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Adrian Danek

Publications and source records attributed to Adrian Danek.

At least 19 recordsLinked to original sources
PubMed2007

Phenotypic variation among brothers with the McLeod neuroacanthocytosis syndrome.

McLeod syndrome is an X-linked multisystem disorder affecting red blood cells, the peripheral and central nervous systems, and skeletal and cardiac muscle. No clear correlations of the clinical findings with the genotype of XK mutations have yet been uncovered. Here, we report the clinical features and progression in 10 affected brothers from 4 families with McLeod syndrome. There is significant variation in clinical presentation within families, including in causes of morbidity and mortality. This phenotypic variation, despite shared mutations, suggests the action of disease-modifying factors that may explain some of the difficulties with genotype-phenotype correlation in McLeod syndrome.

Adult↗
PubMed2006

Head of the caudate nucleus is most vulnerable in chorea-acanthocytosis: a voxel-based morphometry study.

Chorea-acanthocytosis (ChAc; OMIM 200150) is a rare autosomal recessive disease with dysfunction of the erythrocyte membrane, presenting with acanthocytes and neurological manifestations characterized by progressive hyperkinesias (chorea, dystonia) and neuropsychological impairment. Damage to the basal ganglia was described previously in neuropathological and neuroimaging investigations. We analyzed high-resolution MRI of six ChAc patients with mutations in the VPS13A gene (median age, 37 years; mean time since clinical onset, 13 years) with respect to regional atrophy by use of the observer-independent technique of voxel-based morphometry in comparison to 15 age-matched healthy controls. Additionally, global brain atrophy was determined using the standardized brain parenchymal fraction (BPF) method. A robust regional reduction of gray matter density was observed in the head of the caudate nucleus bilaterally and was nearly symmetrical (P < 0.001, corrected for small volumes). No additional gray matter changes were found. In the BPF analysis, there was no significant global brain atrophy. The predilection of atrophy in the head of the caudate nucleus, as suggested by our results, argues for a particular vulnerability of this part of the striatum in ChAc and is in agreement with pronounced neuropsychological disturbances that are thought to rely on these regions.

Adult↗
PubMed2006

Developments in neuroacanthocytosis: expanding the spectrum of choreatic syndromes.

As with other neurodegenerative disorders, research into the group of diseases known under the umbrella term of "neuroacanthocytosis" has greatly benefited from the identification of causative genes. The distinct and unifying aspect of these disorders is the presence of thorny deformations of circulating erythrocytes. This may be due to abnormal properties of red cell membranes, which could lead to insights into mechanisms of neurodegeneration. Research approaches in this field, in addition to examining functions and protein interactions of the affected proteins with particular respect to neurons, have also drawn upon the expertise of hematologists and red cell membrane biologists. In this article, recent developments in the field are presented.

Animals↗
PubMed2006

The challenge of axonal path-finding.

Congenital syndromes of altered nervous system connectivity are reviewed along with recent findings on axonal growth: achiasma, congenital nystagmus, congenital horizontal gaze palsy, mirror movements and the syndromes of Kallmann, Wildervanck, Duane and Marcus Gunn. Identical guidance molecules are most likely involved in making axonal connections after injury and during development. Thus, investigations into variants of connectivity may help develop strategies to treat disconnections of axons in the adult.

Axons↗
PubMed2006

Bernhard von Gudden, neuro-ophthalmology and the Munich School of Neuroanatomy and Psychiatry.

Bernhard von Gudden, psychiatrist to the Royal House of Bavaria (1824-1886), had studied ocular torsion by means of self-observation in the mirror and with the help of after-images for his dissertation of 1848, but later turned to experimental neuroanatomy. Several findings are connected with his name, among them the transverse peduncular tract, part of the accessory optic system. August Forel, Emil Kraepelin and Franz Nissl belonged to his Munich school that took neuroanatomical research as a guiding principle for scientific psychiatry.

Germany↗
PubMed2005

Identification of a VPS13A founder mutation in French Canadian families with chorea-acanthocytosis.

