Meliha Tan

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.

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.

Personality, depression, and anxiety as risk factors for chronic migraine.

This article evaluated risk factors such as personality, depression, and anxiety in relation to migraine transformation in Turkish patients. Thirty-seven patients with chronic migraine and 50 patients with episodic migraine were investigated. The scores for hysteria, hypochondriasis, psychasthenia, depression, and social introversion were all significantly higher in the chronic-migraine group than the episodic-migraine group. Seventy-four percent of the chronic-migraine group and 26% of the episodic-migraine group had depression. Eighty percent of the chronic-migraine group and 36% of the episodic-migraine group had anxiety. The results suggest that depression, anxiety, and personality characteristics such as hysteria, hypochondriasis, psychasthenia, depression, and social introversion may be associated with chronic migraine in Turkish patients.

Incidences of asymmetries for the palmar grasp reflex in neonates and hand preference in adults.

It was hypothesized that adult handedness might be predicted from the neonatal grasp reflex. Grasp reflex was measured from right and left hand (10 trials for each hand) in neonates. According to significance for the difference between the mean grasp reflex strength from the right and left hands, the subjects were designated as right-, left-, and mixed-handers. Adult hand preference was assessed by Edinburgh Handedness Inventory. The percentage of left-handedness (8.3%) in neonates coincided with adult left-handedness (6.3-9.2%). The percentage of consistent right-hand preference in adults coincided with percentage of right-handedness in neonates (25.7%). The high percentage of neonatal mixed-handedness was similar to that to be expected from the right shift model of hand preference. It was concluded that left-handedness and consistent right-handedness may be determined prenatally, under genetic and/or hormonal control, and that a large majority of neonatal handedness, mixed-handers, might change their hand preference in favor of right-handed-ness under socio-cultural and developmental influences of speech centres.

Testosterone and grasp-reflex differences in human neonates

According to the Geschwind-Behan-Galaburda (GBG) hypothesis, prenatal testosterone (T) causes a slowing in the development of the left brain with a consequent compensatory growth in the right brain, creating a reverse organisation of the cerebral lateralisation. That is, left- and right-handedness might be associated with high and low prenatal T levels, respectively. To test this hypothesis, the relations of T levels (umbilical cord blood) to grasp-reflex strengths were studied in human neonates. Handedness was assessed by measuring the grasp-reflex strengths from the right and left hands in 10 trials from each hand alternatively. There were two handedness groups: right-handers (R-L significantly greater than zero) and left-handers (significantly smaller than zero). Contrary to the GBG model, the mean free T concentration was found to be significantly higher in right-handers than left-handers for males and females. There was no significant difference in the total T levels between right- and left-handers. Free T concentrations positively correlated with R-L grasp-reflex strengths, i.e. righthandedness increased as T increased, and left-handedness increased as T decreased. Contrary to these positive correlations, T negatively correlated with the grasp-reflex strengths from the right and left hands. These results partly supported the GBG hypothesis for this spinal-motor-asymmetry model. Total T did not significantly correlate with grasp-reflex strengths. The results suggest that prenatal T may at least play a role in prenatal determination of spinal motor lateralisation, with a possible consequent upward regulation of cerebral lateralisation.

Is low blood magnesium level associated with hemodialysis headache

Objective.—The aim of this study was to evaluate the prevalence, demographic, clinical features, and possible risk factors for hemodialysis headache (HDH).

Sex difference in susceptibility to epileptic seizures in rats: importance of estrous cycle.

