syndrome
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
evolutionary biologist
Evolutionary biology is the subfield of biology that studies the evolutionary processes (natural selection, common descent, speciation) that produced the diversity of life on Earth. It is also defined as the study of the history of life fo ...
quadrupedal
Quadrupedalism is a form of locomotion where four limbs are used to bear weight and move around. An animal or machine that usually maintains a four-legged posture and moves using all four limbs is said to be a quadruped (from Latin ''quattu ...
locomotion and often have severe
learning disabilities
Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficult ...
. Tan postulated that this is an example of " reverse evolution" (atavism). The proposed syndrome was featured in the 2006
BBC2
BBC Two is a British free-to-air public broadcast television network owned and operated by the BBC. It covers a wide range of subject matter, with a remit "to broadcast programmes of depth and substance" in contrast to the more mainstream a ...
Turkey
Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula in ...
has been the primary example of the proposed syndrome. Tan described five members as walking with a quadrupedal gait using their feet and the palms of their hands. In infants, where this is a rare stage prior and sometimes following bipedal walking, such a gait is called "bear crawl". The affected family members also have learning disabilities and their speech is affected. Tan proposed that these are symptoms of Uner Tan syndrome.
In January 2008, Tan reported on another family (four males and two females) located in southern Turkey.
Four other unrelated cases in families are described as having various degrees of UTS. Two males are unable to stand up, while in other cases, can stand up but cannot make a step when standing. Less severe cases use
toe walking
Toe walking refers to a condition where a person walks on their toes without putting much or any weight on the heel or any other part of the foot. This term also includes the inability to connect one's foot fully to the ground while in the stand ...
, which is a normal phase in child gait development.
Genetics
Uner Tan syndrome has been linked to intrafamilial marriage and reproduction, which suggests that it is an autosomal recessive disorder. The main characteristic of this syndrome is habitual quadrupedalism, meaning they can stand up straight until they try to move, then they walk on their hands and knees. According to Tan, the syndrome may be placed in its own category under types of cerebellar ataxias. This simply means it is a type of disorder that involves the cerebellum becoming inflamed, resulting in lack of control of voluntary movements. Uner Tan syndrome falls into this category because it has similar symptoms to other cerebellar ataxia disorders such as disequilibrium syndrome (DES-H) and Cayman Syndrome. These symptoms include
dysarthria
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effective ...
,
nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the involu ...
, and
hypoplasia
Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.
Human geneticist Tayfun Ozcelik discovered homozygosity in a region on chromosome 9p24 in Uner Tan syndrome individuals. The very low density lipoprotein receptor gene (VLDLR) is located in this region, which is involved in the migration of neuroblasts within the brain. Ozcelik found mutations in the VLDLR gene in affected individuals, and suggested that these specific mutations may lead to VLDLR deficiency during the development of the brain. This may affect the proper formation of cerebrocerebellar structures critical for upright walking, resulting in quadrupedal locomotion. Other genes may also be involved in habitual quadrupedalism. For example, in some affected families, chromosome 17p13 was involved, while in other families 17p13 and 9p24 had no effect. This suggests the syndrome is genetically
heterogeneous
Homogeneity and heterogeneity are concepts often used in the sciences and statistics relating to the uniformity of a substance or organism. A material or image that is homogeneous is uniform in composition or character (i.e. color, shape, size ...
.
The researchers took a different approach to isolate the gene that causes this syndrome by comparing the genealogy of all the families in which the syndrome had been reported. The two types of Uner Tan Syndrome, UTS type I and type II show genetic heterogeneity. In two of the first families (Antep and Çanakkale families) it was the VLDLR gene on chromosome 9p24. This is the only family so far to express homozygosity. It is possible for dissimilar mutations in the VLDLR gene to result in the same phenotype as a result of allelic heterogeneity. In the Iskenderun family, a different gene, WDR81 on chromosome 17p13.1-13.3 was isolated . The Iraqi family had CA8 on chromosome 8q isolated. In the last family studied (the Adana family), the researchers were not able to isolate any gene, only a locus on chromosome 13q. This isolation led to the implication of more genes as the causes of quadrupedalism. The fact that chromosome 9p24 had no effect on some families points to the genetic heterogeneity of the syndrome.
Another approach for establishing the genealogy has been to compare UTS with similar syndromes such as disequilibrium syndrome (DES) and Joubert syndrome. UTS seems to be genetically different from DES in that DES can be linked to a single gene, VLDLR, located on chromosome 9p24. When compared with DES, Joubert syndrome has shown links to seven gene mutations. As is the case with almost all diseases, the three syndromes compared show allelic heterogeneity.
Researchers recently isolated a recessive TUBB2B mutation in one of the families diagnosed with UTS. This makes TUBB2B the fifth gene after VLDLR, WDR81, CA8 and ATP8A2, associated with this syndrome. Patients with mutations of TUBB2B are phenotypically similar to those with VLDLR, WDR81 and ATP8A2 mutations. The researchers proposed a tentative reclassification of UTS into three types based on how they present themselves clinically. They attribute the first type (referred to as developmental UTS) to mutations in TUBB2B and VLDLR. Type II (degenerative UTS) is linked to ATP8A2 and WDR81 while type III (UTS without cerebral malformations) implicates CA8.
The problem with identifying the specific mutation that leads to Uner Tan syndrome is the fact that different mutations in a single gene can lead to a wide range of phenotypes. In the VLDLR gene, similar mutations may be responsible for different types of cerebellar ataxias that affect proper locomotion in humans.
Criticism
Neuroscientist
A neuroscientist (or neurobiologist) is a scientist who has specialised knowledge in neuroscience, a branch of biology that deals with the physiology, biochemistry, psychology, anatomy and molecular biology of neurons, neural circuits, and glial ...
Nicholas Humphrey
Nicholas Keynes Humphrey (born 27 March 1943) is an English neuropsychologist based in Cambridge, known for his work on evolution of primate intelligence and consciousness. He studied mountain gorillas with Dian Fossey in Rwanda; he was the fi ...
and medical scientist John Skoyles have argued that the gait of these individuals is due to two rare phenomena coming together, not atavism. First, instead of initially crawling as infants on their knees, they started off learning to move around with a "bear crawl" on their feet. Second, due to their
congenital
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can r ...
brain impairment, they found balancing on two legs difficult. Because of this, their motor development was channeled into turning their bear crawl into a substitute for
bipedalism
Bipedalism is a form of terrestrial locomotion where an organism moves by means of its two rear limbs or legs. An animal or machine that usually moves in a bipedal manner is known as a biped , meaning 'two feet' (from Latin ''bis'' 'doubl ...