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.

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.

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.

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.

Clinical, Neurocognitive, Structural Imaging and Dermatogliphics in Schizophrenia According to Kraepelin Criteria.

INTRODUCTION: A century ago, Kraepelin stated that the distinctive feature of schizophrenia was progressive deterioration. Kraepelin criteria for schizophrenia are: (1) continuous hospitalization or complete dependence on others for obtaining basic necessities of life, (2) unemployment and (3) no remission for the past five years. We aimed to determine the clinical appearance and structural biological features of Kraepelinian schizophrenia. METHODS: The sample consisted of 17 Kraepelinian patients, 30 non-Kraepelinian schizophrenic patients and 43 healthy controls. The Clinical Global Impressions (CGI) and the Positive and Negative Syndrome Scales (PANSS) were used for clinical assessment. The Frontal Assessment Battery (FAB) and the Verbal Fluency and Color Trail Test (CTT) were included in the cognitive battery. Brain magnetic resonance imaging and dermatoglyphic measurements were performed for structural features. RESULT: Duration of illness, hospitalization, suicide attempts, admission type, presence of a stressor and treatment choice were similar between the two patient groups. Treatment resistance and family history of schizophrenia were more common in Kraepelinian patients. PANSS and CGI subscales scores were also higher in this group. Only the category fluency and CTT-I were different in Kraepelinian patients in comparison to the other patient group. Structural findings were not different between the three groups. CONCLUSION: Category fluency, which was lower in Kraepelinian patients, is an important marker of a degenerative process. The collection of severe clinical symptoms, family history of psychiatric illness and nonresponse to treatment in this particular group of patients points to the need to conduct further studies including cluster analysis in methodology.

Human quadrupedalism is not an epiphenomenon caused by neurodevelopmental malformation and ataxia.

Two cases with quadrupedal locomotion (QL) were presented. In both cases, cognitive and psychiatric functions were normal and, no neurological deficits were observed, except for a sequel paralysis of left leg in Case 2. It was suggested that human QL (1) should not be considered as an epiphenomenon caused by neurodevelopmental malformation and ataxia, but (2) may be considered as a re-emergence of the ancestral diagonal QL, and (3) it may spontaneously emerge in humans with entirely normal brains, by taking advantage of neural networks such as central pattern generators that have been preserved for about 400 million years.

Lateralized α-motoneuron excitabilities during lying and standing of healthy individuals in relation to parkinsonian rigidity.

OBJECTIVES: To elucidate mechanisms of Parkinsonian rigidity by assessing excitability of alpha-motoneurons innervating right and left soleus muscles in healthy controls and Parkinson's disease (PD) patients with rigidities in the right, left and both legs. METHODS: One group of 45 controls was recruited and 60 PD patients in three groups: rigidities, predominantly in the right, left and both legs. H-reflex (H) and muscle response (M) were recorded from right and left soleus muscles during stimulations of the posterior tibial nerve at the popliteal fossa while lying and standing. The H/M ratio was taken as an index for motoneuron excitability. RESULTS: Mean H/M ratios were significantly different on the right and left sides, modified by postural changes in controls and PD patients. Analysis of variance showed that in healthy subjects the H/M ratio was: standing>lying (right), lying>standing (left). In right leg rigidity patients, the H/M ratio was greatest during standing, and smallest during lying. In left leg rigidity patients, the H/M ratios on the right and left sides were equally independent of posture. In controls, left H/M>right while lying, left, but

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.

Uner tan syndrome: history, clinical evaluations, genetics, and the dynamics of human quadrupedalism.

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.

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.

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.

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.

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.

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.

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.

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.