Table 1.
PMS patients with neuropsychiatric decompensation reported in the literature
| Case | 1 | 2 | 3 | 4 | 5 | 6 |
| Reference | Stewart and Richards (1976) [14]a | Reeve et al. (1985) [15] | Arinami et al. (1986) [16] b | Millichap (1994) [22] | Sovner et al. (1996) [23] | Kehrer-Sawatzki et al. (1997) [24] |
| Subject | − | − | − | − | − | − |
| Age when reported | 22 y | 28 y | 27 y | 24 y | 21 y | 38 y |
| Sex | Female | Male | Male | Female | Male | Female |
| Genetic abnormality | r(22), de novo | r(22) | r(22) | r(22) | r(22) | r(22) |
| Cognitive deficit, language, and behavioral problems | Severe ID, nonverbal, restless | ID, language limited to a few words. He lived at home, was described as pleasant and interacted well with his family. He worked in a sheltered workshop. | Profound ID, admitted to an institution at age 20 y | Profound ID, nonverbal, hyperactive, polyembolokoilomania | Severe ID | Mental development during early infancy was unremarkable, but language delay became apparent at the age of 4 y. She achieved low grades in primary school and was transferred to a special-needs school at the age of 10 y. |
| Age of onset of decompensation | 18 y | ~24 y | 25 y | 16 y | 17 y | 15 y |
| Signs of decompensation, course of illness, and treatment | At the age of 16 y, the patient had constant tremors of the head, shoulders, forearms and hands, resulting in poor motor coordination. By age 18 y, she became increasingly difficult to feed, behaviorally dysregulated, and would scream periodically. Weight loss, mental, and physical deterioration led to the need for permanent care at the age of 22 y. There remains posturing of her left forearm in a permanently flexed position with ventriflexion of the wrist. She appeared to have contractures but no neurological signs were found. |
Beginning in his early 20s, the patient exhibited a deterioration of mood and behavior, with decreased speech and decline of fine motor skills over a 3 y period. He began having recurrent temper tantrums, including aggression. At other times he would withdraw, appear depressed, and become mute. He presented with truncal instability, bradykinesia, mild spastic paraparesis, resting tremor in the upper extremities, and decreased fine motor skills such that he could no longer fold papers in the vocational rehabilitation program. At the age of 27 y, agitated behavioral outbursts increased in frequency to twice daily and depression with periodic akinetic mutism continued until he required institutionalization. During hospitalization, his behavior remained unmanageable; for 1-2 h periods, he alternated between being entirely passive with avoidance of eye contact and being severely agitated, with stereotyped movements of arms and legs causing severe abrasions. All activities produced stress and increased his aggressive outbursts. He had a short attention span and could not feed himself. Psychopharmacological treatment began with thioridazine at 27 y of age with minimal benefit. He developed extrapyramidal side effects from thioridzaine within 4 weeks of increasing the dose to 1000 mg/d and abrupt discontinuation led to 4 generalized seizures. Phenobarbital, carbamazepine, chlorpromazine hydrochloride, and perphenazine were tried successively or in combination without benefit. Haloperidol worsened his agitation. A trial of methylphenidate hydrochloride resulted in rapid and dramatic improvement of his behavior within 18 h. There was further improvement as the dose was increased (eventually to 30 mg/d) along with diazepam (15 mg/d). His attention span improved so that he was able to dress, eat, and carry out personal hygiene. His mood was improved, he smiled spontaneously, and he recognized and called his family members by name. Motor function also improved, but to a lesser extent. When a dose of methylphenidate was inadvertently missed, his behavior again deteriorated, with passive withdrawal alternating with agitated, aggressive outbursts. He was eventually discharged to a residential program and while he continued to experience behavioral dysregulation and mood cycling, the frequency and severity was significantly decreased. With methylphenidate hydrochloride (40 mg/d) he had no seizures and few outbursts and was able to interact socially. |
At the age of 25 y, the patient exhibited episodes of apathy, insomnia, anorexia, vomiting, mask-like facial expression, tremor of the upper extremities, instability of gait, and convulsions. These symptoms worsened and the patient died at 27 y of age. Necropsy revealed the presence of multifocal meningiomas. The apparent cause of death was a subarachnoid cyst with meningocytic elements at the medullocerebellar angle that had compressed the medulla oblongata and surrounding brain tissues. These findings in a subject with r(22) suggest a diagnosis of neurofibromatosis 2 (NF2). At the age of 20, he had no signs of NF2 on physical exam, although hearing loss was reported. |
At 16 y of age, the patient was placed in a residential home because of aggressive and destructive behavior, insomnia, and refusal to eat. Self-injury was also prominent, with body bruising and insertion of foreign objects in her nose. Occasional seizures were also noted and described as “minor.” She often had a blank stare, and sometimes appeared catatonic. Behavioral modification and use of signs for communication led to improvement. |
At age 17, the patient began to experience cyclical behavioral dysregulation with refusal to eat and get out of bed, sleep maintenance disturbance, decreased speech, and tearfulness. He was stabilized after approximately 2 years with what was described as a “dramatic response” to fluoxetine (40 mg/d), which led to remission of symptoms. Thirteen months later, a slow taper of fluoxetine over 3 months led to a recurrence of symptoms with anorexia, anxiety, negativistic behaviors, and self-injury (hand biting). Fluoxetine (20 mg/d) was restarted with a good initial response, but after 2 months he started to exhibit rapid cycling (3 ‘bad’ days followed by 2 ‘good’ ones). Divalproex sodium was then added. Fluoxetine (60 mg/d) in combination with divalproex sodium (level = 115 μg/ml) led to sustained remission of mood cycling symptoms. |
From the age of 15 y, the patient exhibited progressive deterioration of cognitive function and mood accompanied by increasing dysarthria. At the age of 17 y, she presented with psychotic symptoms (paranoia; hallucinations) with frequent outbursts of aggressive behavior and required institutionalization. Since then, she exhibited parkinsonian symptoms with repeated akinesia. At 38 y, the patient was found to have several peripheral neurinomas and CT scan revealed bilateral vestibular schwannomas, multiple intracranial meningiomas. The MRI also showed an intraspinal tumor (T12) and an Arnold-Chiari type 1 malformation. She was diagnosed with neurofibromatosis type 2 (related to ring 22) and had neurosurgery at 38 y for excision of infratentorial tumors, a meningioma and a neurinoma. A 5-y CT follow-up showed only slight progression of the multiple supra- and infra-tentorial tumors. However, the frequency of seizures increased and she developed tetraparesis mainly affecting the lower extremities. |