Mutations in VPS13A cause chorea-acanthocytosis (ChAc), an autosomal recessive neurodegenerative disorder. VPS13A is located in a tail-to-tail arrangement with GNA14 on chromosome 9q21. ChAc shows substantial allelic heterogeneity, with no single VPS13A mutation causing the majority of cases. We examined 11 patients in four French Canadian ChAc pedigrees for mutations in VPS13A. Affected members of three families were homozygous for a 37-kb deletion of the four terminal exons of VPS13A (EX70_EX73del). This deletion also encompasses the two terminal exons of GNA14. Two affected females in family 4 were homozygous for the splicing mutation 4242+1G>T. Remarkably, the affected males in this highly consanguineous pedigree were compound heterozygotes for EX70_EX73del and 4242+1G>T. PCR analysis of the deletion breakpoint junction revealed that an additional patient with French Canadian ancestry was heterozygous for the EX70_EX73del allele. The identification of a common 9q21 haplotype associated with EX70_EX73del in at least four apparently unrelated ChAc families implies that ChAc shows a founder effect in French Canadians, and that routine testing for EX70_EX73del in suspected ChAc cases may therefore be worthwhile in this population. The deletion breakpoint PCR described here will enable rapid identification of both homozygous and heterozygous carriers of EX70_EX73del.

Age of Onset↗
PubMed2005

Neuroacanthocytosis: new developments in a neglected group of dementing disorders.

Neurological abnormalities associated with spiculated, "acanthocytic" red cells in blood have been summarized as neuroacanthocytosis. This is a heterogeneous group of conditions that can now be clearly subdivided on the basis of genetic discoveries. The core neuroacanthocytosis syndromes are autosomal recessive chorea-acanthocytosis (ChAc) and the X-linked McLeod syndrome (MLS). Huntington's disease-like 2 (HLD2) and pantothenate kinase associated neurodegeneration (PKAN) can now also be included. All of these share dyskinesias, cognitive deterioration and progressive neurodegeneration mainly of the basal ganglia, but they are sufficiently distinct to permit a specific working diagnosis on the basis of clinical, laboratory and imaging findings. In addition, the VPS13A (formerly called CHAC), XK, JPH3 and PANK2 genes, respectively, may be examined for mutations. Unfortunately, little is yet known about the normal and abnormal physiology of the protein products of these genes, but they appear to be involved in membrane function and intracellular protein sorting. Since no cures are yet available, development and study of disease models in experimental animals (mouse, C. elegans) is a priority for current research. From a clinical point of view, the common occurrence of cardiomyopathy in MLS, the transfusion hazards due to the McLeod Kell phenotype and the possibility of improving the violent trunk spasms and orofacial dyskinesias typical for ChAc (with subsequent lip or tongue mutilations and feeding dystonia) by deep brain surgery or stimulation should be considered in patient management.

Amino Acid Sequence↗
PubMed2005

Neuroacanthocytosis.

PURPOSE OF REVIEW: The term neuroacanthocytosis describes a group of phenotypically and genetically heterogeneous disorders, and thus has long been a source of confusion and diagnostic imprecision. It is vital to distinguish between the lipoprotein deficiency disorders which affect gait, but do not cause movement disorders or neuropsychiatric problems, and the diseases described here, of which these are characteristic features. This review summarizes the current state of knowledge regarding this group of diseases in order to facilitate clinical recognition, accurate diagnosis and appropriate management. RECENT FINDINGS: Advances in molecular medicine have enabled us to distinguish precisely among the disorders described under the label of neuroacanthocytosis, most notably between autosomal recessive chorea-acanthocytosis and the X-linked McLeod syndrome. This has facilitated appreciation of the range of phenotypes in each of the various conditions. Acanthocytosis is also found in a smaller percentage of cases with pantothenate kinase-associated neurodegeneration (PKAN) and Huntington's disease-like 2 (HDL2). An improved method of determination of acanthocytosis has been described, which if adopted as standard practice may facilitate detection of these conditions. SUMMARY: Genetic testing has led to increased diagnostic accuracy of the neuroacanthocytosis syndromes, which is essential to extend recognition of these disorders, as well as to improve understanding of the disease process. Most importantly, given the absence of a cure, it is vital for appropriate genetic counselling. Treatments, as in other neurodegenerative conditions, are at present limited to symptomatic therapies.

