¹Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Professor JD Sweatt, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 1010, Birmingham, AL 35294-2182, USA. E-mail: dsweatt@uab.edu

Received 1 February 2013; Accepted 3 February 2013

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Abstract

TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt–Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.

MOST children’s first steps are a momentous occasion – but for little Isabella Groves it’s a breakthrough.One of only 200 people in the world to suffer with a rare genetic condition, medics said she may never walk.But every day she continues to push boundaries as she learns to turn the pages of a book, and communicate using a special app.Isabella, who turns three today, doesn’t talk and has the developmental age of a 12-month-old baby.Diagnosed with Pitt Hopkins Syndrome, she needs to be fed and has no physical awareness.But her positive parents, Leanne and Andrew from Denbigh, live by the motto “never say never”, as they immerse their daughter in everyday tasks, taking her swimming and riding to boost her confidence and quality of life.Speaking to the Daily Post last night, Leanne said: “Izzy was born at home three years ago and at first we didn’t notice anything was wrong.“After a while, we found she seemed a bit behind children her age, she wasn’t making much eye contact and was unable to hold herself up properly, as if she had weak muscles.“I had a gut feeling that something wasn’t right and so we took her to the doctors who referred her to a paediatrician.“When they couldn’t work out what was wrong, Izzy was referred to a geneticist and they carried out tests for one of three rare syndromes.”She added: “When it came back that she had Pitt Hopkins Syndrome, it hit us like a ton of bricks.“The paediatrician had never come across it ever before in her career.

“We did some research on the internet and found it was a condition characterised by severe intellectual disability and developmental delay.

“We were told she would never walk or talk.”

But Izzy, who goes to Castle Day Nursery in Rhuddlan and Ysgol Tir Morfa in Rhyl, has been involved in an intensive physiotherapy programme and has managed to take a few steps unaided.

She doesn’t speak but smiles, laughs and “babbles” words like mama.

Nurse Leanne, who also has a four-year-old son, added: “There are only around five children in the UK with the syndrome and 200 cases worldwide. I got in touch with a research team in Texas – breakthroughs are a long way away but you’ve always got to have hope.

There is no UK charity for Pitt Hopkins but I am trying to change that – there are probably more kids who have it but haven’t been properly diagnosed.”

Leanne admits she doesn’t know what’s around the corner for Izzy. She said: “We’ve been told she could start having seizures between the ages of four and seven and may develop apnea, which means she may stop breathing.

“We are praying it doesn’t come to that and keep trying our best to push through boundaries. Izzy is responding slowly but is making progress.”

The family need to raise £5,000 to start up the charity, so friend Simon Hales, from Prestatyn, is taking part in the 10k Great Manchester Run on May 26 to help their cause. “We’ve been selling Never Say Never wristbands to raise awareness,” added Leanne.

In the UK, Paypal donations via izzyneversaynever@gmail.com To help, call 07771542017.

http://www.dailypost.co.uk/news/health/denbighshire-girl-suffering-rare-condition-3869215