| Proposed diagnosis on review c | Unspecified catatonia | Bipolar disorder with catatonia | Bipolar disorder with catatonia, NF2 | Bipolar disorder with catatonia | Bipolar disorder | Unspecified psychotic disorder, NF2 |
| Loss of skills d | + (M, A, C) | + (L, M, A) | + (M) | + (M, C) | ||
| Other information | Cranial CT scan at 27 y: diffuse mild cortical atrophy and hydrocephalus ex vacuo | Minor partial seizures controlled with phenytoin up to 9 y. Normal CT scan. | ||||
| Case | 7 | 8 | 9 | 10 | 11 | 12 |
| Reference | Anderlid et al. (2002) [13] e | Ishmael et al. (2003) [25] | Ishmael et al. (2003) [25] | Ishmael et al. (2003) [25] | Tsilchorozidou et al. (2004) [26] | Nawab et al. (2007) [27] |
| Subject | − | Subject 1 | Subject 2 | Subject 5 | Case 2 | − |
| Age when reported | 33 y | 12 y | 35 y | 16 y | 52 y | 35 y |
| Sex | Female | Male | Male | Male | Female | Male |
| Genetic abnormality | 100 kb terminal 22q13 deletion including SHANK3, not maternal | r(22) (p11.2;q13), de novo | r(22) (p11.2;q13), 80% of lymphocytes studied showed r(22) | r(22) (p12;q13) | 46,XX,r(22).ish r(22)(p11q13)(TUPLE1+,10H11+,ARSA-)(47)/45,XX,-22(3) | r(22) |
| Cognitive deficit, language, and behavioral problems | Mild ID, speech delay, concentration difficulties at school required remedial education | ID, developmental regression after a febrile seizure at 18 m; speech regression (2-word sentences at 2 y to a few words at 5 y) | ID, nonverbal | ID, nonverbal | Severe ID, nonverbal | Severe ID, nonverbal. Long term residential care since the age of 10 y. |
| Age of onset of deterioration | ~25 y | 12 y | Teenage years | 12 y | 51 y | 23 y |
| Signs of decompensation, course of illness, and treatment |
At 14 y of age the patient was hospitalized due to an acute confusional state and diagnosed with epilepsy. During medication titration she had aggressive outbursts and her personality changed. In her twenties, the symptom severity progressed, and she exhibited loss of skills. By age 30, she showed features of autism spectrum disorder with lack of eye contact, stereotypic movements, and reduced expressive language. Her ability to perform daily living activities deteriorated and she also had balance problems, ataxic gait and urinary incontinence. |
At 12 y of age, the patient showed significant behavioral changes and no meaningful speech. He became destructive at home, breaking objects in the house during outbursts. Psychiatric evaluation was performed and he was diagnosed with bipolar disorder and treated. | The patient had a history of behavioral problems beginning in early childhood that led to increased aggression and hyperactivity as he became older. | At 12 y of age, the patient had an episode of status epilepticus followed by chronic seizures requiring antiepileptic therapy. Mental and physical decompensation ensued. He developed sensorimotor polyneuropathy demonstrated on nerve conduction and electromyographic studies. Brain MRI showed diffuse cerebral and cerebellar atrophy. Leukocyte arylsulfatase A (ARSA) levels were low, suggesting juvenile onset metachromatic leukodystrophy; however, molecular confirmation of ARSA deficiency was not done. |
The patient developed generalized seizures at 51 y (3 seizures per year). She had pronounced cyclical mood swings. At age 52 y, she had posturing suggestive of catatonia. CT revealed multiple intracranial meningiomas and cerebral atrophy. She was diagnosed with neurofibromatosis 2, related to her ring 22. As expected, mutation analysis of the NF2 gene in blood DNA was negative. There were no cutaneous signs of neurofibromatosis and no indication for surgical treatment. She developed status epilepticus and probable aspiration pneumonia, and died shortly after the diagnosis was established. |
The patient displayed cyclical changes in behavior with alternating mood shifts between mania and depression. Cycle duration varied and could occur in mixed state or change on a daily basis. During the manic phases he made noises, screamed and laughed inappropriately, was hyperactive, showed poor concentration especially while eating, and was unable to feed himself. He also had reduced need for sleep. During the depressed phases, he was lethargic, didn't eat properly, and exhibited motor retardation, apathy, and social avoidance. The intensity of symptoms worsened between age 23 y and age 35 y and his physical abilities also deteriorated. At 35 y, he was wheelchair bound. At this time, he was diagnosed with rapid cycling bipolar disorder. He had been initially treated with haloperidol with no benefit. Carbamazepine resulted in some improvement characterized by longer periods of cycling. This improvement was augmented by quetiapine but the effects were brief. Olanzapine was then used as an alternative but without benefit. Divalproex sodium eventually resulted in marked improvement. |
| Proposed diagnosis on review c | Unspecified catatonia | Bipolar disorder | Unspecified mood disorder | Metachromatic leukodystrophy | Bipolar disorder with catatonia, NF2 | Bipolar disorder with unspecified decompensation |
| Loss of skills d | + (L, M, A) | + (C) | + (M, A) | |||
| Other information | Brain CT scan at 14 y and MRI at 30 y both normal | Brain MRI at 18 months: prominent cisterna magna and mild cerebellar “atrophy”; at 12 y: giant cisterna magna and mild cerebellar “atrophy” (likely congenital cerebellar hypoplasia) | ||||
| Case | 13 | 14 | 15 | 16 | 17 | 18 |
| Reference | Durand et al. (2007) [2] | Durand et al. (2007) [2] | Gauthier et al. (2010) [28] | Gauthier et al. (2010) [28] | Gauthier et al. (2010) [28] | Gauthier et al. (2010) [28] |
| Subject | Family ASD 2 (eldest brother) | Family ASD 2 (youngest brother) | Family PED 419, subject II-1 (eldest brother) | Family PED 419, subject II-2 (middle brother) | Family PED 419, subject II-3 (youngest brother) | S00161 |
| Age when reported | 20 y | 20 y | NA | NA | NA | 23 y |
| Sex | Male | Male | Male | Male | Male | Female |
| Genetic abnormality | SHANK3 frameshift mutation (NM_033517.1:c.3679dupG, p.Ala1227Glyfs*69), de novo (germline mosaicism) | SHANK3 frameshift mutation (NM_033517.1:c.3679dupG, p.Ala1227Glyfs*69), de novo (germline mosaicism) | SHANK3 nonsense mutation (NM_033517.1:c.3349C>T, p.Arg1117*), de novo (germline mosaicism) | SHANK3 nonsense mutation (NM_033517.1:c.3349C>T, p.Arg1117*), de novo (germline mosaicism) | SHANK3 nonsense mutation (NM_033517.1:c.3349C>T, p.Arg1117*), de novo (germline mosaicism) | SHANK3 missense mutation (NM_033517.1:c.1606C>T, p.Arg536Trp) R536W, de novo |
