How good is Cincinnati Children’s Hospital at using Precision Medicine to treat kids with autism + ID ?

 

Cincinnati Children’s cares for patients and families from all 50 US states and dozens of other countries each year – including children with complex or rare disorders.

So, how good is Cincinnati Children’s Hospital at using precision medicine to treat kids with for autism + ID ?

Spoiler alert, I will leave you to answer the above question. It is up to you to decide!

I will give them 10 out 10 for at least trying to use genetic testing to improve the outcomes.

I was very surprised to find a paper with case studies showing how the clinicians tried to use mutations in autism/ID genes to develop a matching therapy.

If you are interested you can use your skills to see what kind of precision medicine you would have tried.

One of the children does have Glass syndrome (SATB2), which our reader Ling is interested in. I hoped they would do something clever, in fact what they did was find a fracture in his foot. Low bone density is a feature of this syndrome and an undiagnosed fracture in your foot is going to hurt and can trigger self-injurious behavior.

There is even a Pitt Hopkins kid, there is plenty in this blog about that syndrome.

The idea of the paper was to show that running WES/WGS on their residential kids with autism + ID resulted in better care and so reduced nights per year in the hospital.

The case studies are the interesting part. The logic of the paper is deeply flawed because the kids who did not get special insights after the WES/WGS also showed a dramatic reduction in their nights per year at the hospital. Also, in the diagnosed cohort / treatment group", many kids did not actually receive any treatment. (see table 4)

 DiCo = Diagnosed Cohort

Undico = Undiagnosed Cohort

You can look up all members of the DICo cohort that got a definitive genetic testing result.

There are plenty of familiar genes, I am really surprised these kids had not previously been diagnosed

You can see the therapy they tried. Judge for yourself. I would have done much more, but the authors are the doctors ! They did have some successes.

Click on this link to open the full table with 56 patients:

Table 4 | Conferring a Genetic Diagnosis for Children with Neurodevelopmental Disorders in the Inpatient Psychiatry Setting May Reduce Hospital Stays and Improve Behavior | Advances in Neurodevelopmental Disorders

I was amazed at how much time these kids with autism + ID spend in Cincinnati Children’s Hospital. They are in hospital for 2 to 4 weeks a year, year after year. This must cost someone a fortune.

Why are these kids in hospital so much? It looks like Intermittent Explosive Disorder (IED), the fancy name for self-injurious behavior. In the US, and some other countries, when your kid's behavior gets really bad you call the police and they get taken to the ER at the local hospital and some then make it to specialist units like Cincinnati Children's Hospital. Most parents across the world never have this option, and I actually think this is better. There is rarely any magic at the ER in these cases; better to find the solution at home, without spending $50,000.

  

Broader Landscape of Precision Medicine for Autism + ID in the U.S.

Cincinnati Children’s is one of roughly 15 specialized centers in the U.S. that manage children with severe autism and intellectual disability in residential or inpatient settings. Another well-known example is Kennedy Krieger Institute at Johns Hopkins, which has historically piloted innovative, often unpublished interventions for rare genetic syndromes. Across these centers, the use of whole exome or genome sequencing is slowly becoming more common, but actionable, gene-targeted therapies remain rare. Most “precision medicine” efforts focus on enhanced monitoring, early detection of medical complications, and tailored behavioral or supportive interventions rather than disease-modifying treatments. This context highlights both the promise and current limitations of precision medicine in neurodevelopmental disorders.

My blog is really all about disease-modifying treatments.

We did see that when Dr Kelley was at Kennedy Krieger/Johns Hopkins they did lots of clever things that are out of the mainstream, but were not published in the literature.

Today’s paper is definitely a step forward, because we can all see how much/little is being done.  

The paper is very readable, just click on the link and read it.

Conferring a Genetic Diagnosis for Children with Neurodevelopmental Disorders in the Inpatient Psychiatry Setting May Reduce Hospital Stays and Improve Behavior 

https://link.springer.com/article/10.1007/s41252-025-00466-w

These 56 diagnosed patients formed the Diagnosed Cohort—DiCo. Details of variant classification and interpretation are included in Table 4. A further 81 patients received nondiagnostic genetic testing results, including negative findings or VUS findings not felt to explain the phenotype or lacking functional evidence (forming the Undiagnosed Cohort—UndiCo). We then quantified the total inpatient psychiatric hospital days 12 months before and 12 months after genetic test result delivery. 

