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Dysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function.

Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. Here, we report the first patient heterozygous for 2 novel mutations in VLDLR. An 18-month-old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. Magnetic resonance imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in 5 families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia, and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically, and molecularly well-defined genetic syndrome.

A new model of the uniqueness, nature and evolution of human bipedality is presented in the context of the etiology of the balance disorder of dysequilibrium syndrome. Human bipedality is biologically novel in several remarkable respects. Humans are (a) obligate, habitual and diverse in their bipedalism, (b) hold their body carriage spinally erect in a multisegmental "antigravity pole", (c) use their forelimbs exclusively for nonlocomotion, (d) support their body weight exclusively by vertical balance and normally never use prehensile holds. Further, human bipedalism is combined with (e) upper body actions that quickly shift the body's center of mass (e.g. tennis serves, piggy-back carrying of children), (f) use transient unstable erect positions (dance, kicking and fighting), (g) body height that makes falls injurious, (h) stiff gait walking, and (i) endurance running. Underlying these novelties, I conjecture, is a species specific human vertical balance faculty. This faculty synchronizes any action with a skeletomuscular adjustment that corrects its potential destabilizing impact upon the projection of the body's center of mass over its foot support. The balance faculty depends upon internal models of the erect vertical body's geometrical relationship (and its deviations) to its support base. Due to the situation that humans are obligate erect terrestrial animals, two frameworks - the body- and gravity-defined frameworks - are in constant alignment in the vertical z-axis. This alignment allows human balance to adapt egocentric body cognitions to detect body deviations from the gravitational vertical. This link between human balance and the processing of geometrical orientation, I propose, accounts for the close link between balance and spatial cognition found in the cerebral cortex. I argue that cortical areas processing the spatial and other cognitions needed to enable vertical balance was an important reason for brain size expansion of Homo erectus. A novel source of evidence for this conjecture is the rare autosomal recessive condition of dysequilibrium syndrome. In dysequilibrium syndrome, individuals fail to learn to walk bipedally (with this not being due to sensory, vestibular nor motor coordination defects). Dysequilibrium syndrome is associated with severe spatial deficits that I conjecture underlie its balance dysfunction. The associated brain defects and gene mutations of dysequilibrium syndrome provide new opportunities to investigate (i) the neurological processes responsible for the human specific balance faculty, and (ii) through gene dating techniques, its evolution.

A peculiar clinical presentation characterized by the triad of opsoclonus,myoclonus and ataxia, mainly in a form of dysequilibrium, is usually associated with infectious or paraneoplastic processes. Serial cerebrospinal fluid (CSF) analysis in two patients with opsoclonus-myoclonus-dysequilibrium syndrome suggestive of viral encephalitis were performed from disease onset for up to 8 months. A cell count, cytology, total protein and glucose concentrations in CSF, the blood-CSF barrier function, intrathecal synthesis of immunoglobulins (Ig) in class M, G and A expressed as IgM, IgG and IgA indices and oligoclonal IgG bands were monitored. Cellular and humoral alterations in both patients were slight at the onset becoming more pronounced a month later. The kinetics of the CSF changes mirrored the subacute clinical deterioration and subsequent recovery. The delayed response in the CSF measures and the gradual clinical deterioration suggest the development of subacute brain inflammation. A mononuclear pleocytosis, including macrophages and plasma cells, increased within the first month and then normalized during the following weeks. Intrathecally synthesized IgM occurred only transiently after one month of illness, whereas intrathecal IgG production increased during the first month and persisted for at least eight months. An increasing number of oligoclonal IgG bands during the course, indicative of expanding local intrathecal synthesis, was noted. The dynamics of these CSF changes supports the hypothesis that opsoclonus-myoclonus syndrome is a post-infectious immune- mediated condition.

In eight children with the dysequilibrium syndrome, an autosomally recessively inherited syndrome of cerebral palsy, low serum dopamine-β-hydroxylase activity was found. This indicates a diminished activity of the sympathetic nervous system in this syndrome.

Background Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes. Methods SNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used. Results We identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function. Conclusions We have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.