| Cognitive deficit, language, and behavioral problems | ID, autism, language limited to some words and short sentences | Severe ID, autism, nonverbal | Borderline ID (IQ 72); graduated from high school in a special educational program for children with intellectual difficulties. No autistic features. | Mild ID, hyperactivity in childhood | Moderate ID (IQ 36); attended education institutions for children with intellectual deficits | Borderline ID (IQ 73), speech impairment, poor academic and social performance. No ASD traits. |
| Age of onset of deterioration | 20 y | 16 y | 19 y | 21 y | 16 y | 11 y |
| Signs of decompensation, course of illness, and treatment |
After moving to a new residential program at 20 y of age, aggressive outbursts began with significant loss of skills, including language and toileting. He also developed anorexia and marked weight loss. At 23 y, the patient had a seizure-induced aspiration, was hospitalized, and died within a few days. |
At 16 y of age, the patient had an episode of aspiration with loss of consciousness, which necessitated hospitalization. After moving to a new residential program at 16 y, loss of skills was noted in autonomy and toileting. He also developed weight loss. At 17 y of age, he developed epilepsy and was started on clonazepam. A second episode of aspiration occurred at the age of 20 y. Since then, he required a special diet with soft foods and no liquids. The patient died a few years later, after further behavioral decompensation. |
Diagnosed with schizoaffective disorder | Diagnosed with schizophrenia | Diagnosed with schizophrenia | Diagnosed with schizoaffective disorder |
| Proposed diagnosis on review c | Unspecified decompensation | Unspecified decompensation | Schizoaffective disorder | Schizophrenia | Schizophrenia | Schizoaffective disorder |
| Loss of skills d | + (L, A) | + (A) | ||||
| Other information | One seizure at age 10 y. | |||||
| Case | 19 | 20 | 21 | 22 | 23 | 24 |
| Reference | Pasini et al. (2010) [29] | Bonaglia et al. (2011) [3] | Bonaglia et al. (2011) [3] | Willemsen et al. (2011) [30] | Verhoeven et al. (2012) [31], Egger et al. (2016) [32] f | Verhoeven et al. (2012) [31], Egger et al. (2016) [32] g |
| Subject | − | Subject P10 | Subject P30 | Patient 7 | Patient 1 (younger brother) (Verhoeven), Patient 6 (Egger) | Patient 2 (older brother) (Verhoeven), Patient 5 (Egger) |
| Age when reported | 18 y | 40 y | 40 y | 48 y | 29 y | 31 y |
| Sex | Female | Female | Female | Male | Male | Male |
| Genetic abnormality | r(22) with 1 Mb duplication of 22q13.33 and 600 kb terminal 22q13.33 deletion, de novo | 8.1 Mb terminal 22q13 deletion, de novo | 3.4 Mb terminal 22q13 deletion | 1.8 Mb terminal 22q13 deletion | 2.15 Mb terminal 22q13 deletion, de novo (germline mosaicism) | 2.15 Mb terminal 22q13 deletion, de novo (germline mosaicism) |
| Cognitive deficit, language, and behavioral problems | Severe ID, language limited to a few words, autistic-like behavior | Severe ID, nonverbal. Lived in an institution for the cognitively impaired | Severe ID, poor speech | Severe ID, no speech, good social interaction | Severe ID, severe speech deficit (virtually absent speech, single words only), mild features of ASD including obsessive behaviors, sleep disturbances, hyperactive behaviors with temper tantrums | Severe ID, moderately impaired development of speech and language (poor articulation, simple sentences), good social interaction, episodes of aggressive behavior |
| Age of onset of deterioration | 17 y | 39 y | 39 y | 45 y | 17 y | 27 y |
| Signs of decompensation, course of illness, and treatment |
At the age of 17 y, the patient developed intense psychomotor agitation, severe anxiety, aggressive behavior, and insomnia. Her clinical course of illness was characterized by periods of mood cycling, hyperactivity, and self-injury. Treatment with both benzodiazepines and haloperidol was unsuccessful. Risperidone was titrated rapidly to 6 mg/d over a 2-week period and led to worsening anxiety, insomnia, and psychomotor agitation and the dose was reduced. Symptoms progressively improved at risperidone 0.5 mg twice daily. After 6 months of treatment, she showed no psychomotor agitation, aggressive behavior, anxiety, or insomnia. |
The patient had her first seizure at the age of 3 y, and the second at the age of 34 y. At 39 y, her seizures became more frequent and prolonged, despite antiepileptic treatment. Neurological evaluation at age 40 y showed spastic paraparesis, with upper limbs maintained in a flexed position and flexed knees. She also showed decreased sensitivity to pain and tactile stimuli. At age 43 y, she experienced rapid motor and cognitive decline and was no longer able to stand, walk, or make eye contact. The spastic tetraparesis also markedly increased. Right renal agenesis was diagnosed during a control abdominal ultrasound and the patient died at 47 y from renal failure while in a vegetative state. |
The patient had long standing epilepsy (onset at 5 y). She experienced a progressive neurological deterioration beginning at age 39 y, with cortical tremor. |
The patient's general functioning began to markedly decline after a hospital admission because of severe pneumonia complicated by respiratory insufficiency at 45 y of age. He was no longer able to walk, had feeding problems due to swallowing difficulties, and became dependent on tube feeding. His social interaction also diminished. He developed seizures. Brain MRI was normal, except for mild enlargement of the cisterna magna and central atrophy. By 48 y of age, he was wheelchair dependent and showed hypertonia with spastic posture of the hands and feet. The patient died from pneumonia at the age of 49 y. |
The patient presented at age 17 y with marked weight loss and behavioral changes, including loss of interest in daily activities, social withdrawal, and severe anxiety. Major depression was initially diagnosed and 2 years later, he began to show symptoms of disinhibited behavior, sleep disturbances, and compulsive rituals. Eventually irritability emerged in the context of major depression, in addition to ongoing loss of interest and marked sleep disturbance. Bipolar disorder was later diagnosed. Fluoxetine was initially started with the diagnosis of major depressive disorder but had to be stopped after 6 months because of behavioral side effects. Citalopram was later started due to worsening symptoms but it was replaced by divalproex sodium (900-1200 mg/d) in combination with haloperidol because of persistent psychomotor agitation. Despite treatment, symptoms persisted and citalopram was reintroduced without benefit. Eventually nortriptyline was added to divalproex sodium, which stabilized his mood and behavior for a period of 5 y. More recently, his treatment regimen included divalproex sodium (600 mg/d; level = 39 μg/ml) and quetiapine (800 mg/d) with stabilization of mood and behavior. |
