Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.

The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/ß-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of ß-tubulin to fold or become assembled into the α/ß-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.

Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred.

The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.

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

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 single-nucleotide 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.

Unertan syndrome: a new variant of Unertan syndrome: running on all fours in two upright-walking children.

A new variant of Unertan Syndrome (UTS) is described in two Turkish children who exhibit both bipedal and quadrupedal locomotion and have normal cognitive abilities, including speech and intelligence. Quadrupedal locomotion was used by these individuals for rapid motivity when needed. An X-linked autosomal recessive transmission appears to be responsible for the UTS trait, with no intrafamilial marriages. The children did not show any neurological signs and symptoms except for a positive Babinski sign and an inability to perform a tandem walk. The results suggest that quadrupedality may result from using ancestral neural networks when needed. The preference for the quadrupedal gait as a hidden skill may be an example of learned dynamical adaptation to limited motor control, pointing out a phase transition in system dynamical terms. Human quadrupedality may have important consequences regarding human evolution with respect to the transition from quadrupedalism to bipedalism, which is generally recognized as important trait in the hominization process during human evolution.

Effects of progesterone on total brain tissue adenosine deaminase activity in experimental epilepsy.

Single seizure and epilepsy is one of the most commonly encountered neurologic disorders in elderly individuals, arising as a result of complex and often multiple acquired underlying pathologies. Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy and inhibits progression to status epilepticus. Adenosine deaminase is the enzyme for the regulation of adenosine levels. Therefore any change in adenosine deaminase levels will reflect to adenosine levels. Adenosine deaminase levels were decreased in the groups that were given progesterone. Progesterone may have an antiseizure effect with the additional finding decreased levels of adenosine deaminase that would have resulted in increased adenosine levels that exerts anticonvulsant effect via GABA-A receptors. Further studies are needed to evaluate the role of progesterone effects on adenosine deaminase levels and its mechanism(s) in the pathogenesis.

Antiepileptogenic effects of glutathione against increased brain ADA in PTZ-induced epilepsy.

Adenosine has been shown to play a significant role as a modulator of neuronal activity in convulsive disorders, acting as an endogenous anticonvulsant agent. Any change in adenosine deaminase (ADA) levels will reflect to adenosine levels. In the present study, we have investigated the effect of glutathione on brain tissue ADA levels due to seizures induced by convulsive and subconvulsive dose of pentylenetetrazol (PTZ) in mice. ADA levels due to seizures induced by convulsive and subconvulsive pentylenetetrazol were measured using the Giusti method. ADA levels were higher in the experimental epilepsy groups than in the control and sham groups. ADA levels significantly decreased in the glutathione groups, which may have antiseizure effects. Decreased levels of ADA would be due to increased adenosine levels, protecting against oxidative stress.

A special case of anencephaly in an early-born baby with an exagerated prognastic face: further example for human devolution.

A 7-month-old baby was born in a village near Iskenderun (Turkey) where "Unertan Syndrome" with quadrupedality and primitive cognitive abilities was discovered. The clinical diagnosis was anencephaly. However, his head did not show the classical symptoms of anencephaly because it was covered with bony structures. The baby has an ape-like, prognasthic head with low-set ears and flapped ear flaps. The other parts of the body were similar to humans with broad shoulders and a short neck. This may be a further example of human devolution, which was first reported by Tan (2005, 2006a,b,c). A genetic defect affecting the head development including brain may be responsible for the reappearance of the ape-like head in a human being. This human devolution, or evolution in reverse, suggests that the same gene or gene-pool as well as the interactions between genes may be responsible for the transition from our ancestors into human beings with regard to an orthognasthic head, and brain development.

Right brain is important for students' achievements in science.

Relations between the hearing durations of right and left ears and points on the introductory examination for entrance to the Science School of Ataturk University in Erzurum were investigated in 31 male and 13 female students. The hearing duration of the left ear was significantly associated with the scores of the examination for the university entrance, the hearing duration for the right ear being not significantly related to the examination scores. The results suggest that the right brain would be beneficial for the students' achievements in science.

