Unertan Syndrome: A Case Series Demonstrating Human Devolution

Tan, Üner; Karaca, Sibel; Tan, Meliha; Yilmaz, Bekir; Bagci, Namik Kemal; Özkur, Ayhan; Pençe, Sadrettin

doi:10.1080/00207450701667857

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…Subsequent homozygosity mapping indicated that the phenotype of this family was linked to chromosome 17p (11). Thereafter, three additional families from Turkey (12)(13)(14) and another from Brazil (15) with similar phenotypes have been described, and video recordings illustrating the quadrupedal gait have been made (10)(11)(12). Here, we report that VLDLR is the gene responsible for the syndrome in two of these four Turkish families and report additional gene mapping studies that indicate the disorder to be highly genetically heterogeneous.…”

mentioning

confidence: 86%

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans

Özçelık

Akarsu

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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102

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Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype associated with dysarthric speech, mental retardation, and varying degrees of cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest this phenotype. In two families (A and D), shared homozygosity among affected relatives mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the reelin signaling pathway involved in neuroblast migration in the cerebral cortex and cerebellum. Sequence analysis of VLDLR revealed nonsense mutation R257X in family A and singlenucleotide deletion c2339delT in family D. Both these mutations are predicted to lead to truncated proteins lacking transmembrane and signaling domains. In two other families (B and C), the phenotype is not linked to chromosome 9p. Our data indicate that mutations in VLDLR impair cerebrocerebellar function, conferring in these families a dramatic influence on gait, and that hereditary disorders associated with quadrupedal gait in humans are genetically heterogeneous.genetics ͉ Unertan syndrome O bligatory bipedal locomotion and upright posture of modern humans are unique among living primates. Studies of fossil hominids have contributed significantly to modern understanding of the evolution of posture and locomotion (1-5), but little is known about the underlying molecular pathways for development of these traits. Evaluation of changes in brain activity during voluntary walking in normal subjects suggests that the cerebral cortices controlling motor functions, visual cortex, basal ganglia, and the cerebellum might be involved in bipedal locomotor activities (6). The cerebellum is particularly important for movement control and plays a critical role in balance and locomotion (7).Neurodevelopmental disorders associated with cerebellar hypoplasias are rare and often accompanied by additional neuropathology. These clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathology, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal abnormalities, and cutaneous disorders, among others (8). Quadrupedal locomotion was first reported when Tan (9, 10) described a large consanguineous family exhibiting Unertan syndrome, an autosomal recessive neurodevelopmental condition with cerebellar and cortical hypoplasia accompanied by mental retardation, primitive and dysarthric speech, and, most notably, quadrupedal locomotion. Subsequent homozygosity mapping indicated that the phenotype of this family was linked to chromosome 17p (11). Thereafter, three additional families from Turkey (12-14) and another from Brazil (15) with similar phenotypes have been described, and video recordings illustrating the quadrupedal gait have been made (10-12). Here, we report that VLDLR is the gene responsible for the syndrome in two of these four Turkish families and report additional gene mapping st...

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mentioning

confidence: 86%

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans

Özçelık

Akarsu

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…In families A and B respectively, Barany’s caloric nystagmus test indicated the central and peripheral vestibular systems were impaired [8], while in family C the vestibular system was normal [25]. This means there was no unique vestibular defect associated with the syndrome.…”

Section: Vestibular Systemmentioning

confidence: 99%

Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the Dynamics of Human Quadrupedalism

Tan

2010

TONEUJ

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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.

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“…Due to the small size of this additional sample, statistical analyses were restricted to the data obtained from Family A (#1 above). Supplementary videos from other publications were either not available online [11], [12], were provided by publisher in a format (.wcp) not readily viewable [9], or were of insufficient quality for reliable quantitative analysis [15], [20].…”

Section: Methodsmentioning

confidence: 99%

Human Quadrupeds, Primate Quadrupedalism, and Uner Tan Syndrome

et al. 2014

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Since 2005, an extensive literature documents individuals from several families afflicted with “Uner Tan Syndrome (UTS),” a condition that in its most extreme form is characterized by cerebellar hypoplasia, loss of balance and coordination, impaired cognitive abilities, and habitual quadrupedal gait on hands and feet. Some researchers have interpreted habitual use of quadrupedalism by these individuals from an evolutionary perspective, suggesting that it represents an atavistic expression of our quadrupedal primate ancestry or “devolution.” In support of this idea, individuals with “UTS” are said to use diagonal sequence quadrupedalism, a type of quadrupedal gait that distinguishes primates from most other mammals. Although the use of primate-like quadrupedal gait in humans would not be sufficient to support the conclusion of evolutionary “reversal,” no quantitative gait analyses were presented to support this claim. Using standard gait analysis of 518 quadrupedal strides from video sequences of individuals with “UTS”, we found that these humans almost exclusively used lateral sequence–not diagonal sequence–quadrupedal gaits. The quadrupedal gait of these individuals has therefore been erroneously described as primate-like, further weakening the “devolution” hypothesis. In fact, the quadrupedalism exhibited by individuals with UTS resembles that of healthy adult humans asked to walk quadrupedally in an experimental setting. We conclude that quadrupedalism in healthy adults or those with a physical disability can be explained using biomechanical principles rather than evolutionary assumptions.

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Unertan Syndrome: A Case Series Demonstrating Human Devolution

Cited by 12 publications

References 27 publications

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans

Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans

Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the Dynamics of Human Quadrupedalism

Human Quadrupeds, Primate Quadrupedalism, and Uner Tan Syndrome

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