The patient first presented at the age of 27 y with an unstable pattern of mood and activity with recurrent depressive episodes. He was diagnosed with atypical bipolar disorder and treated with carbamazepine (400 mg/d) and paroxetine (30 mg/d) with good effect. This regimen was eventually replaced by divalproex sodium (900 mg/d; level = 69 μg/ml) and quetiapine (150 mg/d), which resulted in marked improvement of functioning. |
| Proposed diagnosis on review c | Bipolar disorder | Progressive neurological disorder | Progressive neurological disorder | Progressive neurological disorder | Bipolar disorder | Bipolar disorder |
| Loss of skills d | + (M, C) | + (M) | ||||
| Other information | Macrocephaly (>97th centile), with normal height and weight (at age 40 y). | Brain MRI at 29 y: hypoplasia of the cerebellar vermis, enlarged cisterna magna, and mild enlargement of the lateral ventricles | Brain MRI at 31 y: hypoplasia of the cerebellar vermis, enlarged cisterna magna, and mild enlargement of the lateral ventricles | |||
| Case | 25 | 26 | 27 | 28 | 29 | 30 |
| Reference | Denayer et al. (2012) [11], Breckpot et al. (2016) [33] | Denayer et al. (2012) [11] | Denayer et al. (2012) [11] | Denayer et al. (2012) [11] | Vucurovic et al. (2012) [10] | Smith et al. (2012) [34] |
| Subject | Patient 4 (Denayer), Patient 2 (Breckpot) | Patient 5 | Patient 6 | Patient 7 | − | − |
| Age when reported | 25 y | 43 y | 46 y | 51 y | 18 y | 23 y |
| Sex | Female | Female | Male | Female | Male | Female |
| Genetic abnormality | 97 kb terminal 22q13 deletion including SHANK3, de novo | 1.7 Mb terminal 22q13 deletion | 1.2 Mb terminal 22q13 deletion | 3.4 Mb terminal 22q13 deletion | Translocation t(14;22) with 3 small microdeletions of the SHANK3 region and a 748 kb terminal 14q32.33 duplication. The 3 deletions occurred de novo. | 22q13.3 deletion syndrome (no details) |
| Cognitive deficit, language, and behavioral problems | Severe ID, single words, ASD | Severe ID, single words | Profound ID, no speech | Profound ID, no speech | Severe ID, poor language development, inattention, hyperactive and impulsive behavior, sleep disorder associating successive hypersomnia and insomnia periods. No autistic features. | Global developmental delay, nonverbal |
| Age of onset of deterioration | 19 y | 30 y | 16 y | ~22 y | 16 y | 18 y |
| Signs of decompensation, course of illness, and treatment |
Extreme cycling of mood and psychomotor activity, disruptive behavior, self-injury, echolalia and anxiety. The patient was diagnosed with bipolar disorder (with rapid cycling and psychotic features) at the age of 19 y. Later, symptoms of catatonia developed, in which the patient stopped moving and talking, and required tube feeding. Initial treatment with antipsychotics and benzodiazepines led to a poor response. Higher doses led to increases in body temperature and the fear of neuroleptic malignant syndrome, and neuroleptics were discontinued. Several days after discontinuation, the patient was hospitalized due to a sudden decrease in blood pressure with decreased consciousness that was thought to be due to excess benzodiazepines, but may have been a catatonic stupor, since it was followed by other signs of catatonia. Paroxetine was started. Afterwards, the patient exhibited more pronounced mood swings with fluctuating agitation, anxiety, loss of language and social skills, including no longer recognizing her mother; she stopped eating independently and lost continence. Paroxetine was stopped after her temperature rose and she became more restless. Lithium, divalproex sodium, and carbamazepine led to partial response but continued symptoms. After the diagnosis of catatonia was established, the patient was treated with lorazepam, and a few years later with ECT. Psychiatric symptoms are currently under control. |
Bipolar disorder with progressive loss of skills |
Mood cycling with irritability, and sleep disturbance. Bipolar disorder was diagnosed at 16 y. At 27 y of age, the patient was hospitalized in the intensive care unit due to neuroleptic malignant syndrome during a manic episode treated with high doses of haloperidol. After this hospitalization, the patient lost the ability to walk or eat independently, requiring extensive rehabilitation. At 40 y, he was hospitalized for septic shock due to aspiration pneumonia. He subsequently again lost skills of ambulation, language, eating independently, toileting, and dressing. These skills have not returned and the patient is currently spastic and wheelchair-bound despite ongoing treatment with divalproex sodium. |
Diagnosed with bipolar disorder at 22 y. Experienced status epilepticus at 45 y of age and subsequently became totally dependent and bedridden. |
At the age of 10 y, the patient had an episode of psychomotor agitation with insomnia lasting 3 days. At around the age of 16 y, he displayed depressive mood and social isolation. Antidepressant treatment was started and within 2 months, he became increasingly agitated with insomnia, impulsivity, and aggression. Inpatient psychiatric hospitalization was required, where he was found to be euphoric, disinhibited, with decreased need for sleep, psychomotor agitation, anorexia with weight loss, and poor attention span with concentration difficulties. His mood would also rapidly shift to depression and he was diagnosed with bipolar disorder. He developed stereotyped behavior with regression of expressive speech and lost bladder control at the age of 17. Early-onset dementia was hypothesized. Antidepressant treatment exacerbated psychomotor agitation. Carbamazepine and aripiprazole stabilized his mood changes and improved attention and concentration. Motor hyperactivity persisted. |
New onset irritability, aggressive behaviors, and periodic catatonia (every 6-8 weeks) developed at the age of 18 y. Treatment with lorazepam was reportedly beneficial. ECT had been tried in the past without success. |
| Proposed diagnosis on review c | Bipolar disorder with catatonia | Bipolar disorder | Bipolar disorder, likely brain insult secondary to septic shock | Bipolar disorder, brain insult secondary to status epilepticus or underlying cause of status epilepticus | Bipolar disorder | Unspecified catatonia |
| Loss of skills d | + (L, A) | + | + (L, M, A) | + (M, A) | + (L, A) | |
| Other information | Brain MRI at 9 y and CT at 19 y were normal | Brain CT at 19, 25 and 41 y: corticosubcortical atrophy | Brain CT at 19 and 30 y: normal; at 40 y: basal ganglia infarctions | Brain CT at 43 y: mild corticosubcortical atrophy | Normal brain MRI at 16 y. Analysis of cerebrospinal fluid revealed a slight decrease in amyloid beta, low total tau and normal phosphorylated tau protein. | |
| Case | 31 | 32 | 33 | 34 | 35 | 36 |
| Reference | Verhoeven et al. (2013) [12] | Messias et al. (2013) [35], McKelvey et al. (2018) [36] | Soorya et al. (2013) [17] | Leblond et al. (2014) [7] | Guilherme et al. (2014) [37] | Serret et al. (2015) [38] |
| Subject | − | − | SH25 | AUN_002 | Patient 5 | Case 1 |
| Age when reported | 70 y | 41 y | 45 y | NA | 15 y | 21 y |
| Sex | Female | Female | Male | Male | Male | Male |
| Genetic abnormality | 611 kb terminal 22q13 deletion | r(22) with a terminal 22q13.32q13.33 deletion | 4.4 Mb terminal 22q13 deletion, de novo | SHANK3 frameshift mutation (NM_033517.1:c.4014_4015delAG, p.Gly1339Glufs*5), not maternal | 46,XY,r(22)(p13q13.33) with 154 kb terminal deletion, de novo | SHANK3 frameshift mutation (NM_033517.1:c.3605_3608delCCCT, p.Ser1202Cysfs*81), de novo |
| Cognitive deficit, language, and behavioral problems | Severe ID, severe language delay with monosyllabic word sentences, and behavioral problems | Moderate ID, verbal, friendly | ID, ASD, aggression | Severe ID, nonverbal, ASD | Development was unremarkable until the age of 2 y, when he presented diminished speech and social interaction. Autism | Severe ID, ASD, limited language (uses short sentences to make requests, echolalia, stereotypic language). He enjoyed sports, particularly biking. |
| Age of onset of deterioration | Twenties h | 32 y | 17 y | NA | 15 y | 13 y |
| Signs of decompensation, course of illness, and treatment |
Challenging, negativistic behaviors intensified over several years and necessitated institutionalization at the age of 19. During her 20s, speech became mainly incomprehensible. Mood cycling, disinhibited behaviors, and sleep disturbances markedly increased. During this period, the patient underwent several surgical corrections for painful cramping and abnormal posturing of the hands (neuroleptic-induced tardive dystonia). Over the following 3 decades, episodes of psychomotor agitation and sleep disturbances persisted. In addition, there were recurrent gastro-intestinal complaints for which no underlying cause could be found. Over subsequent years, her behavioral presentation remained mainly unchanged, although there were several periods during which inactivity was more prominent. At the age of 64 y, the patient developed mania with anxiety and agitated behavior and treatment was initiated. Despite treatment, her condition gradually deteriorated over a period of 5 y. The diagnosis of bipolar disorder was established. Treatment was started with divalproex sodium, and later replaced by carbamazepine. One year later, lithium was added. Maintenance treatment included lithium carbonate (800 mg/d; level = 0.7 mmol/l) and carbamazepine (1,000 mg/d; level = 7.1 mg/l), as well as pipamperone (40 mg tid). Due to ongoing symptoms, lithium was gradually tapered off, and staff members utilized behavioral strategies with the patient, which resulted in improvement of behavior and sleep. Carbamazepine was then reduced to 600 mg/d with pipamperone (40 mg tid) as maintenance therapy. |
Mood and behavior were stable until her first psychiatric hospitalization at the age 32 y, when she began having cyclic episodes of mood dysregulation and loss of skills, including bathing, dressing, and feeding. The episodes lasted for periods of weeks, during which she became nonverbal, confused, detached, and incontinent. She often stared at her hands, at times shaking or screaming, and refused to eat. Symptoms responded poorly to SSRI or benzodiazepine monotherapy, but relatively quickly to quetiapine (300 mg twice daily), with significant improvements in affect, speech, and level of independence. Psychotic symptoms resolved and there was normalization of her sleep/wake cycle. However, cyclical episodes of depression and catatonia persisted, eventually requiring hospitalization. After admission for prolonged catatonia at age 41, a brain MRI revealed bilateral acoustic neuromas and multiple intracranial meningiomas, consistent with neurofibromatosis type 2 (related to ring 22). She had no additional physical findings of NF2. Neurosurgery was not deemed necessary. After multiple subsequent pharmacological treatments failed, she was treated with ECT with significant improvement in mood. The patient is currently stable on lithium and citalopram. She has stable mild sensorineural hearing loss, no seizure activity and no change in her tumors on annual monitoring with MRI. |
Loss of language and toileting skills after being placed in a residential program. | The patient began experiencing generalized tonic-clonic seizures at 8 y, which were resistant to treatment. Regression was reported late in life (no other information available), in addition to ataxia and dysmetria. | New onset aggression after he started having seizures at the age of 15 y. Seizures were controlled with carbamazepine; aggressive behavior was treated with haloperidol and risperidone. |
After moving from an autism day-care center to an autism unit at 13 y, the patient showed progressively reduced motor, verbal, and daily living skills. He stopped his favorite activities and became behaviorally dysregulated, with increased impulsivity, negativistic behavior, and apathy. Sleep disturbance with insomnia appeared. At age 15 y, the patient required hospitalization in a child and adolescent psychiatric unit. The patient received different psychotropic medications that were partially effective but accompanied by multiple side effects. Antipsychotics were able to control aggressive behaviors and insomnia, but induced catatonia and elevated muscle enzymes. Benzodiazepines reduced catatonia symptoms but didn't control impulsivity, and increased psychomotor agitation, confusion, and insomnia. Mood stabilizers had no clinical efficacy and induced side effects, such as DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) with carbamazepine. Antidepressants were not effective. Among multiple drug associations, only the combination of aripiprazole and clonazepam showed partial efficacy, facilitating the improvement in daily living, language, and motor skills for about 12 months, but with no impact on behavior. Methylphenidate was not effective and induced insomnia, violence and shouting. Lithium was initially introduced in association with other psychotropic medications (e.g., methylphenidate) and for a short period (<2 months), without clear clinical effects. At age 19, there was no significant improvement, and the diagnosis of bipolar disorder was suspected. Lithium (1500 mg/d) and melatonin (4 mg/d) led to symptom stabilization over 3 months. Agitation, aggressiveness and impulsivity disappeared. The patient regained autonomy in everyday life, and urinary and bowel incontinence stopped. He no longer showed opposition, participated in activities with other patients, and began riding his bicycle again. As he no longer had sleep disturbances, melatonin was discontinued after 3 months. One year after the beginning of lithium therapy, the patient moved to an adult group home and had recovered his baseline level of functioning. At a follow-up of 2 y, he remained stable on lithium (1500 mg/d; level = 0.8 mEq/l). |