Individual 10 is a 17-year-old male with autism, intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Additional medical history includes large habitus and obesity, non-alcoholic fatty liver disease, high-arched palate, dental crowding, foot pain, and back pain. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry admission identified a likely pathogenic de novo variant in SATB2(NM_001172509.2):c.169G > A p.(Gly57Ser), diagnostic for SATB2-Neurodevelopmental disorder (glass syndrome). Intellectual disability, behavioral challenges, and craniofacial dysmorphology are well described in this condition. Furthermore, osteopenia and epilepsy have been reported in patients with this condition. After observing slightly elevated alkaline phosphatase levels on previously completed routine labs, 192 u/L (40–150 u/L normal range) bone density scans were ordered and were normal. With ongoing foot and back pain, x-rays and MRI studies were ordered and demonstrated a hairline toe fracture. The patient was placed in a walking boot to allow for recovery of the fracture. Being vigilant for fracture evaluation in a condition with known osteopenia was important to care for this patient. Bone pain is a likely contributor to behavior outbursts.

Individual 15 is a 13-year-old male with autism, mild intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Medical history also includes obesity, large stature, and macrocephaly. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry stay identified two variants in TBC1D7. One nonsense variant: TBC1D7 NM_001318809.1:c.6dup p.(Glu3Ter), and an in-trans variant consisting of a duplication of 335 bps in exon 6 arr[GRCh37]chr613,307,82,613,308,161 × 3 predicted to disrupt the reading frame of TBC1D7. Both variants were listed as VUS; however, on review of the literature, nonsense and loss-of-function biallelic variants have been reported in this gene with a phenotype of patients with intellectual disability and macrocephaly. Thus, with a consistent phenotype and two predicted loss-of-function variants, a clinical diagnosis of TBC1D7-NDD was conferred. As TBC1D7 is the third subunit of the TSC1-TSC2 complex, we initiated a trial of rapamycin, an mTOR inhibitor, to target autism comorbidities of aggression and irritability. Parental report after 6 months of medication trial was that aggressive symptoms had subjectively improved.

Individual 30 is an individual with autism and intellectual disability, admitted to inpatient psychiatry for self-injurious behavior management. The patient is nonverbal with behavioral stereotypies. Physical exam was notable for up-slanting palpebral fissures and multiple café-au-lait macules on the abdomen, back, and flank, along with axillary freckling. Genetic testing (exome) was initiated during inpatient psychiatry stay and identified a variant in NF1: (NM_001042492.3):c.7870-9 T > G p.? which, though listed as a VUS, was predicted to affect the splice site and alter protein function. As the patient qualified for a clinical diagnosis of NF1 with more than 6 café-au-lait macules and axillary freckling, the patient was conferred a diagnosis of NF1. Following this diagnosis, an MRI of the brain and orbits was ordered per NF1 tumor surveillance protocols, which identified a plexiform neurofibroma within the supra- and infrazygomatic left masticator space, superficial to the masseter and temporalis muscles, extending into the left temporomandibular joint, with mild anterior displacement of the mandibular condyle. Plexiform neurofibromas can be painful, and in a nonverbal patient it may be difficult to communicate this pain. A high-dose ibuprofen prescription was provided to the patient to treat any presumed pain, which also translated into less frequent behavioral outbursts.

In SATB2 there are not enough osteoblasts, the cells that build your bones. Activating Wnt can substitute for some missing SATB2 function (lithium, telmisartan, statins etc).

For NF1 you likely need a PAK1 inhibitor. They exist and the cheap one is now controversial because of its use to treat Covid-19. If I mention the name post-Covid my post gets deleted! Other options are bee propolis rich in Caffeic Acid Phenethyl Ester (CAPE), which is safe, or the experimental Fragile X drug FRAX486 still sitting on the shelf at Roche, who had bought Genentech, who had bought Afrexis, set up by a Japanese Nobel Laureate I once wrote about. I remember because Susumu Tonegawa was a faculty member at MIT when his son, an MIT freshman, killed himself. A sad story indeed. 

I recall being contacted a long while back by a Canadian whose adult child with severe autism had just received a genetic diagnosis that suggested a PAK1 inhibitor as a therapy. Of course, nothing was being done about it, and he ended up at my blog.  Did he persevere or give up?  One of our readers, long ago, was using FRAX486, so it is possible.

