Regards,

Said and Sonal

The Open Neurology Journal, 2010, 4, 78-89
1874-205X/10 2010 Bentham Open
Open Access
Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the
Dynamics of Human Quadrupedalism
Uner Tan*,1
Department of Physiology, Çukurova University, Medical School, 01330 Adana, Turkey
Abstract: This review includes for the first time a dynamical systems analysis of human quadrupedalism in Uner Tan
syndrome, which is characterized by habitual quadrupedalism, impaired intelligence, and rudimentary speech. The first
family was discovered in a small village near Iskenderun, and families were later found in Adana and two other small villages
near Gaziantep and Canakkale. In all the affected individuals dynamic balance was impaired during upright walking,
and they habitually preferred walking on all four extremities. MRI scans showed inferior cerebellovermian hypoplasia
with slightly simplified cerebral gyri in three of the families, but appeared normal in the fourth. PET scans showed a decreased
glucose metabolic activity in the cerebellum, vermis and, to a lesser extent the cerebral cortex, except for one patient,
whose MRI scan also appeared to be normal. All four families had consanguineous marriages in their pedigrees,
suggesting autosomal recessive transmission. The syndrome was genetically heterogeneous. Since the initial discoveries
more cases have been found, and these exhibit facultative quadrupedal locomotion, and in one case, late childhood onset.
It has been suggested that the human quadrupedalism may, at least, be a phenotypic example of reverse evolution. From
the viewpoint of dynamic systems theory, it was concluded there may not be a single factor that predetermines human
quadrupedalism in Uner Tan syndrome, but that it may involve self-organization, brain plasticity, and rewiring, from the
many decentralized and local interactions among neuronal, genetic, and environmental subsystems.

Best, Nicholas Humphrey

**

As you will know, I and my colleagues from England published an early account of the syndrome in the Ulas family (your family B) in 2005.

http://www.lse.ac.uk/collections/CPNSS/pdf/DP_withCoverPages/DP77/DP7705.pdf

Since then I have been involved with Stefan Mundlos in researching your family A which was first “discovered” by us as a result of the BBC TV documentary. We have also more recently researched a family with a similar syndrome in Iraq. A report of the Iraqi family “Life on all fours” appeared in the London Times in November last year.

http://www.timesonline.co.uk/tol/life_and_style/health/article2671426.ece

We (Mundlos and his team) have a paper in press in EJHG which describes our own findings with your family A. I’m glad to say we are in complete agreement with you about the genetics of family A. We will shortly also be publishing our genetic findings with the Iraqi family, in whom we have found yet another different mutation.

Our own conclusions about the origins of quadrupedal locomotion are different from yours. We see it as an adaptive compensation for problems with balance (caused by congenital cerebellar hypoplasia in some cases , or in other cases that we know of by later-onset conditions such as Parkinsonism). We do not believe that so-called “Unertan syndrome” is a useful diagnostic category, or that it has the scientific significance that Tan wants to attach to it (evidence of “backwards evolution”).

However we still regard these cases as being of great interest from the point of view of human development. They provide “text-book cases” of how genes and environment interact to determine the phenotypic outcome, and of how disparate influences can lead to a convergence on an unusual “attractor state” — namely, in this case palmigrade quadrupedalism. We also think that the fact that palmigrade quadrupedalism is still in modern humans an attractor state may tell us something about human pre-history (perhaps our ancestors were indeed palm-walkers rather than knuckle-walkers).

“UTS and DES

Although the UTS is proven to be a unique syndrome not described before in the scientific literature, there is a syndrome which should be discussed with regard to the UTS. The disequilibrium syndrome (DES) was first introduced into the scientific literature by Hagberg, Sanner, and Steen (1972). Later, Sanner (1973) re-studied this syndrome and provided evidence for an autosomal recessive pattern of inheritance since many patients in one region of Sweden originated from parental consanguinity. The DES is also found among the Hutterites of Montana (Schurig et al., 1981; Palister & Opitz, 1986). Similar cases were later reported by Glass, Boycott, Adams, et al. (2005) in 12 Hutterites, similar to the former clan, except that the latter study included MRI scans.

