language but little speech Plays simple computer games |
Case 30 Female 16 years 8 months | Terminal deletion with interstitial duplication [6.4 Mb] 46,XX,del [22](q13.3); arr[hg18] 22q13.31(43,276,438-49,691,432)x1, 22q13.31(42,835,935-43,272,271)x3 | Minimal language Toilet trained for urine in daytime Fed self with fork Could put on clothes if in correct position | Mycoplasma pneumonia | Age 14 First episode depressed with catatonia Then OCD and manic symptoms Five+ mood episodes | Age 15 Lost daytime continence Lost interest in play and relatedness Decreased feeding self Decreased vocalization | Mood episode in past year Three years since regression Moderate recovery Has regained energy and vocalization, not daytime continence |
Case 31 Female 49 years 9 months | Terminal deletion [5.0 Mb] (5 Mb terminal deletion with the breakpoint at 22q13.31) | Spoke a few words Toilet trained Fed self Ambulatory | None noted | Age 14 First episode manic Then repeated mood episodes at intervals of five or more years Three+ mood episodes | Age 47 Loss of skills with each psychiatric episode; recovered each time until age 47, then lost all language Lost ability to walk Lost feeding skills | Two years since last mood episode; Two years since regression No recovery No language Incontinent Cannot stand or walk, has difficulty maintaining sitting Cannot feed self Needs total care |
Case 32 Female 31 years 11 months | Terminal deletion [76 kb] 46,XX; arr[hg19] 22q13.33(51,121,452-51,197,838)x1 dn | Spoke in full sentences Toilet trained Intact ADLs Planned recipes and cooked Worked with young children Ran with running group Volunteered at nursing home | None noted | Age 14 First episode anxiety/OCD Then mania Then depression with slow recovery over 2 years followed by severe mood cycling years later Three+ mood episodes | No loss of skills | Mood episode in past year (resolving) No regression |
Case 33 Female 41 years 0 month | Terminal deletion [481 kb] arr[hg18] 22q13.33(49,210,245-49,691,432)x1 | Single words Never toilet trained Fed self Undressed and pulled on pants Read sight words Poured drinks Rode tricycle Played with dolls | None noted | Age 7 First episode bizarre behavior with agitation, disorientation and insomnia (possible brief psychotic episode) Then OCD and new pica, followed by mania 10+ mood episodes | Age 16 Lost all meaningful speech; repeats words Unable to feed self, eats by lowering face to plate Unable to assist with dressing Lost all play Elopes frequently | Mood episode in past year 25 years since regression No recovery |
Case 34 Female 17 years 8 month | Terminal deletion [53 kb] arr[hg19] 22q13.33(51,144,903-51,197,838)x1 | Spoke in full sentences Toilet trained Fed self Dressed self Retrieved and poured cereal Did puzzles Played with Legos | Multiple social stressors | Age 14 First episode depressed with anorexia and incontinence Then mania and new pica Five+ mood episodes | Age 14 Decreased speech Decreased play Decreased dressing Decreased continence | No episode in past year Four years since regression Moderate recovery of language, self-care and play skills |
Case 35 Female 23 years 1 month | Sequence variant – Frameshift NM_033517.1:c.4086_4087delAC, p.Arg1363Glnfs*31 | Phrase speech with echolalia Toilet trained Fed self Poured milk Dressed self with assistance Needed help with ADLs Pretend play | Multiple social stressors | Age 12 First episode depressed with confusion, new incontinence and catatonia Then mania Three+ mood episodes | Age 12 Steady ongoing regression Lost all speech Incontinent Lost all self-care skills | Mood episode in past year 11 years since regression No recovery Requires constant supervision Only able to walk short distances with difficulty Cannot climb stairs |
Case 36 Female 15 years 0 month | Sequence variant – Frameshift NM_033517.1:c.4065_4066delTG, p.Val1357Glyfs*4 dn | Spoke in full sentences Toilet trained Dressed self Fed self Read sight words Used tablet Math at 1st grade level | Social stressors | Age 14 First episode catatonic with urinary retention, insomnia and pica; did not recognize family; paranoid One episode | Still recovering from first episode with catatonia; cannot yet determine new baseline or whether lost skills meet criteria for regression | Eight months since onset of psychiatric illness Continues to regain language, personality, and orientation Still not able to open and use hands for ADLs Intermittently incontinent |
Case 37 Female 17 years 5 months | Sequence variant – Nonsense NM_033517.1:c.4333C > T, p.Gln1445* dn | Phrase speech Toilet trained Fed self Dressed self with assistance Imaginative play Wrote name Copied text Drew pictures | Menses End of school year | Age 15 First episode depressed with insomnia, severe separation anxiety, apathy, decreased speech and interaction, swallowing difficulties, and catatonia One mood episode | Age 15 Lost most speech Lost ability to chew food Increased dependence for ADLs Lost all academic skills Lost imaginary play | No episode in past year Two years since regression Moderate recovery Regained some speech Eats normally Mostly continent Continues to not have academic skills, drawing skills, or imaginary play skills |
Case 38 Female 16 years 9 months | Sequence variant – Frameshift NM_033517.1:c.2763delG, p.Pro922Argfs*34 dn | Spoke in full sentences Toilet trained Sociable | Menses UTI | Age 13 First episode hypomanic Then 2 years later manic with aggression, incontinence; anxiety, talking to self, compulsions, then catatonia Three manic episodes | Age 15 Lost all speech Lost ability to feed self Incontinent Decreased social interaction | No episode in past year One year since regression Substantial recovery Recovered language Recovered feeding Improved social interaction Continues with intermittent incontinence |