Conclusion

The interesting part of today’s paper for me was to see what therapy was considered for the 56 cases with a single genetic diagnosis. This is something I have done quite a lot of over the years. More people should be doing it.

Many parents tell me they are very disappointed when clinicians refuse to try and treat their child with a genetic diagnosis. It is as if the geneticist thinks “Okay there is the diagnosis, job done … next patient please”.

So, as I said at the start of this post, 10/10 to Dr Shillington for trying to help these kids, and 10/10 for sharing what she did. As to what she actually did, it was not as good. Maybe she should read this blog for ideas, Hah ! 😃

Glass Syndrome / SATB2-associated syndrome – Osteoporosis and ERβ

The world’s longest glass bridge is in China.

Today’s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.

Glass Syndrome / SATB2-associated syndrome is another of those single gene types of autism, so you can think of SATB2 as another autism gene.  As we will see in today’s post SATB2 is involved in much more than autism and is very relevant to osteoporosis and some types of cancer.

While autism caused by SATB2 is very rare, diseases in old age quite often involve the SATB2 gene being either over expressed or under expressed. As a result there is much more research on SATB2 than I expected.

The current research into Glass Syndrome / SATB2-associated syndrome is mainly collecting data on those affected, rather than investigating therapies. There are some links later in this post, for those who are interested.

The research into SATB2, unrelated to childhood developmental disorders, is much more science heavy and already contains some interesting findings.   

I have only made a shallow study, but it seems that you can reduce SATB2 expression with a drug called Phenytoin and potentially increase expression via an estrogen receptor beta agonist. We saw in earlier posts that an estrogen receptor beta agonist might well be helpful in broader autism.

As with other single gene types of autism, it will be important to look at all the downstream effects caused by a lack of SATB2, some of which will very likely overlap with what occurs in some idiopathic autism or with other single gene autisms.

In Johns Hopkins’ simplification of autism into either hyper-active pro growth signaling, or hypo-active, SATB2 fits into the latter. It is associated with small heads and a small corpus callosum; that is the part that joins the left side of the brain to right side.

I think it is fair to say that SATB2 is associated with partial agenesis of the corpus callosum (ACC), a subject that has been covered in earlier posts.

I have mentioned two therapies recently that seem to help in certain variants of  ACC. The reason SATB2 causes partial agenesis of the corpus callosum (ACC) is well understood.  SATB2 needs to be expressed in the neurons that extend axons across the corpus callosum, in effect you need to build a bridge across from one side of the brain to the other and all the connections across that bridge need to match up and not be jumbled up. In some people with SATB2 they have an apparently normal corpus callosum (the bridge) but it does not work properly (the connections do not function).

SATB2 is also associated with a cleft palette, this occurs because the roof of the mouth (another bridge) does not join correctly left to right. You end up with an unwanted opening into the nose.

Building bridges is never an easy business. The Chinese have found this with their recent glass bridges, as in this post’s photo above. It looks like SATB2 is the “bridging” protein for humans, if the SATB2 gene is mutated you do not make enough of the SATB2 protein. The less SATB2 expression the more consequences there will be.

The other extreme also exists, too much SATB2 expression. That will lead to too much growth which makes it another cancer gene. In cases of aggressive prostate cancer SATB2 is over-expressed. So a therapy to slow this cancer would be to reduce SATB2 expression. For Glass Syndrome we would want the opposite. 

There is SATB2 associated syndrome research, but it is still at the stage of collecting data on people who are affected and investigating what particular mutation is present.

The logical next stage is to see more precisely the role SATB2 plays in different parts of the brain. By seeing how SATB2 interacts with the world around it, it may be possible to correct for the lack of it.  For example there is an interaction with Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. This look very relevant to building bridges.

Confusingly, Ctip2 is also called B-cell lymphoma/leukemia 11B encoded by the BCL11B gene. 

A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis.

BCL11B/CTIP2 is highly expressed in GABAergic interneurons of the mouse somatosensory cortex

The research relating your bones looks the most advanced and already suggests possible therapies to both increase and reduce SATB2 expression.

