What remains

After saying goodbye to the Paces, Gupta and I run into Wolf, who has just finished scoring Gina’s evaluations. Her brief description of the results — Gina as a 2-to-4-year-old, which somehow does not seem quite right to either Wolf or Gupta — inspires a discussion between them about one of CDD’s most unsettling puzzles: Among the apparent erasures in CDD’s cruel reversal, what remains?

Wolf and Gupta both say many people with CDD have assets that standardized autism screens do not reveal. Gina’s language skills seem beyond the 3-year-old level the test perceived. Ditto with the fast math, the solitaire, the word-finding puzzle prowess. And with the connections of trust and comfort she makes with people such as Wolf, Gupta and me after knowing us for only a few hours.

The 8-year-old boy in Gupta’s video is now in his teens, and also speaks mainly in two-word phrases. “Then all of a sudden he’ll be like, ‘No, I don’t want to do that,’” Wolf tells us.

Are his and Gina’s skills truly gone, Wolf and Gupta ask, or just obscured, like memories we can’t recall?

“You feel like it’s still in there,” Gupta says quietly. “Don’t you?”

Wolf nods.

Later that afternoon, Gupta and I sit down with her colleague Kevin Pelphrey to discuss the CDD study that he and Gupta have repeatedly been overhauling for more than three years. (Pelphrey has since moved from Yale to George Washington University, in Washington, D.C., but he and Gupta continue to collaborate on this project.)

Gupta, Pelphrey and the many collaborators on this CDD study face a difficult problem: They’re studying a condition about which science knows almost nothing. The very things that distinguish it — its severity, rarity and opacity — make it ludicrously hard to study. This is science at its earliest, most difficult, and most confounding. It’s mostly bumping into strange shapes in the dark and trying to figure out what they mean.

The study draws together data from psychological and cognitive testing, family histories, eye tracking, genetic analysis and brain imaging in more than two dozen people with CDD. Progress has been slow, they explain, partly because, like Gina, few people with CDD can lie still in scanners or tolerate blood draws. It has also taken time because Gupta and Pelphrey kept finding things that defied their expectations. “There was a lot of ‘This can’t be right … ,’” says Pelphrey.

Given CDD’s severity, for instance, they had hoped to find a few powerful genes at fault, but did not. They had thought they might find brain activity disrupted in ways characteristic of the severest cases of classic autism, but did not. In general, they had thought they’d find the underlying neurobiology of an especially debilitating sort of autism. They did not.

Instead, says Pelphrey, their findings suggest a fairly typical brain — that is, the brain of a person without autism — with key processes halted at, or perhaps pushed back to, early developmental stages.

In eye-tracking studies, for instance, he and Gupta had expected people with CDD to scan faces much as most people with autism do: by paying more attention to the mouth than to the eyes. Instead, the participants with CDD scanned faces as typical infants do between 4 and 12 months of age, according to one leading model of face processing.

This theory holds that between about 4 and 6 months, an infant moves from one way of looking at faces to another. Baby-eye-gaze geeks call these stages of gaze during infancy ‘conspec’ and ‘conlern;’ we can think of them as ‘eyes-only’ and ‘eyes-plus.’ In the eyes-only stage, up to 4 to 6 months, a baby looking at a face looks almost solely at the eyes. In the eyes-plus stage, which begins after 6 months, the baby still looks frequently at the eyes, but also begins glancing quickly elsewhere around the face, presumably to collect social information.

The participants with CDD looked at eyes as if they were infants who were just starting to use the eyes-plus mode; they still devoted most of their attention to the eyes. People with autism generally follow neither of these patterns. They give the eyes no more attention than they give to the mouth, nose or hairline. The gaze of the CDD participants suggests not a loss of social interest, but a return to an earlier form of facial and social processing. What does this mean? Pelphrey and Gupta’s answer is essentially a prolonged head-scratch; they can only speculate that some developmental pathway devoted to reading faces has suffered a big reversal.

That’s just one small study, of course. (Only 5 of their 25 participants would sit still for eye tracking.) Gupta and Pelphrey might have ignored it if their brain imaging work did not also suggest that people with CDD are more like neurotypical infants or toddlers than like adolescents or adults on the spectrum. For instance, when seven of their CDD participants got in the brain scanner and looked at faces versus houses, their brain activity more closely resembled that of typically developing children between 1 and 3 years of age than that of people on the spectrum. This finding too suggests that specific developmental reversals may be at work in CDD.

A third stream of data, from genetics, seems to point the same way. In an analysis of 15 participants with CDD, Gupta found that 14 carry rare mutations in one or more of 40 genes. The genes stand out for three reasons: They have never been linked to autism; they are expressed not in brain regions usually associated with autism, but rather in those Pelphrey found altered in brain scans of people with CDD; and postmortem studies of gene expression have shown that 11 of the 40 genes surge in activity in those areas between ages 3 and 8 — the period during which CDD usually emerges.

These results seem to support the idea that mutations in these genes contribute to CDD’s emergence — and perhaps to the reversals Gupta and Pelphrey found in their eye-tracking and brain scanning studies.

Gupta looks pained as she acknowledges that with so few people studied, these findings are merely suggestive. Yet she and Pelphrey say their results strongly support the idea that CDD is a distinct sort of autism with unique biological underpinnings, and that it’s important to follow these new clues about what may be going amiss.

Neuroscientist Rebecca Saxe of the Massachusetts Institute of Technology applauds this effort, amid autism’s vast heterogeneity, to bear down on particular processes in “the smaller, more specific group” with CDD. Understanding CDD, she says, is important both as a reminder of autism’s huge variations, “and because it may provide a clue to one of autism’s most mysterious and emotionally devastating symptoms in some cases of autism: regression.”

As it happens, the deeper biological investigation that Gupta and Pelphrey propose would constitute a return of sorts to CDD’s beginnings. In the decades after Heller wrote up CDD, most scientists thought the condition arose from some biological anomaly. When the crude tools of that time found nothing biological, theory and research moved elsewhere, but with little effect. Now, with new tools and these new clues in hand, Pelphrey and Gupta may be able to follow strands of biological evidence that simply weren’t visible before.