There are significant differences between the DES and the UTS. Those affected with the UTS habitually walk in a quadripedal fashion without any sign of dysequilibrium, whereas those with the DES habitually walk bipedally with a broad-based ataxic gait due to cerebellar hypoplasia. This is the most important difference between the UTS and the DES. Although both syndromes result from autosomal recessive inheritance due to intra-familial marriages, the genetic defect differs. That is, the gene responsible for the DES is localized to chromosome region 9p24 (Boycott et al., 2007), while the gene responsible for the UTS is localized to chromosome 17p, at least in the affected individuals of the first family described (Turkmen et al., 2006), which has been confirmed by our collaborative work with Tayfun Ozçelik at Bilkent University in Ankara, Turkey (unpublished studies). However, we were unable to confirm this result in the affected individuals of the second and third families, suggesting that the UTS may be a multigenic disorder. Speech is at the very primitive level in the affected members of the first family. They cannot name objects in everyday use, generally understanding only themselves; their neighbors cannot understand them. The affected individuals of the second and third families do not use a language. To communicate, they use only one or two sounds, while those affected with the DES use their mother language, which is, however, dysarthric and unintelligible. There is mild-to-moderate mental retardation in the DES, but there is severe mental retardation with no conscious experience at all in patients with the UTS. Furthermore, there was no short stature in subjects with the UTS, while most of the subjects with the DES exhibit short stature. There was no intention tremor in most of those affected with the UTS, while there was intention tremors in most affected with the DES. The common features between the UTS and the DES include: autosomal recessive inheritance, exaggerated deep tendon reflexes (primarily in the lower extremities), and rarely, epilepsy. Thus, the UTS and the DES are different pathologic conditions, exhibiting different clinical signs and symptoms. The MRI scans are completely similar in the DES and in some affected individuals of the first and third families with the UTS, i.e., the inferior cerebellum and the inferior vermis being absent with a mild gyral simplification in both the DES and the UTS. However, these structures were nearly normal in the affected individuals of the second family (Tan, 2006b). Moreover, the cerebro-cerebellar structures were completely normal in the MRI scans of an individual exhibiting only the main symptom of the UTS, i.e., habitual walking on all four extremities without any mental disturbances (Tan, 2007). The integrity of the vestibular system has not been studied thus far in those affected with the DES. In contrast, the vestibular system was tested using Barany’s caloric nystagmus test in the affected individuals of the first family (Tan et al., 2007), which indicated a defect in the central vestibular system, comprising the neural nuclei in the brain stem responsible for postural reflexes, gravity-dependent reflexes, and spatial orientation. There was a defect in the peripheral vestibular system in the affected individuals of the second family (Tan et al., 2007), i.e., damage to the nerve of the inner ear which controls balance. Interestingly, the peripheral and central vestibular systems were normal in the affected individuals of the third family presented in the present work. These results exclude the possibility that a defective vestibular system would be responsible for the UTS. In sum, the above mentioned differences between the UTS and the DES suggest that these two disorders may be entirely different with respect to clinical and central neural mechanisms.”

As I understood, there are two genetic loci linked to the syndrome. One gene has been found, and turned out to be the gene linked previously to Disequilibrium syndrome, later renamed VLDLRCH. I will wait for an answer whether some cases of Unertan syndrome might really be “rediscovered” VLDLRCH, which is described in Hutterite communities, for example. There must exist descriptions of Hutterite cases, why not compare them with Turkish families’ members affected by the syndrome. It is interesting what will be the second gene, that on the chromosome 17..

I was interested in VLDLRCH because VLDLR, along with ApoER2, is one of the reelin receptors, and reelin brain levels are reported to be consistently low in cases of schizophrenia and psychotic bipolar disorder. Reading about molecular mechanisms of schizophrenia is a kind of my hobby. I was adding some info to the reelin-related wikipedia pages now and then, and only yesterday struck upon the quaint “Unertan syndrome”.

I think you’re missing my argument. It’s certainly plausible that these ataxia cases have a genetic cause (or causes), and the genes that are involved might be interesting.

But the hypothesis that these genes were themselves involved with the origin of bipedality (or language) requires different evidence. In particular, it requires a comparison with chimpanzees or other hominoids, showing that the human form exhibits functional changes. Even better would be evidence of selection on the gene within the human lineage.

That is what we have for FoxP2, for example — not only is it implicated in the pathological form of SLI, but it is also clearly different between humans and other hominoids, and shows good evidence of selection on the human lineage. And even then, we still don’t know what it does or why it was selected.

A contrary example is FGFR3, some mutations of which cause achondroplasia. This developmental reduction in body size may be compared to the vast increase in body size that evolved during human evolution. But as far as we know, that increase did not involve any adaptive changes to FGFR3, and there is no particular evidence of selection on the gene in the human lineage.

So my point is that studying the pathology is *not* studying the origins of bipedality. There’s no necessary connection between the two, nor is there any expectation that we will learn about one from the other.

I would say that the PNAS paper puts the situation very well — it says in the conclusion that the identification of VLDLR-based pathologies may lead to more insight about the neural mechanisms that maintain gait in humans.