Ratio of fourth to second fingertip extensions in relation to serum estradiol and testosterone levels in men and women.

Sex differences in second (2D) and fourth (4D) fingertip extensions relative to the middle fingertip and 4D:2D fingertip extension ratios were studied in men and women. Body height positively correlated with index fingertip extensions, not with ring fingertip extensions, nor with their ratio. Mean 2D extension (both hands) was smaller in women than men; mean 4D extension (right hand) was smaller in men than women; 4D:2D fingertip extension ratios from both hands were larger in women than men. Serum estradiol concentration negatively correlated with 2D extensions for both hands (no significant correlation with 4D extensions), but positively correlated with 4D:2D extension ratios for both hands. Serum testosterone concentration positively correlated with 2D extensions of both hands (no significant correlation with 4D extension), but negatively correlated with 4D:2D extension ratios for both hands. These relations were also studied in men and women separately. It was concluded that the 4D:2D extension ratio was greater in women than in men; 2D and 4D extensions and 4D:2D extension ratios may be determined prenatally by sex hormones; fingertip extensions may be predictive of adult and prenatal sex hormone levels.

Association of height and weight with second to fourth digit ratio (2D:4D) and sex differences.

Sex difference in 2D:46 digit ratio was studied in 386 right-handed students. The lengths of index (2D) and ring (4D) fingers were measured using a caliper. Height and weight of participants were recorded. Body height correlated negatively with right- and left-hand digit ratios in the total sample (N = 386); correlations were significant for the left-hand digit ratio of men and for the right-hand digit ratio of women (no significant correlations with weight). Males had a significantly lower 2D:4D ratio than females. After controlling for height, sex differences in right- and left-hand digit ratios completely disappeared. The results suggest that height of adults reflecting prenatal hormone status may play a role in differences between men and women in 2D:4D digit ratio for right-handers.

Sex differences in quadrupedal walking gaits of Uner Tan syndrome cases, healthy humans and nonhuman primates.

BACKGROUND: Uner Tan syndrome (UTS) cases with habitual quadrupedal locomotion (QL), impaired intelligence, and dysarthric or no speech predominantly use lateral sequence (LS) gait like nonprimates rather than the predominantly diagonal sequence (DS) gait of nonhuman primates. However, these studies neglected possible sex-related differences in these gait types. OBJECTIVES: (1) To assess the possible sex-related gait types in UTS cases, healthy infants and adults with requested QL, and the nonhuman primates. (2) To test the hypothesis that sex differences may exist in quadrupedal walking gaits in UTS cases, healthy humans, and nonhuman primates. METHODS: The UTS cases were filmed, the other study groups were taken from public open 'youtube' videos, which were used to assess the walking gait types as DS and LS. The right and left hind-limb phase values were calculated separately for males and females to allow a possible sex difference in walking gaits to be determined. RESULTS: Females predominantly used DS gait, contrary to males with predominantly LS gait. CONCLUSIONS: Consistent with the working hypothesis, the results suggested a biological sex-related trend in preferred walking gaits exists in all of the human and nonhuman primates using QL.

Siblings in Kars, Turkey, with Uner Tan syndrome (quadrupedal locomotion, severe mental retardation, and no speech): a novel theory for the evolution of human bipedalism.