The role of SATB2 in skeletogenesis and human disease

The above paper (the full version is not public)  is very detailed and shows how important SATB2 may be in bone diseases and therefore be of wide clinical relevance.  It also suggests that it could be treated by gene therapy.

Molecular Regulation of SATB2 by Cytokines and Growth Factors

It appears that the anti-epileptic drug (AED) Phenytoin reduces SATB2 expression, which is the opposite of what we want, but shows that modification is possible.

Osteoporosis,  SATB2, Estrogen and ERβ

There already is much in this blog about estrogen/estradiol and estrogen receptor beta. There are was a phase in this blog when there were many comments about disturbed calcium metabolism in family members.

It appears they may be connected via SATB2.

Older people lack estrogen, particularly females, and this is associated with osteoporosis.

Very recent research shows that there is an ERβ-SATB2 pathway (ERβ = estrogen receptor beta, which is activated by estrogen). So a reduction in estrogen during aging reduces signaling along the ERβ-SATB2 pathway (making less SATB2).

We know from earlier posts that people with autism tend to have a reduced number of ERβ receptors and also a lower level of estrogen/estradiol. This might explain some of the problems readers reported with bones in their family members.

This raises the question of what happens to SATB2 expression when you add a little extra estrogen/estradiol. The implication from the Chinese study highlighted later is that this may well be one way to make more SATB2 from the non-mutated copy that you have (you likely have one mutated copy and one clean copy of this gene). This is something that should be investigated.

How to treat Glass Syndrome/SATB2?

Ideally you would use gene therapy to treat Glass Syndrome/SATB2; this will in future decades very likely be possible.  In the meantime the more old-fashioned options must be relied upon.

We know that people with partial agenesis of the corpus callosum (ACC) face challenges, some of which match those faced  with Glass Syndrome/SATB2. We know certain types of ACC do respond to treatment, based on research, so it would seem highly likely that treatment for  Glass Syndrome/SATB2 should be possible.

Very likely some of the myriad of treatments researched for autism may be helpful. But which ones?

The treatment proposed by Knut Wittkowski for very early intervention in idiopathic autism to alter the trajectory from severe autism towards Asperger’s looks interesting and particularly because our reader Ling finds it helpful for her daughter with SATB2. Knut’s research identified Ponstan (mefenamic acid) as a target drug to minimize the cascade of damaging events that occurs as autism progresses in early childhood.

Here you would hope that some researcher would create a mouse model of Glass Syndrome/SATB2 and then see if Ponstan (mefenamic acid) has any effect, not to mention estradiol.

Websites with Information on Glass Syndrome/ SATB2 associated syndrome 

http://satb2gene.com/

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38022/pdf

https://ghr.nlm.nih.gov/condition/satb2-associated-syndrome#synonyms

Some Research Relating to SATB2

Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex

Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, β-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.

Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (μ-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2^−/− striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.

Upregulation of SATB1 Is Associated with Prostate Cancer Aggressiveness and Disease Progression

Genotype and Phenotype in 12 additional individuals withSATB2-Associated Syndrome

SATB2-Associated Syndrome

Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017a]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.

Other neurologic manifestations

·         Hypotonia, particularly during infancy (42%)

·         Clinical seizures (14%)

·         EEG abnormalities without clinically recognizable seizures [Zarate et al 2017a]

·         Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).

Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).

This is likely to be the most relevant paper, even though the tittle might not suggest it:-

Estrogen regulates stemness and senescence of bone marrow stromal cells to prevent osteoporosis via ERβ-SATB2 pathway

Decline of pluripotency in bone marrow stromal cells (BMSCs) associated with estrogen deficiency leads to a bone formation defect in osteoporosis. Special AT-rich sequence binding protein 2 (SATB2) is crucial for maintaining stemness and osteogenic differentiation of BMSCs. However, whether SATB2 is involved in estrogen-deficiency associated-osteoporosis is largely unknown. In this study, we found that estrogen mediated pluripotency and senescence of BMSCs, primarily through estrogen receptor beta (ERβ). BMSCs from the OVX rats displayed increased senescence and weaker SATB2 expression, stemness, and osteogenic differentiation, while estrogen could rescue these phenotypes. Inhibition of ERβ or ERα confirmed that SATB2 was associated with ERβ in estrogen-mediated pluripotency and senescence of BMSCs. Furthermore, estrogen mediated the upregulation of SATB2 through the induction of ERβ binding to estrogen response elements (ERE) located at -488 of the SATB2 gene. SATB2 overexpression alleviated senescence and enhanced stemness and osteogenic differentiation of OVX-BMSCs. SATB2-modified BMSCs transplantation could prevent trabecular bone loss in an ovariectomized rat model. Collectively, our study revealed the role of SATB2 in stemness, senescence and osteogenesis of OVX-BMSCs. Collectively, these results indicate that estrogen prevents osteoporosis by promoting stemness and osteogenesis and inhibiting senescence of BMSCs through an ERβ-SATB2 pathway.