| Proposed diagnosis on review c | Bipolar disorder with catatonia | Bipolar disorder with catatonia, NF2 | Unspecified decompensation | Likely neurological disorder | Unspecified decompensation | Bipolar disorder with catatonia |
| Loss of skills d | + (L) | + (L, A) | + (L, A) | + (M) | + (L, M, A) | |
| Other information | Brain MRI at 70 y: cortical atrophy, particularly in the frontal region, and subtle periventricular white matter changes | Normal head CT | Normal brain MRI and EEG | |||
| Case | 37 | 38 | 39 | 40 | 41 | 42 |
| Reference | Serret et al. (2015) [38] i | Egger et al. (2016) [32] | Egger et al. (2016) [32] | Egger et al. (2016) [32] | Egger et al. (2016) [32] | Egger et al. (2016) [32] |
| Subject | Case 2 | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 7 |
| Age when reported | 17 y | 44 y | 22 y | 33 y | 23 y | 21 y |
| Sex | Female | Male | Female | Female | Female | Female |
| Genetic abnormality | SHANK3 nonsense mutation (NM_033517.1:c.2425G>T, p.Glu809*), de novo | 63 kb 22q13.33 deletion including SHANK3 | Unbalanced translocation 11;22 with derivative chromosome 22, 11q24.2q25 duplication of 8.77 Mb and terminal 22q13.33 deletion of 512 kb | 1.98 Mb 22q13.32q13.33 deletion | Unbalanced translocation 8;22 with terminal 22q13.33 deletion, de novo | 88 kb 22q13.33 deletion including SHANK3 |
| Cognitive deficit, language, and behavioral problems | Severe ID, ASD. She presented echolalia and stereotypic language with words and short sentences used in everyday life and in context. She enjoyed sports, especially rock climbing and gymnastics. | Profound ID, virtually absent speech, single words only | Mild to moderate ID, limited speech and receptive language, ritualistic/compulsive behaviors, sleep disturbances. Attended special education until the age of 18 y. | Mild to moderate ID, poor articulation, simple sentences | Profound ID, absent speech | Mild to moderate ID, elementary sentences |
| Age of onset of deterioration | 12 y | Late adolescence j | Late adolescence | Late adolescence j | Late adolescence j | Late adolescence j |
| Signs of decompensation, course of illness, and treatment |
Major clinical changes were observed after the patient left her day-care center for an autism unit at age 12. She exhibited behavioral dysregulation, lost toileting skills, and slowly lost motor and verbal skills. She developed impulsive and aggressive behaviors. Her posture became hunched and she remained frequently motionless, needing physical stimulation in order to move. This was followed by further deterioration of skills, incontinence and insomnia. By age 16 y, the diagnosis of catatonia-like symptoms was considered and treatment with clonazepam (0.9 mg/d) was started. The patient rapidly improved and in a few months regained motor abilities, normal body posture, language, participation in activities, and autonomy. Sleep disturbances and fecal incontinence stopped but nocturnal enuresis persisted. These improvements continued for about 8 months. However, psychomotor agitation and increased verbal output progressively increased. She lost weight while continuing to eat normally (lost 8 kg in 8 months), so clonazepam was progressively tapered. During the next 4 months, she regained weight, but then regressed again by losing motor and verbal skills. She presented once again with catatonia-like symptoms including aggressiveness and insomnia. Clonazepam (0.9 mg/d) was reintroduced but led to psychomotor agitation, increased verbal output, impulsivity, and insomnia, necessitating psychiatric hospitalization. Clonazepam was switched to lorazepam (3 mg/d), complicated by confusion, fecal incontinence, agitation and insomnia. By age 17 y, the diagnosis of bipolar disorder was established and lithium (1000 mg/d; level = 0.7 mEq/l) was started with clonazepam (0.2 mg/d). The behavioral symptoms stabilized and she exhibited improved verbal and motor abilities, participation, sleep and autonomy. However, nocturnal enuresis persisted. Clonazepam was discontinued after 4 months. After 1 year of lithium treatment, the behavioral dysregulation stabilized and the patient returned to her baseline level of functioning, without adverse effects. |
Diagnosed with bipolar disorder. Treatment with pipamperone (120 mg/d), lamotrigine (350 mg/d), and levothyroxine (125 μg/d) resulted in marked stabilization of mood and behavior. |
Beginning in late adolescence, the patient had recurrent mood changes paralleled by an increase of pre-existing autistic behaviors. Treatment with paroxetine resulted in behavioral deterioration with possible hallucinations. On addition of haloperidol, later replaced by risperidone, the patient developed a serotonin syndrome for which she was hospitalized. Discontinuation of all psychotropic medication and symptomatic treatment resulted in a rapid remission of symptoms and she was discharged to her parent’s home. A urinary tract infection diagnosed during the hospitalization was thought to have contributed to her initial deterioration of behavior. Because her general functioning did not reach baseline levels she was referred for evaluation and diagnosed with bipolar disorder. Treatment with divalproex sodium was started. After 6 months, a dose of 600 mg/d (level = 45 μg/ml) resulted in notable stabilization of mood and behavior, although baseline levels of function were still not fully attained and the addition of quetiapine is being considered. |
Diagnosed with bipolar disorder. Treatment with divalproex sodium (600 mg/d) and quetiapine (300 mg/d) resulted in marked improvement of functioning. |
Diagnosed with bipolar disorder |
Diagnosed with bipolar disorder. Treatment with quetiapine (1000 mg/d) resulted in marked improvement of functioning. |
| Proposed diagnosis on review c | Bipolar disorder with catatonia | Bipolar disorder | Bipolar disorder | Bipolar disorder | Bipolar disorder | Bipolar disorder |
| Loss of skills d | + (L, M, A) | |||||
| Other information | Brain MRI, EEG and biological analyses performed at the time of regression were normal | Normal brain MRI at age 22 y | Brain MRI: Hypoplasia of cerebellar vermis and mild ventricular enlargement | |||