Acanthocytes↗
PubMed2005

Eye movements in chorea-acanthocytosis.

PURPOSE: To describe the eye movement abnormalities in patients with chorea-acanthocytosis (ChAc), a form of neuroacanthocytosis. This autosomal recessive, neurodegenerative disorder with aberrant erythrocyte morphology (acanthocytosis) is caused by mutations in the VPS13A gene. In contrast to Huntington's disease (for which ChAc has occasionally been mistaken), ocular involvement in ChAc has not been systematically studied. METHODS: Three patients aged 26, 30, and 44 years with ChAc and six normal volunteers aged 31 to 48 years were included. Patients had dystonia, chorea, parkinsonism, dysarthria, dysphagia, seizures, cognitive abnormalities, and acanthocytosis. All had heterozygous VPS13A mutations and degeneration of the basal ganglia on magnetic resonance imaging (MRI) typical of ChAc. Patients had an extensive clinical and laboratory work-up. Neuro-ophthalmic examinations and eye movement recordings made with the magnetic search coil technique assessed patients' fixation characteristics, horizontal and vertical saccades, pursuit, and antisaccades. These were compared to the data of control subjects. RESULTS: Patients exhibited more than 30 square-wave jerks (small saccadic intrusions) per minute, versus 0 to 8 in the control subjects, as well as fractionated (multistep) and hypometric horizontal and vertical saccades. Decreased saccadic peak-velocity and reduced saccadic range were more pronounced for vertical saccades. Pursuit testing performed in two patients showed low gain. Results of antisaccade testing done in one patient were abnormal. CONCLUSIONS: The findings suggest brain stem involvement as an additional site of neurodegeneration outside the basal ganglia in ChAc. Patients with this progressive, intractable disease have pronounced ocular motor abnormalities. Eye movement recordings could assist in diagnosing ChAc, monitoring its progression and possible treatment evaluation.

Adult↗
PubMed2005

The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia.

OBJECTIVE: Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects. METHOD: A cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 matched comparison subjects (mean age=47.2 years, SD=14.0) was conducted. Participants underwent a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring. RESULTS: CADASIL subjects had pronounced impairments of the timed measures (Stroop II and III, Trail Making Test, symbol digit, digit cancellation). Measures of error monitoring (Stroop III, Trail Making Test, symbol digit, maze task) were also significantly affected but to a lesser extent. Prominent deficits further included verbal fluency and ideational praxis. Recall, orientation, and receptive language skills were largely preserved. Subgroup analyses indicated a similar profile in subjects with early and advanced impairment of global cognitive performance. CONCLUSIONS: The findings highlight processing speed as the most substantial area of cognitive impairment in CADASIL subjects, with less pronounced yet significant deficits in other aspects of executive performance and attention. This profile of cognitive impairment is present at an early stage and enables the construction of targeted test batteries for clinical trials. It is hypothesized that the profile of dysfunction described here represents the core of the cognitive syndrome associated with small vessel disease and subcortical ischemic vascular lesions.

Attention↗
PubMed2004

Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels.

BACKGROUND: Microvascular alterations contribute to the development of stroke and vascular dementia. The goal of this study was to evaluate age and hypertension related changes of the basal lamina in cerebral microvessels of individuals, who died from non-cerebral causes. RESULTS: We examined 27 human brains: 11 young and 16 old patients. Old patients were divided into two subgroups, those with hypertension (n = 8) and those without hypertension (n = 8). Basal lamina changes of the cerebral microvessels were determined in the putamen using antibodies against collagen type IV and by quantitative analysis of vessel number, total stained area of collagen, thickness of the vessel wall and lumen, and relative staining intensity using immunofluorescence. The total number of collagen positive vessels per microscopic field was reduced in old compared to young subjects (12.0+/-0.6 vs. 15.1+/-1.2, p = 0.02). The relative collagen content per vessel (1.01+/-0.06 vs. 0.76+/-0.05, p = 0.01) and the relative collagen intensity (233.1+/-4.5 vs. 167.8+/-10.6, p < 0.0001) shown by immunofluorescence were higher in the older compared to the younger patients with a consecutive reduction of the lumen / wall ratio (1.29+/-0.05 vs. 3.29+/-0.15, p < 0.0001). No differences were observed for these parameters between old hypertensive and non-hypertensive patients. CONCLUSIONS: The present data show age-related changes of the cerebral microvessels in sections of human putamen for the first time. Due to the accumulation of collagen, microvessels thicken and show a reduction in their lumen. Besides this, the number of vessels decreases. These findings might represent a precondition for the development of vascular cognitive impairment. However, hypertension was not proven to modulate these changes.