OBJECTIVE: To investigate siblings from Kars (n  =  2), Turkey, with diagonal-sequence quadrupedal locomotion (QL), severe mental retardation, and no speech (Uner Tan syndrome, UTS), in relation to the evolutionary emergence of human bipedal locomotion (BL). METHODS: Video recordings were made to assess gaits. Brain MRI scanning was performed to visualize the cerebro-cerebellar malformations. Genome-wide association analyses were performed in venous blood samples. RESULTS: One of the two men with UTS showed early-onset QL and late-onset BL without infantile hypotonia, the other consistent QL with infantile hypotonia. No homozygosity was found in the genetic analysis. The family lived under extremely poor socioeconomic conditions. CONCLUSIONS: Low socioeconomic status may be a triggering factor for the epigenetic emergence of UTS. The neural networks responsible for the ancestral diagonal-sequence QL, evolutionarily preserved since about 400 MYA, may be selected during locomotor development, under the influence of self-organizing processes during pre- and postnatal periods. The diagonal-sequence QL induced ipsilateral limb interference in UTS cases as in nonhuman primates. To overcome this condition, our ancestors would prefer the attractor BL. This novel theory for the evolution of human bipedalism was evaluated in light of dynamical systems theory.

Early diagnosis of diabetic neuropathy using double-shock stimulation of peripheral nerves.

OBJECTIVE: The purpose of this study was to determine the changes in the amplitudes of a sensory nerve action potential (NAP) to a conditioning stimulus given prior to a test stimulus at 2-8 ms intervals in healthy subjects and patients with diabetes mellitus with no clinical signs of neuropathy and normal nerve conduction velocities (NCVs), to be able to diagnose peripheral neuropathy at its very early stages. METHODS: NAPs in the superficial branch of the radial nerve were recorded in healthy subjects (28 women and 7 men) and type II diabetes patients without neuropathy (22 women and 12 men). Radial nerve was first stimulated with a single shock and then with double shocks at intervals of 2, 3, 4, 5, 6, 7, and 8 ms; NAP amplitudes and NAP1/NAP2 ratios were calculated in normals and diabetics. NCVs were within the normal ranges (>50 m/s) in all subjects. RESULTS: Of the independent variables--group (control, patient), sex (male, female), and hand (right, left)--only group significantly influenced NAP amplitude; mean NAP amplitude (single shock) was significantly lower in patients than controls. NAP1/NAP2 ratios were slightly below one (facilitation) in controls; it was above one at 1-8 ms stimulus intervals (inhibition) in diabetics, which was strongest at smallest intervals, gradually decreasing, and almost disappearing as the stimulus interval approached 8 ms. CONCLUSIONS: Using double-shock stimuli, an early diagnosis of peripheral neuropathy would be possible in diabetics without clinical signs of peripheral neuropathy and exhibiting no slowing in NCV.

Second to fourth digit ratio and hand skill in Austrian children.

Prenatal exposure to testosterone is thought to promote the development of the right-hemisphere and increase the incidence of sinistrality. A direct test of this hypothesis has previously been problematic because of the difficulty of indirectly assessing prenatal sex steroid exposure. Evidence now suggests that the ratio between the length of the second and fourth digits (2D:4D) is related to prenatal testosterone exposure. We tested whether digit ratio is related to the degree of hand skill such that low 2D:4D (indicating high levels of testosterone in utero) may be correlated with enhanced left-hand performance. In right-handed children, high 2D:4D correlated with improved right-hand skill and low 2D:4D correlated with enhanced left-hand skill. Correlations were found to be similar for girls and for boys. Since low 2D:4D has been previously reported to be associated with faster left-hand speed compared to right in Afro-Caribbean children with very low mean 2D:4D, the present finding in a Caucasian population with high mean 2D:4D suggests that a tendency of improved left-hand performance due to prenatal testosterone may be found across ethnic groups.

Covariation of sex differences in mental rotation with body size.

Sex difference in mental rotation ability was reconsidered. The Vandenberg-Kuse figures were administered to 120 male and 76 female students from the Medical School of BlackSea Technical University in Trabzon, Turkey to assess the mental rotation ability. Students' height and weight were measured. As expected, men outperformed women on this test and had greater height and weight. Number correct on mental rotation test significantly correlated with height and weight for the total sample and for men, but only with weight for women. Using weight as covariate, the sex difference was no longer significant. The mean mental rotation score was significantly higher for heavy women than for light men. There was a positive correlation between weight and mental rotation test scores for heavy women, but height and weight were negatively correlated with mental rotation test scores for light men. These results suggest that there is no sex difference in mental rotation ability as measured.