| Case | 43 | 44 | 45 | 46 | 47 | 48 |
| Reference | Breckpot et al. (2016) [33] | Fokstuen et al. (2016) [39] | Egger et al. (2017) [40] | Tabet et al. (2017) [41] | Tabet et al. (2017) [41] | Tabet et al. (2017) [41] |
| Subject | Patient 1 | − | − | P3 | P9 | P11 |
| Age when reported | 46 y | NA | 43 y | 16 y | 27 y | 37 y |
| Sex | Female | NA | Male | Female k | Female | Female |
| Genetic abnormality | 97 kb 22q13.33 deletion including SHANK3, de novo | SHANK3 frameshift mutation (NM_033517.1:c.3637dupC, p.His1213Profs*83) | SHANK3 frameshift mutation (NM_033517.1:c.4523delC, p.Thr1508Serfs*36) | 22q13.33 deletion diagnosed by FISH, de novo | Unbalanced translocation t(2;22) with 5.07 Mb terminal 22q13 deletion, paternally derived | 716 kb 22q13 terminal deletion, de novo |
| Cognitive deficit, language, and behavioral problems | Profound ID, autistic behavior | ID, mutism | Severe ID, limited verbal skills, ASD; destructive, self-injurious and withdrawal behaviors during childhood | ID, non verbal (language regression at 18 m), autistic traits | ID, non verbal, oppositional defiant disorder | ID, speech delay, no autistic traits |
| Age of onset of deterioration | 20 y j | NA | ~16 y | 22 y | 17 y | NA |
| Signs of decompensation, course of illness, and treatment |
Diagnosed with unspecified psychosis and catatonia. Inpatient in an adult psychiatric unit. The first signs of severe regression started around the age of 20 y. The first catatonic episode was treated with lorazepam, the second with ECT, with good response. Although ECT resulted in remission of the catatonic symptoms, the psychotic symptoms remain, with inconsistent response to psychopharmacological treatment. |
Unspecified psychotic symptoms |
After being institutionalized at age 9 y, the patient‘s general functioning remained relatively adequate over the following years. Subsequent to an institutional reorganization, his behavior decompensated with loss of language, motor functioning, and continence. At 16 y, there was severe mood and behavior dysregulation with sleep disturbance and anxiety. Over the following decade, the patient had sustained sleep disturbance and alternating episodes of apathy, impulsivity, food refusal and weight loss. Bipolar disorder (with rapid cycling features) was suspected. Several psychotropic medications were tried with equivocal results and poor tolerability. At 24 y, treatment with carbamazepine and divalproex sodium was prescribed with limited benefit. Lamotrigine and olanzapine were reported to induce tardive dyskinesia. Olanzapine was replaced by clozapine, which induced severe constipation, recurrent seizures, and agranulocytosis. Treatment was then restricted to clorazepate. At age 42 y, olanzapine, divalproex sodium, and lamotrigine were started, but the instability persisted, with intermittent aggressive and apathetic episodes. After the diagnosis of PMS due to a SHANK3 mutation was established at age 44 y, lithium was started and titrated to 700 mg/d (level = 0.5 μg/ml) in addition to olanzapine (10 mg/d). Over the course of several months, lithium resulted in marked stabilization of mood and behavior. |
Severe hyperactivity and lack of sleep with subsequent loss of skills, particularly speech at the age of 22 y. | Severe status epilepticus at age 17 y despite treatment with antiepileptic medication, leading to loss of cognitive skills, loss of visual acuity, and loss of locomotion. | Diagnosed with bipolar disorder and perceptual disturbances (hallucinations). |
| Proposed diagnosis on review c | Unspecified psychotic disorder with catatonia | Unspecified psychotic disorder | Bipolar disorder | Unspecified decompensation | Unspecified decompensation | Bipolar disorder |
| Loss of skills d | + | + (L, M, A) | + (L) | + (M, C) | ||
| Other information | Cerebral and cerebellar atrophy; postoperative seizure | Brain MRI at 42 y: discrete loss of cerebral tissue predominantly in the left hemisphere with enlarged sulci. | ||||
| Case | 49 | 50 | 51 | 52 | 53 | 54 |
| Reference | Tabet et al. (2017) [41] | Ballesteros et al. (2017) [42] | Lyons-Warren et al. (2017) [43] | De Rubeis et al. (2018) [4] | De Rubeis et al. (2018) [4] | De Rubeis et al. (2018) [4] |
| Subject | P83 | − | − | S12 | B2 (MZ twin) | B3 (MZ twin) |
| Age when reported | 23 y | 13 y | 16 y | 42 y | 14 y | 14 y |
| Sex | Male | Female | Female | Female | Female | Female |
| Genetic abnormality | 619 kb 22q13 terminal deletion, de novo | 2.7 Mb 22q13 terminal deletion l | r(22) with 1.036 Mb terminal 22q13 deletion | SHANK3 frameshift mutation (NM_033517.1: c.4906_4921dupTCCCCCTCGCCGTCGC, p.Pro1641Leufs*58), de novo | SHANK3 frameshift mutation (NM_033517.1: c.4065_4066delTG, p.Val1357Glyfs*4), de novo | SHANK3 frameshift mutation (NM_033517.1: c.4065_4066delTG, p.Val1357Glyfs*4), de novo |
| Cognitive deficit, language, and behavioral problems | ID, speech delay, ASD, ADHD, aggressive behavior | ID, ASD | ID, ASD; as a child, loss of previously mastered vocabulary | Profound ID, verbally fluent until age 12-13 y | Mild ID, speaks in full sentences but developed word finding difficulties. No ASD. Aggression. | Mild ID. Spoke in full sentences but regressed at 9 y to only say 2-3 words, regained some vocabulary but fluctuating language. No ASD. Aggression. |
| Age of onset of deterioration | 20 y | 11 y | 16 y | 12-13 y | 13 y | 9-10 y |
| Signs of decompensation, course of illness, and treatment | Loss of cognitive skills with worsening social communication impairment and increased stereotyped behaviors at 20 y. |
Behavioral dysregulation with catatonic features and regression at age 11 y that required psychiatric hospitalization. Different pharmacological treatments, such as antipsychotics and benzodiazepines, failed to improve symptoms and led to multiple adverse events. Lithium therapy stabilized behavioral symptoms and allowed the patient to recover her baseline level of functioning. After the first menstruation there was cycling through periods; risperidone was suggested as adjunctive therapy but the patient later stabilized with lithium monotherapy. |
Symptoms began at age 16 y with a personality change and subsequent episodes of unprovoked anger. The patient developed painless growths on both arms. Brain MRI revealed bilateral vestibular and spinal schwannomas (which had not been observed when MRI was performed at 8 y), consistent with a diagnosis of neurofibromatosis type 2 (related to ring 22). EEG revealed an epileptogenic focus over the left temporal region. The patient subsequently had 1 episode of suspected seizure. She was treated with bevacizumab with significant improvement in her mood. |
Intermittent periods of behavioral dysregulation with loss of cognitive, motor and language skills. Sometimes preceded by viral infection. Cognitive ability declined from borderline intellectual functioning before puberty to profound ID at age 42. The patient was verbally fluent but became non-verbal. She was walking independently at 20 months but currently is unable to walk more than several steps without support. Psychotic symptoms were reported and characterized by auditory and visual hallucinations. She had episodic periods of mania and depression, insomnia, decreased appetite and weight loss, unsteady gait, and catatonic posturing. |
“Manic like” behavior | “Manic like” behavior |
| Proposed diagnosis on review c | Unspecified decompensation | Bipolar disorder with catatonia | Unspecified decompensation, NF2 | Bipolar disorder with catatonia | Unspecified mood disorder | Unspecified mood disorder |
| Loss of skills d | + (L, C) | + | + (L, M, C) | |||
| Other information | Normal brain MRI at 14 y and 18 y. Macrocephaly (OFC 57 cm, 99th centile), with normal height and weight (at age 42 y). | Brain MRI at 14 y: mild cerebellar tonsillar ectopia. Atypical absence seizures, onset at 14 y. Episode of idiopathic intracranial hypertension at 12 y. Normal OFC (30th centile) at 14 y. | Normal brain MRI at 14 y. Atypical absence and tonic seizures, onset at 7 y. Macrocephaly (OFC 57 cm, 98th centile) at 14 y. | |||
| Case | 55 | 56 | ||||
| Reference | Kildahl et al. (2018) [44] | Jungová et al. (2018) [45] | ||||
| Subject | − | − | ||||
| Age when reported | 22 y | 30 y | ||||
| Sex | Male | Female | ||||
| Genetic abnormality | 30 kb interstitial deletion extending from SHANK3 to ACR | 54 kb deletion partially overlapping SHANK3, de novo | ||||
| Cognitive deficit, language, and behavioral problems | Severe ID, ASD, language limited to simple phrases | Mild speech delay, spoke in full sentences; no autistic traits. Because of low grades in primary school, she was transferred to a special-needs school at the age of 10 y. IQ 60 at 15 y. After finishing school she had a part-time job as a manual worker. | ||||
| Age of onset of deterioration | Late teens | 23 y | ||||
| Signs of decompensation, course of illness, and treatment |
Behavioral changes observed during the late teens, with a cyclical pattern of increased motor activity alternating with periods of decreased activity. At 22 y, the patient was hospitalized and received the diagnoses of ID, ASD, and bipolar disorder. Several treatments were initially attempted without success, including olanzapine, levopromazine for agitation, alimethazine for sleep, and mirtazapine for depression. At the time he received the diagnosis of bipolar disorder, divalproex sodium treatment was initiated. The patient became more calm and exhibited increased social interaction. Although episodes of psychomotor agitation continued, they were less severe and his mood was more stable. The patient also now receives more adapted care, particularly regarding his underlying ASD symptoms. |
The patient was hospitalized at 23 y because of an acute psychotic episode with agitation and insomnia during a respiratory infection with fever (38.5°C). She was treated with olanzapine, benzodiazepine, and maprotiline, and discharged 3 weeks later with full recovery. From the age of 25, she had intermittent loss of bladder control, memory impairment, inattention, partial loss of independence, easy fatigability, and loss of language skills - screaming meaningless words and repeating the same sentences. These behavioral changes were triggered by mild febrile episodes (37–38°C); they occurred initially 3-4 times per year, and later around once a month. The fever was sometimes associated with mild pharyngitis but other times the cause was unclear. No depressive symptoms were observed. Maprotiline was suspended for possible side effects, olanzapine was continued with good effect but was later replaced by quetiapine due to excessive weight gain. Between the ages of 27 and 30 y, the patient was admitted to the hospital 5 times for severe episodes, diagnosed as either psychotic disorder or bipolar disorder. The episodes began with insomnia and incoherence soon after the onset of fever. Examination also revealed pychomotor agitation, instability, mutism (little to no verbal response), screaming, “delusions,” and “intermittent spastic paraparesis of the upper left extremity.” These episodes continued after the fever subsided and lasted 1-3 weeks. Treatment with divalproex sodium, chlorprothixene and benzodiazepine was effective for remission of psychosis, mood, and behavior dysregulation. After recovery, she returned to her previous level of functioning, except after the fifth hospitalization. This episode was the most severe; she was unable to understand instructions, displayed rigidity, catatonia, and had to be catheterized due to urinary retention. After discharge, her cognitive and verbal abilities worsened, and she now requires instructions from her parents to perform basic activities. |
||||
| Proposed diagnosis on review c | Bipolar disorder | Bipolar disorder with catatonia | ||||
| Loss of skills d | + (L, A, C) | |||||
| Other information | Extensive medical investigations over the years were non contributory. Brain MRI showed incipient cortical atrophy. |
ADHD attention deficit hyperactivity disorder, ASD autism spectrum disorder, CT computed tomography, ECT electroconvulsive therapy, EEG electroencephalography, ID intellectual disability, kb kilobase, Mb megabase, MZ monozygotic, MRI magnetic resonance imaging, NA not available, NF2 neurofibromatosis type 2, OFC occipito-frontal circumference, PMS Phelan-McDermid syndrome, r(22) ring chromosome 22, SSRI selective serotonin reuptake inhibitor, tid 3 times a day, y years
aPatient initially described by Richards et al. [46]
bPatient initially reported by Kondo et al. [47] (Case 5)
cThe diagnosis reported in the publication is mentioned above, in ‘Signs of decompensation, course of illness, and treatment’, when available.
dLoss of skills: L=language, M=motor, A=activities of daily living, C=cognitive
ePatient also reported very briefly in a study of subtelomeric rearrangements [48]
fSubject also reported by Willemsen et al. [30] (Patient 9)
gSubject also reported by Willemsen et al. [30] (Patient 8)
hNeuropsychiatric decompensation was reported to have occurred during the “second decade” in the original article; when contacted, the authors stated that it occurred during her twenties.
iPatient also reported by Leblond et al. [7] (AUN-003) and Darville et al. [49] (Patient 1)
jInformation provided by author
kPatient listed as male in Table S2 but referred to as ‘her/she’ in the clinical description in the supplement
lPatient was mistakenly reported to have a mutation in SHANK3; she has a 22q13 terminal deletion