We define the neurological characteristics of familial cases from multiple branches of a large consanguineous family with cerebellar ataxia, mental retardation (MR), and dysequilibrium syndrome type 3 caused by a mutation in the recently cloned CA8 gene. The linkage analysis revealed a high logarithm of the odds (LOD) score region on 8q that harbors the CA8 in which a novel homozygous c.484G>A (p.G162R) mutation was identified in all seven affected members. The patients had variable cerebellar ataxia and mild cognitive impairment without quadrupedal gait. The brain MRI showed variable cerebellar volume loss and ill-defined peritrigonal white matter abnormalities. The Fluorodeoxyglucose Positron Emission Tomography (FDG PET) revealed hypometabolic cerebellar hemispheres, temporal lobes, and mesial cortex. This report expands the neurological and radiological phenotype associated with CA8 mutations. CA8 involvement should be considered in the differential diagnosis of other genetically unresolved autosomal recessive cerebellar ataxias. © 2011 Wiley-Liss, Inc.

Background Acute interhemispheric subdural hematoma (AISH) is an extremely limited complication in patients on maintenance hemodialysis. Diagnostic difficulties result from a fact that symptoms of acute hematoma such as headache, nausea, vomiting, apathy, sleepiness, paresthesia and seizures may also suggest dysequilibrium syndrome, dialytic dementia as well as hypertensive encephalopathy. Case Description A case of acute interhemispheric subdural hematoma during long-term dialysis is presented. Conclusion AISH caused by hemodialysis is a very important complication. It is sometimes difficult to differentiate from dysequilibrium or dialysis dementia. Clinicians must pay closer attention on neurological examination of hemodialyzed patient. Surgical treatment must be as prompt as possible because of the possible sudden worsening of the patient's clinical condition.

Two rare cases of Wernicke's encephalopathy (WE) in non-alcoholic patients on hemodialysis (HD) are reported. They presented with the clinical triad of WE (ophthalmoplegia, ataxia and disturbance of consciousness) and intravenous administration of thiamine led to complete elimination of these manifestations. Reduced plasma thiamine levels prior to the administration confirmed the diagnosis of WE. Interestingly, a reduction in plasma thiamine levels by about half was seen in one of the patients on HD, suggesting that thiamine, a water-soluble vitamin, can be depleted with HD. In the literature, nine HD-dependent patients have been reported to develop WE, seven of whom were diagnosed postmortem. Their premortem diagnoses included uremic encephalopathy, dysequilibrium syndrome and dialysis dementia, which can often complicate HD and present symptoms similar to those of WE. We therefore emphasize that WE, even though a rare complication, should be suspected in all patients on HD who present with at least one of the clinical triad of WE.

Neurological disorders may be seen in end-stage renal disease patients due to uraemia or to complications of dialysis. A dysequilibrium syndrome may be seen, usually soon after or towards the end of haemodialysis. This group of patients has no particular findings on MRI. On the other hand, the osmotic demyelination syndrome has definitive MRI findings, not to date reported with the dysequilibrium syndrome. We report a patient with end-stage renal disease and the dysequilibrium syndrome who showed findings of osmotic demyelination on MRI. The patient had a convulsion after a first haemodialysis, with quadriparesis and hyperactive deep tendon reflexes and bilateral Babinski signs. The upper motor neurone signs lasted for a week. Meanwhile, he was also dysarthric and had dysphagia. He recovered neurologically without any residuum following appropriate treatment and there was improvement on MRI.

