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Table 2 Case summaries

From: Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Case #
Gender
Age at time of study
Genetic defectLevel of functioning prior to onset psychiatric illness 1Reported possible triggering stressorsAge onset psychiatric illness; psychiatric diagnoses by DM-ID-2 criteria; associated features; number of episodesAge and areas of regression after onset psychiatric illness 2, 3Years 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 notedAge 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 transitionAge 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
46,XX,r [22](p13q13.3).ish r [22](ARSA-)
Phrase speech
Never toilet trained
Dressed self with prompts
Read some sight words
Did puzzles
URIAge 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 transitionAge 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
PneumoniaAge 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 notedAge 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 notedAge 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 notedAge 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 skillsMood 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-enteritisAge 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 skillsNo 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 notedAge 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
MensesAge 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 skillsMood 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
MensesAge 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 skillsMood 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 deficitsAge 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 transitionAge 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 infectionAge 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 infectionAge 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 notedAge 8
First episode manic,
then depressive episodes
10+ episodes
No lasting loss of skillsMood 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 notedAge 32
First episode depressed
Then recurrent depressed episodes with severe anxiety, SIB
Then mania with catatonia
10+ mood episodes
No lasting loss of skillsMood 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
PubertyAge 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 skillsNo 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 infectionAge 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 infectionAge 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
MensesAge 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 pneumoniaAge 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 notedAge 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 notedAge 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 skillsMood 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 notedAge 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 stressorsAge 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 stressorsAge 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 stressorsAge 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 regressionEight 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
  1. Abbreviations: ADLs activities of daily living, dn de novo, dx diagnosis, ECT electroconvulsive therapy, ICU intensive care unit, OCD obsessive-compulsive disorder, PANDAS pediatric autoimmune neuropsychiatric disorder associated with streptococcus, PECS Picture Exchange Communication System, UTI urinary tract infection, URI upper respiratory tract infection
  2. 1 All were ambulatory and able to feed themselves with utensils prior to psychiatric illness
  3. 2 Cases 11, 14, 17, 22, 30, 33, and 35 had regression in speech, play, and social interaction before age 8, as well as subsequent regressions accompanying psychiatric illness at an older age
  4. 3 Regression defined as loss of skills that persisted at least 6 months after resolution of acute psychiatric episode
  5. 4 Regression occurred years after onset of psychiatric illness
  6. 5 “Symptoms” used when sub-threshold for diagnosis of either depressive or manic episode