Sex difference in seizure susceptibility is one of the unresolved issues of epilepsy. It is known that estrogen is excitatory and progesterone is inhibitory to the central nervous system. Therefore, it is to be expected that seizure susceptibility may be associated with the estrous cycle, which should be tested in epilepsy research. Otherwise, different results in epilepsy studies could be an artifact of the estrous cycle. Reports in the literature are inconsistent about testosterone effects on seizures. In light of these considerations, sex differences in seizure susceptibility were restudied in rats. There was no significant sex difference in mean latencies to picrotoxin-induced seizures; prestrous-females had the shortest latencies to epileptic seizures compared to males and estrousfemales. With testosterone-injected rats, there was either no sex difference in latencies (to akinetic and focal seizures) or females had significantly shorter latencies than males (to status epilepticus, generalized tonic-clonic seizures, and myoclonic seizures). Testosterone-treated male rats had a significantly longer mean latency than controls for status epilepticus only; otherwise, these males showed no significant differences between mean latencies before and after testosterone (to focal, myoclonic, or generalized tonic-clonic seizures). In females, mean latencies to myoclonic seizures and status epilepticus were significantly shorter after testosterone than before. It was concluded that there is a sex difference in susceptibility to epileptic seizures in rats, provided that the estrous cycle is taken into account. Testosterone may increase and decrease seizure susceptibility in females and males, respectively. These effects may be important for understanding the mechanisms of epileptic phenomena and may provide some important clues to epilepsy treatment.

Unertan syndrome: a case series demonstrating human devolution.

A large family with six individuals exhibiting the Unertan syndrome (UTS) was identified residing in southern Turkey. All of the individuals had mental impairments and walked on all four extremities. The practice of intra-familial marriages suggested that the UTS may be an autosomal recessive disorder, similar to previously described cases. The inferior portions of the cerebellum and vermis were absent as evidenced by MRI and CT scans. The height and head circumference of those affected were within normal ranges. Baranys test suggested normal vestibular system function. The subjects could not name objects or their close relatives. The males (n = 4) could understand simple questions and commands, but answered questions with only one or two sounds. The females (n = 2) were superior to the males with respect to language skills and walking, suggesting an association between walking and speaking abilities. One male exhibited three walking patterns at the same time: quadripedal, tiptoe, and scissor walking. Another male used two walking styles: quadripedal and toe-walking. It is emphasized that there are important differences between the UTS and the disequilibrium syndrome. It is suggested that the inability to walk upright in those affected with the UTS may be best explained by a disturbance in lateral-balance mechanisms, without being related to the cerebello-vestibular system. An interruption of locomotor development during the transition from quadripedality to bipedality may result in habitual walking on all four extremities and is normal in some children. Because quadripedal gait is an ancestral trait, individuals with the UTS, exhibiting a manifestation of reverse evolution in humans, may be considered an experiment of nature, useful in understanding the mechanisms underlying the transition from quadripedality to bipedality during human evolution. The proposed mutant gene or gene pool playing a role in human quadrupedality may also be responsible for human bipedality at the same time. Herein there is no intent to insult or injure; rather, this report is an endeavor to better understand human beings. Supplementary materials are available for this article. Go to the publishers online edition of International Journal of Neuroscience for the following free supplemental resource(s): video clips.

Spinal MRI Findings of Guillain-Barré Syndrome

Guillain-Barré syndrome is a relatively common, acute, and rapidly progressive, inflammatory demyelinating polyneuropathy. The diagnosis is usually established on the basis of symptoms and signs, aided by cerebrospinal fluid findings and electrophysiologic criteria. Previously, radiologic examinations have been used only to rule out other spinal abnormalities. We report a case of systemic lupus erythematosus associated with Guillain-Barré syndrome with marked enhancement of nerve roots of the conus medullaris and cauda equina on MR imaging. These MR observations may help confirm the diagnosis of Guillain-Barré syndrome.

Abducens nerve palsy and optic neuritis as initial manifestation in brucellosis

Cranial nerve involvement in brucellosis is rare. We present a case of brucellosis presenting with optic neuritis and abducens nerve palsy on the left side. Cerebrospinal fluid findings indicated Brucella meningitis with high protein count, low sugar level and pleocystosis. In addition, Brucella agglutination test (Wright test) was found to be 1/128 in cerebrospinal fluid. Serum agglutination test for Brucella was also positive at 1/1280. This case was diagnosed as brucellosis involving optic and abducens nerves. The patient was treated by ceftriaxone (intravenous), rifampicin (orally) and doxycycline (orally). Two months later the patients vision acuity in the left eye had moderately improved and the patients left abducens palsy had almost disappeared. In conclusion, cranial nerve involvement in brucellosis can have good prognosis if anti-Brucella treatment is undertaken early.