Control of osmolarity, as well as sodium, urea, and water balance in anuric patients under intermittent haemodialysis therapy is fundamentally different from subjects with normal kidney function. Whereas in subjects with normal kidney function excretion of solutes and water is performed continuously, during dialysis, within a short period of time most sodium and only a small amount of urea are removed convectively with the ultrafiltration of water (1 litre of ultrafiltrate = 8.5 g sodium chloride and about 1.5 g urea). On the other hand most urea and a small amount of sodium is removed by diffusion, depending on the dialyser clearance and the difference in concentration between plasma and dialysis fluid. The relatively short period of treatment induces acute changes in fluid volume, urea, and sodium concentration as well as in plasma osmolarity, which in healthy subjects never happen. The consequence are side-effects of dialysis therapy such as osmotic dysequilibrium syndrome, muscle cramps, symptomatic hypotension, and thirst. Having no mechanism to excrete sodium during the long period between two dialyses, the anuric patient only has the possibility to dilute a high sodium concentration by drinking or to minimize sodium ingestion. Consequently the amount of fluid ingestion depends on the amount of sodium chloride ingestion by eating and probably on an increase in sodium concentration due to dialysis treatment itself. Among other methods profiling of ultrafiltration and sodium concentration in dialysis fluid has been proposed to optimize dialysis therapy. To evaluate the benefit of profiling to the patient the basic conditions of water and solute distribution and exchange in dialysis therapy have to be considered.

Even in the absence of clinically apparent seizures, patients undergoing chronic dialysis often exhibit abnormal EEG activity, which is usually attributed to the type of dialysis or to the dysequilibrium syndrome. To find out whether these abnormalities occurred only during dialysis sessions, 10 children with end-stage renal failure undergoing chronic dialysis were continuously monitored for 52 h during dialysis and between two sessions. The EEG tracing was abnormal in 5 children. Two had paroxysmal aspecific slow waves towards the end of the sessions, with a fall in blood pressure, malaise and fainting. In 3 children EEG abnormalities – also present in the interdialytic period – were not clinically apparent. Long-term EEG monitoring in these cases distinguished between the electrical events that were related to dialysis and those that were not. It also suggested that, rather than being dialysis-dependent, these events frequently reflect a basic neurological disorder.

Although the occurrence of Wernicke's encephalopathy (WE) in patients on dialysis is frequently alluded to, review of the literature reveals only 3 described cases. We describe 5 patients on dialysis who developed WE in the absence of alcoholism or other predisposing factors. The clinical diagnoses included uremic encephalopathy (2 patients), dysequilibrium syndrome (1), dialysis dementia (1), and brainstem hemorrhage (1). At postmortem examination, classic findings of WE were evident. The rarity of WE in patients on dialysis may in part be explained by studies indicating a genetic defect in transketolase activity. Patients on dialysis are also potentially at risk for thiamine deficiency because of anorexia, vomiting, and intravenous alimentation. Other factors altering thiamine requirements, such as glucose load or infections, may also contribute. Preventable and potentially curable, WE should be suspected in all patients on dialysis who have an unexplained neurological picture.

We report a nonprogressive neurological disorder in at least 11 Hutterites with healthy but consanguineous parents. In several of the affected, hypotonia was noted at birth. Retarded motor and mental development became apparent during the first year of life. The age of unsupported walking varied from 5-21 years. Consistent signs were unsteady, broadly based gait and stance, exaggerated deep tendon reflexes mainly in the lower limbs, and mild to moderate mental retardation. Variable signs were extensor plantar reflexes (9/11), short stature (-2SD in 8/11), strabismus (7/11), small muscle mass (6/11), mild intention tremor (3/11), cataracts (1/11), and epilepsy (1/11). CAT scans in two affected sisters showed slight enlargement of the fourth ventricle in one and hypoplasia of the cerebellum in both. The disorder is probably the same as that described earlier under the heading, dysequilibrium syndrome.

Bergstrom, K. and Sanner, G. (Departments of Diagnostic Radiology and Paediatrics, University Hospital, Uppsala, Sweden). Pneumoencephalography in non-progressive ataxic syndromes. A study of 26 children and adolescents. Acta Paediatr Scand, 63:732, 1974.—Twenty-six patients with a congenital non-progressive ataxic syndrome underwent pneumoencephalography (PEG). The patients were classified clinically into four groups: (I) The dysequilibrium syndrome (DES). (II) The dysequili brium syndrome with cataract. (III) Transitional form (TF). (IV) Simple ataxia (SA). In patients with signs of dysequilibrium different PEG changes were found; 16 of the 21 patients had cerebellar abnormalities. In all but one of the evaluable cases with signs of DES and cerebellar abnormalities on PEG a small antero-superior part of the vermis was characteristic, which might be of patho-genetic importance. None of the 5 patients with SA had a small cerebellar vermis. It was suggested that PEG may be of diagnostic help in infancy in presumptive ataxic conditions, but is neither of prognostic importance nor of diagnostic help for delineating specific hereditary forms.