Sex differences in verbal and spatial ability reconsidered in relation to body size, lung volume, and sex hormones.

Sex differences in verbal and nonverbal abilities were reconsidered in relation to bodily measures and sex hormones in Turkish university students. Perceptual-verbal ability was evaluated using As Test. To assess the nonverbal abilities, the mental rotation test and Cattell's Culture Fair Intelligence Test were used. As expected, the 53 women performed better than men on the As Test; 79 men had a higher mean than the 53 women on the mental rotation task; there was no sex difference on Cattell's IQ Test. Cattell IQs correlated only with tidal volume of lungs. Scores on the As Test did not show significant correlations with body size and lung capacities. Mental rotation was significantly correlated with height, weight, and lung volume. With covariates of height, weight, and vital capacity, sex differences in mental rotation completely disappeared, but the difference on the As Test increased while Cattell IQ remained sex-neutral. With testosterone as covariate, the sex difference on the As test increased but on the mental rotation task disappeared; Cattell IQ was sex-neutral. With covariates of estradiol and progesterone, sex differences on the As test disappeared; mental rotation scores and Cattell IQ were not influenced. Under a combined covariation of height, weight, and testosterone, sex differences in mental rotation reversed, women scoring better than men; after adding estradiol or progesterone instead of testosterone to this model, sex differences on mental rotation completely disappeared, but verbal ability and Cattell IQ were not changed. These results suggest that Cattell's Culture Fair Intelligence Test is unique in resistance to sex differences; perceptual-verbal ability was the most sex-specific mental trait but with dependence on estradiol; mental rotation, on the contrary, was least sex-specific, depending on body size, lung volume, sex hormones, and their combined actions, which explains women's better performance.

Two families with quadrupedalism, mental retardation, no speech, and infantile hypotonia (Uner Tan Syndrome Type-II); a novel theory for the evolutionary emergence of human bipedalism.

Two consanguineous families with Uner Tan Syndrome (UTS) were analyzed in relation to self-organizing processes in complex systems, and the evolutionary emergence of human bipedalism. The cases had the key symptoms of previously reported cases of UTS, such as quadrupedalism, mental retardation, and dysarthric or no speech, but the new cases also exhibited infantile hypotonia and are designated UTS Type-II. There were 10 siblings in Branch I and 12 siblings in Branch II. Of these, there were seven cases exhibiting habitual quadrupedal locomotion (QL): four deceased and three living. The infantile hypotonia in the surviving cases gradually disappeared over a period of years, so that they could sit by about 10 years, crawl on hands and knees by about 12 years. They began walking on all fours around 14 years, habitually using QL. Neurological examinations showed normal tonus in their arms and legs, no Babinski sign, brisk tendon reflexes especially in the legs, and mild tremor. The patients could not walk in a straight line, but (except in one case) could stand up and maintain upright posture with truncal ataxia. Cerebello-vermial hypoplasia and mild gyral simplification were noted in their MRIs. The results of the genetic analysis were inconclusive: no genetic code could be identified as the triggering factor for the syndrome in these families. Instead, the extremely low socio-economic status of the patients was thought to play a role in the emergence of UTS, possibly by epigenetically changing the brain structure and function, with a consequent selection of ancestral neural networks for QL during locomotor development. It was suggested that UTS may be regarded as one of the unpredictable outcomes of self-organization within a complex system. It was also noted that the prominent feature of this syndrome, the diagonal-sequence habitual QL, generated an interference between ipsilateral hands and feet, as in non-human primates. It was suggested that this may have been the triggering factor for the attractor state "bipedal locomotion" (BL), which had visual and manual benefits for our ape-like ancestors, and therefore enhancing their chances for survival, with consequent developments in the psychomotor domain of humans. This was put forward as a novel theory of the evolution of BL in human beings.

Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.

Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans.