Potential for treatment of severe autism in tuberous sclerosis complex

Table 1 Criteria for clinical diagnosis of tuberous sclerosis complex

Major features	Minor features
Cortical tubers	Dental enamel pits
Subependymal nodules	Hamartomatous rectal polyps
Subependymal giant cell astrocytoma	Bone cysts
Hypomelanotic macules (3 or more)	Cerebral white matter radial migration lines
Shagreen patch	Gingival fibromas
Facial angiofibromas or forehead plaque	Nonrenal hamartoma
Multiple renal nodular hamartomas	Retinal achromatic patches
Nontraumatic ungual or periungual fibromas	“Confetti” skin lesions
Cardiac rhabdomyoma, 1 or >	Multiple renal cysts
Pulmonary Lymphangiomyomatosis and/or renal angiomyolipomas

Tuberous sclerosis complex (TSC) can be clinically diagnosed as definite, probable, or possible based on the presence or absence of a specific combination of major and minor features. Definite TSC: two major features or one major and two minor features; Probable TSC: one major and one minor feature; Possible TSC: one major feature or two or more minor features.

Table 2 Prevalence studies for autism in tuberous sclerosis complex

Instrument	Administration method(time)	Children with severe or profound ID included (Y/N)	Measured prevalence of autism in TSC (N)	Ref.
ADOS	Observation schedule (20-30 min)	N	29% (28) +ADI	[18]
			15-33% (4 age-based groups of 12-15)
ADI	Structured Interview (2-3 h)	Y-severe	54% (13)	[15,16]
			20% (20)
SRS	65-item Screening Questionnaire (15-20 min)	N (37 w/IQ data)	52% (21)	[22]
SCQ	40-item Screening Questionnaire (15-20 min)	Y-severe	43% (21)	[22]
Hunt and Dennis Questionnaire	321 item interview/13-item subset for autism (1-4 h)	Y-estimates only	50% (90)	[2,9,14,23]
			26% (23)
			24% (21)
			5% (131)
DSM III-R	Checklist (10-20 min)	Y-severe	61% (28)	[3]

These are reviewed studies reporting epidemiology of autism in tuberous sclerosis complex (TSC). ADI: Autism diagnostic interview; DSM: Diagnostic and statistical manual of mental disorders; ADOS: Autism diagnostic observation schedule; SRS: Social responsiveness scale; SCQ: Social communication questionnaire; Y: Yes; N: No.

Table 3 Selected preclinical models of tuberous sclerosis complex

Model	Genetic manipulation	Behavioral effects	Seizures	Autism	Synaptic plasticity	Neuropathology	Rapamycin	Ref.
Tsc1+/- mice	Heterozygous Tsc1 deletion, exons 6-8	↓Hippocampal dependent learning	None	↓Social interaction	-	None	-	[58]
Tsc2+/- Eker rat	Spontaneous autosomal dominant (Heterozygous)	-	-	-	↓LTP, ↓LTD, ↑PPF	-	-	[61]
Tsc2+/- Eker rat	Spontaneous autosomal dominant (Heterozygous)	No learning and memory deficits	No spontaneous	↓Social interaction, ↓↓ after seizure induction	-	-	-	[59]
Tsc2+/-	Heterozygous disruption in second exon	↓Hippocampal dependent learning	-	-	↓Threshold for L-LTP	-	Reversed all	[93]
Tsc2+/- or WT pups from Tsc2+/- or WT dams	Heterozygous Tsc2 deletion	↑Maternal care by Tsc2+/- dams	-	↑Vocalization in WT and Tsc2+/- pups of Tsc2+/- dams	-	-	-	[60]
Tsc2+/-	Heterozygous Tsc2 deletion	-	-	-	↓mGluR-LTD,	-	Reverses deficits in protein-synthesis-dependent mGluR-LTD	[62]
					↓Arc synthesis
Tsc1fl/flNestin-rtTA(+)TetOp-cre(+)	Mosaic homozygous Tsc1 deletion in cortical neural progenitors	-	Yes+	-	-	Heterotopias with enlarged, pS6+ neurons	↑Survival, ↓seizures, ↓neuropath	[94]
						White matter nodules
Tsc1fl/-Syn1-Cre	Homozygous Tsc1 deletion in neurons from mid-gestation; (heterozygous in all other cells)	-	Yes+	-	-	Dysplastic neurons	↑Survival, ↑myelination, ↑body weight, ↓neurologic impairment	[95,96]
						↓Cortical organization
						↓Myelin
Tsc1fl/fl Emx1-Cre	Homozygous Tsc1 deletion in early embryonic neural progenitors	-	Yes+	-	-	↓Cortical organization	↓Seizures, ↑survival, ↓glial abnl, ↑weight, ↓brain size	[97]
						↑Brain size
						↓Myelin
						tHick astrocyte processes
Tsc1fl/fl Nestin-Cre	Homozygous Tsc1 deletion in differentiating neurons	-	-	-	↑EPSCs	↑Cell size	↓Spine width ↑spine length	[98]
					↑AMPA	↑Spine width
						↑Spine length
						↓Spine density
Tsc1fl/fl Syn1-Cre	Homozygous Tsc1 deletion in neurons	-	No spontaneous	-	↑EPSCs	No gross abnormalities	-	[99]
			Epileptiform discharges		↑AMPA
Tsc1fl/fl GFAP-Cre	Homozygous Tsc1 inactivation in glial-fibrillary acidic protein (GFAP)-+ cells		Yes+, ↓Glt1			↑Astrocytes	↑Glt1, ↑survival ↓neuropath Early: prevented epilepsy, Late: decreased seizure frequency	[100,101]
						↑Brain size
						↓Hippocampal organization
Tsc2fl/fl GFAP-Cre	Homozygous Tsc2 inactivation in GFAP + cells	-	Yes++, ↓Glt1	-	-	↑Astrocytes	↑Survival, ↓seizures, ↓neuropath	[102]
						↑Brain size
						↓Hippocampal organization
Tsc1fl/+L7-Cre, or Tsc1fl/flL7-Cre	Heterozygous or homozygous Tsc1 deletion limited to cerebellar Purkinje cells	Normal acquisition, ↓reversal of spatial learning in homozygous mutants	-	↓social interaction in both genotypes ↑grooming, vocalization	PC ↓excitability in heterozygous, ↓↓ in homozygous	PC loss in homozygous, ↑PC dendritic spine density in both heterozygous and homozygous	Reversed pathological and behavioral abnormalities	[64]
Tsc2fl/- , or Tsc2fl/-Pcp2-Cre	Heterozygous Tsc2 deletion (global), or homozygous Tsc2 deletion in cerebellar Purkinje cells, heterozygous in other cells	-	-	↑repetitive behavior in homozygous, ↓social interaction in both genotypes	-	PC loss in homozygous,	Reversed social deficits	[63]

These are existing preclinical models designed to re-capitulate neurologic features of tuberous sclerosis complex (TSC). - Not examined; +: Mild seizure severity; ++: Moderate seizure severity.