Acute renal failure in critically ill patients is seldom an isolated problem but is more usually associated with multiple organ failure. When choosing an extracorporeal kidney replacement therapy, these other failing organs must be taken into account. Therefore the choice of an artificial kidney in patients requiring intensive care depends on both the efficacy of the technique and its possible adverse effects on cerebral, pulmonary and cardiovascular function. The most important pathogenic factors in the development of dysequilibrium syndromes, arterial hypoxemia and hypotension are treatment timing, diffusive solute transfer, bio-incompatible membranes and some specific dialysate components (buffer, electrolyte concentrations). It is important to understand the mechanisms by which these factors exert their adverse effects. Application of these pathophysiological mechanisms to the cardiopulmonary and neurologic status of the individual patient permits the prediction of their clinical outcome. This approach will lead to individualised treatment selection, thereby avoiding deleterious side-effects without loss of efficacy.

Les auteurs ont etudie l'aspect de l'excretion des aminoacides et des acides organiques chez trois des patients decrits par Schuring et col. (1981) avec le syndrome de desequilibre. Les ressemblances cliniques avec l'acidurie 4-hydroxybutyrique ont rendu interessante la mesure de l'activite de la succinique semialdehyde dehydrogenase dans les lymphocytes isoles du sang peripherique de ces patients. Les resultats montrent que, en depit des similitudes cliniques, le syndrome de desequilibre et l'acidurie 4-hydroxybutyrique semblent etre des entites pathologiques distinctes

Specific problems discussed include blood access and complications thereof, pediatric dialyzers with reference to priming volumes, efficiency of clearance and dysequilibrium syndrome, ultrafiltration and weight monitoring, and hemodialysis for intoxications.

The optimality of prenatal and perinatal conditions, serum levels of radioreceptor-assayable somatomedins and activity of catechol-0-methyltransferase in erythrocytes were examined in 13 dysequilibrium (DES) patients. No differences from normal controls were found. As a group, the DES patients were not more exposed to non-optimal prenatal and perinatal events than healthy controls. No association between DES and somatomedin levels or between DES and catechol-0-methyltransferase activity was demonstrated.

Visual evoked potentials (VEP) were recorded in 20 children undergoing dialysis for chronic renal failure. VEP before treatment (72 h after last dialysis) were pathological in 17 patients (85%); responses obtained 3 h after treatment were abnormal in only 6 cases (30%). Furthermore, all patients improved after treatment, except two who were unchanged. However, VEP recorded immediately after dialysis were worse in 4 of 7 patients than before treatment, probably as an effect of the dysequilibrium syndrome; they improved spontaneously afterwards. The acute changes caused by dialysis seem to be more evident in children than in adults. No correlations have been found between blood chemistry indexes and VEP modifications. Finally, VEP have proved to be more sensitive than EEG in identifying a central nervous system (CNS) dysfunction in these uremic patients.