Therefore, SATB2 is a novel anti-osteoporosis target gene.

3.2 Estrogen enhanced SATB2 levels, pluripotency and alleviated senescence of OVX-BMSCs.

Estrogen has been shown to promote bone formation and proliferation both in vivo and in vitro (Wang, J. et al., 2014; Du, Z. et al., 2015; Kim, R. Y. et al., 2015), so we asked whether estrogen affected SATB2 expression, stemness and osteogenic differentiation of BMSCs. We found that both Sham-BMSCs and OVX-BMSCs treated with 10-8M estrogen (Matsumoto, Y. et al., 2013) regained the colony forming capacity as compared to the control (Fig. 2A). Higher expression levels of SATB2, Nanog, Sox2 and Oct4, were observed in BMSCs treated with estrogen relative to the control group (Fig. 2B, C). These results were further confirmed by human BMSCs (Fig. 2D). The role of estrogen on anti-senescence was verified by the decreased SA-β-gal positive cells and alleviated expression of senescence markers (Fig. 2E, F). After osteogenic induction, the expression of osteogenic markers, Runx2 and OCN, significantly increased (Fig. 2G and H). Consistently, estrogen significantly enhanced the mineralized node formation (Fig. 2I). Interestingly, the expression of osteoclast-related activator, RANKL, and inhibitor, OPG, significantly changed in OVX-BMSCs treated with estrogen (Fig. 2J).

Together, these results suggest that estrogen rescued pluripotency and alleviated senescence of OVX-BMSCs accompanied by a higher expression of SATB2.

3.4 SATB2 is a confirmed target of ERβ.  

Estrogen is known to regulate gene expression by binding to ERs, which subsequently binds to EREs present in promoters (Klinge, C. M. 2001). Analysis of 2 kb upstream and 50bp downstream of SATB2, using Promo 3.0 software, showed the presence of three putative EREs that had (achieved through site-directed mutagenesis at the ERβ binding site in the SATB2 promoter). As anticipated, ERβ overexpression induced by estrogen increased luciferase activity in wild-type but not mutant promoter region A (Fig. 4C, D). 

 Further, to check dynamic recruitment of ERβ to the EREs following estrogen treatment, we used chromatin immunoprecipitation (CHIP). CHIP analysis was conducted in OVX-BMSCs with or without estrogen treatment using antibodies specific to ERβ or IgG control. This revealed that following estrogen treatment, various putative EREs facilitated dynamic recruitment of ERβ. Furthermore, the binding of ERβ was considerably more robust in region A than other regions (Fig. 4E). Thus, the induction of SATB2 by estrogen is mediated by the binding of ERβ to various EREs present in the SATB2 promoter.

Discussion

Although it is well-known that osteoporosis due to estrogen deficiency is associated with bone loss, the detailed mechanisms underlying this are not fully understood (Liao, L. et al., 2013; Villa, A. et al., 2015; Wang, J. et al., 2016). We recently found that the expression of SATB2 was associated with ERs, especially ERβ, after estrogen treatment of BMSCs (Fig. 3A). In this study, we successfully established an ovariectomized rat model of postmenopausal osteoporosis and showed that STAB2 was associated with estrogen-ERβ complex in OVX-BMSCs. Moreover, our data demonstrated that SATB2 was a downstream effector of ERβ. The induction of SATB2 by estrogen was mediated by binding of ERβ to various EREs present upstream of SATB2. Our study suggested the central role of SATB2 in the etiology of postmenopausal osteoporosis, suggesting it as a candidate target of osteoporosis prevention and treatment.

                                                                                                                                 

Conclusion

Our reader Ling is busy researching this syndrome and this is a good place to post comments with her findings, so others can find them later.