Adult↗
PubMed2004

Chorein detection for the diagnosis of chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a severe, neurodegenerative disorder that shares clinical features with Huntington's disease and McLeod syndrome. It is caused by mutations in VPS13A, which encodes a large protein called chorein. Using antichorein antisera, we found expression of chorein in all human cells analyzed. However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntington's disease cells. This suggests that loss of chorein expression is a diagnostic feature of ChAc.

Acanthocytes↗
PubMed2002

Medial prefrontal and subcortical mechanisms underlying the acquisition of motor and cognitive action sequences in humans.

The anterior medial prefrontal cortex (AMPC) in humans is involved in affect and in regulating goal-directed behaviors. The precise function of the AMPC, however, is poorly understood. Using magnetic resonance imaging, we found that bilateral regions in the AMPC were selectively recruited to compute the reliability of subjects' expectations that developed when subjects were learning sequences of cognitive tasks. In contrast, regions similarly recruited in learning sequences of motor acts were found in the ventral striatum. Our results show that beyond the execution of motor acts, the AMPC is selectively engaged in computing the relevance of cognitive goals that subjects intend to achieve. This indicates that the fronto-striatal circuit, including the ventral striatum and AMPC, subserves hierarchically distinct evaluative processes mediating the human ability to build behavioral plans, ranging from motor to cognitive action plans.

Adult↗
PubMed2002

Clinical features and molecular bases of neuroacanthocytosis.

The term acanthocytosis is derived from the Greek for "thorn" and is used to describe a peculiar spiky appearance of erythrocytes. Acanthocytosis is found to be associated with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis. Abetalipoproteinaemia is an autosomal recessive condition, characterised by absence of serum apolipoprotein B containing lipoproteins leading to fat intolerance and fat-soluble vitamin deficiency. This results in a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa. Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia. Some of its features, including choreic movements, peripheral neuropathy with areflexia, elevated serum creatine kinase levels and myopathy are shared by another form of neuroacanthocytosis, McLeod syndrome. Patients affected by this X-linked disorder also show abnormal expression of Kell blood group antigens and a permanent haemolytic state. In addition to these cases, acanthocytosis is occasionally associated with other neurological disorders, such as Hallervorden-Spatz disease. For each of the neuroacanthocytosis syndromes we review the main clinical features and their molecular bases. The recent molecular genetics findings are the first step towards the understanding of the pathogenetic mechanisms and eventually the search for effective treatments.

Abetalipoproteinemia↗
PubMed2002

Imaging cortical anatomy by high-resolution MR at 3.0T: detection of the stripe of Gennari in visual area 17.

The brain can be parcellated into numerous anatomical and functional subunits. The classic work by Brodmann (Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909) identified areas of the cerebral cortex based on histological differences. An alternative to his cytoarchitectonic approach is the myeloarchitectonic approach. MRI has excellent white/gray matter contrast in the brain due to the presence of myelin, and thus seems uniquely suited for in vivo studies of cortical myeloarchitecture. Here it is demonstrated that the stripe or stria of Gennari can be consistently detected in human occipital cortex. T(1)-weighted images obtained at 3T from six of 10 normal volunteers, with resolutions of 350 x 350 x 600 mu clearly demonstrate this myelin-rich intracortical layer. It is concluded that the striate cortex (area 17 of Brodmann) of the human brain can be delineated in vivo on T(1)-weighted images, potentially enabling detection of specific cortical boundaries within individual brains.

Brain Mapping↗