Background. Among dialysis patients in the last 10 years the incidence of intradialytic dysequilibrium syn- model drome and symptomatic hypotension has increased significantly. Profiled haemodialysis (PHD), a new dialysis technique based on intradialytic modulation Introduction of the dialysate sodium concentration according to pre-elaborated individual profiles, has been set up to In the last 10 years the dialysis population has greatly reduce intradialytic imbalances and the incidence changed in age, (40% of patients are older than 65 of dysequilibrium syndrome and symptomatic hypo- years), and clinical traits: in particular the incidence tension. of patients with cardiovascular pathology has increased The present paper illustrates a new mathaematical from 25 to 50% both in the USA and in Europe. This model for solute kinetics, single-compartment for qualitative change in the dialysed population has sodium and two-compartment for urea, aimed at caused a reduction in mean survival rate, an increase improving the use of PHD. The model allows the in cardiovascular morbidity and a reduction in clinical sodium profile to be elaborated a priori, before each tolerance to extracorporeal sessions [1]. Consequently dialysis session, according to the patient’s clinical needs the main clinical intradialytical complications, disequiland respecting the individual sodium mass removal ibium syndrome and symptomatic hypotension, are and weight gain. now on the increase and their incidence ranges between Method. The mathaematical model was first derived 5 and 15% for dysequilibrium syndrome and 20 and and then applied to determining a rational dialysate 35% for hypotension [2‐5]. sodium profile. A procedure which allows the method One of the pathophysiological reasons for these to be tuned to individual clinical needs on the basis of complications is the removal of toxins with too fast a routine measurements performed before each session reduction in extracellular osmolarity during the first is also presented. The proposed method was validated half of the extracorporeal session [6‐10]. The main in vivo during seven dialysis sessions, each performed consequences are a loss in fluid refilling from the extraon a diVerent patient. to the intravascular compartment and the fluid shift Results. The comparison beetween data predicted by from extra- to intracellular which, combined with the the model and those obtained in vivo shows a good eVects of ultrafiltration, produces an overall reduction correspondence in particular concerning the time in circulating volume [11‐14]. As a clinical conpattern of blood urea and sodium. The comparison sequence the reduction in circulating volume causes between the model prediction and in vivo determined hypovolaemia with symptomatic hypotension while sodium and urea plasma curves showed standard devi- the intracellular fluid shift causes dysequilibrium ations (2.25 mEq/l for sodium and 0.87 mmol/l for syndrome. urea) only slightly higher than those attributable to The number of patients suVering from symptoms laboratory measurement errors. Moreover, in vivo due to dysequilibrium during dialysis, including implementation of PHD by our model enables one to hypotensives episodes, remains significant, due in part remove an amount of sodium mass comparable with to limited development of dialysis regimes designed to the a priori quantity predicted by the model. reduce osmotically induced fluid shifts.

in association with many pathologic processes, but not with hypoglycemia. In pediatric patients ACB has been described in association with brain tumors, increased intracranial pressure, optic neuritis, orbital and extraorbital infections, degenerative diseases of the central nervous system, l ischemia and anoxia, 7 uremia$ and lactic acidosis. 8 In addition, ACB has been described as a post-ictal phenomenon in children ~ and as a complication of a dysequilibrium syndrome in a child undergoing hemodialysis. 1~ In our patient, recurrent episodes of transient loss of vision apparently occurred in several hypoglycemic attacks, as described by the parents, and was observed during his hospitalization. This patient fulfilled the diagnostic criteria for CB, i.e., loss of vision in the presence of normal pupillary reflexes without ophthalmologic diseases. The absence of optokinetic nystagmus provided further evidence for this diagnosis. It may be assumed that the visual loss is the result of hypoglycemia-induced aberration of cerebral function. Transient cortical blindness is a common manifestation of cerebral anoxia in children, 1. 7, ~ most probably related to greater vulnerability of the occipital cortex in this age group to various noxious conditions, and hypoglycemia may be one of them. Cerebral oxygen consumption is reduced in hypoglycemia, so that a state of relative hypoxia also exists; adenosine triphosphate synthesis is deficient and does not meet brain energy demands, especially those related to the sodium pump and neurotransmitter synthesisY In patients with ACB, the clinician should be alert to the possible association of this condition with hypoglycemia, and blood glucose determination is suggested in the evaluation of patients with ACB.

SUMMARYThe effect of hemodialysis upon plasma cortisol levels and the electroencephalograms of uremic patients was examined with respect to the possible contribution of altered plasma cortisol to the dialysis-induced CNS dysequilibrium syndrome. It was concluded that alterations in plasma cortisol do not have a significant role in this syndrome. In addition, it was demonstrated that hemodialysis does alter, in time and amount, the pattern of cortisol secretion in uremic subjects. The alterations in cortisol secretion were not related to the uremic state or to the amount of fluid removed during dialysis. The value of frequent sampling during a dynamically changing situation was demonstrated. The results were discussed in relation to the central nervous system control of cortisol secretion.