Fabry disease--a metabolic disorder with a challenge for endocrinologists?

OBJECTIVE: To revisit Fabry disease, a rare X-linked metabolic glycosphingolipid storage disease caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). METHOD: Summary of the existing knowledge of Fabry disease including the clinical feature of Fabry disease and the recent breakthrough in the treatment of Fabry patients with the development of recombinant human alpha-gal A. CONCLUSION: The diffuse organ manifestations of Fabry disease resemble medical endocrinological diseases, and medical endocrinology might be an appropriate speciality to manage the treatment in collaboration with other specialists and clinical geneticists.     

Is Huntington disease a developmental disorder?

The recently discovered roles of huntingtin in non-differentiated cells indicate that it is a key molecule in brain development. Humbert argues that the haploinsufficiency of wild-type huntingtin in Huntington disease might lead to various cellular alterations well before the onset of symptoms and ultimately cause disease.The construction of an organism is a complex process that involves a developmental challenge: the orchestrated proliferation, migration and differentiation of cells, leading to the assembly of organs. Huntingtin—the protein that is mutated in the neurodegenerative disorder Huntington disease—is widely expressed in the early developing mouse embryo, in which it has an essential role. The most compelling proof that huntingtin is essential for early development is that inactivation of the murine gene results in defects in extra-embryonic tissues and embryonic death at embryonic day 7.5 (Dragatsis et al, 1998). My group has recently directly linked a cellular function of huntingtin to brain development (Godin et al, 2010a). Indeed, huntingtin regulates cortical neurogenesis through, at least in part, its role during spindle pole orientation.The growing evidence that huntingtin functions during development opens the door to viewing Huntington disease as a developmental disorder. Development could be abnormal in carriers of the mutant protein and precede the manifestation of the disease by decades. Changes during development might not have phenotypical consequences until the mature cells are required to function later in life. Indeed, a given protein will not function in the same context during development and adulthood, and the resulting phenotypes of these functions will not be the same. Furthermore, compensatory mechanisms that respond to abnormal development might be overwhelmed when the organism is ageing. We have not yet identified all of the neurodevelopmental defects—both functional and morphological—involved in Huntington disease. However, there are changes in the brain before the onset of disease, including a smaller intracranial adult brain volume in pre-manifest Huntington disease carriers (Nopoulos et al, 2010). It is tempting to consider that this might be a consequence of altered brain development.A complex molecular picture of the biology of huntingtin is emerging, suggesting that it is a scaffold protein that could couple many cellular events. Huntingtin regulates the assembly of the dynein–dynactin complex for axonal transport and Golgi apparatus organization (Caviston et al, 2007; Gauthier et al, 2004). During cell division, this role extends to a complex that also contains NuMA, a component that is essential for the organization of microtubules at the spindle pole (Godin et al, 2010a). Furthermore, NuMA and the Goloco-containing protein LGN form a complex that regulates the interaction between astral microtubules and the cell cortex (Du & Macara, 2004). Therefore, huntingtin could also participate in the distribution of the dynein–dynactin complex at the cell cortex and, as a consequence, regulate mitosis at several points. Similarly, huntingtin could regulate the assembly of other supramolecular complexes that are involved in various cell pathways, as suggested by the diverse nature of its interactors (Kaltenbach et al, 2007). For example, huntingtin interacts with the β-catenin destruction complex and thus participates in the tight regulation of the steady-state levels of β-catenin (Godin et al, 2010b; Kaltenbach et al, 2007). This might be crucial to regulate the Wingless/Wnt signalling pathway, known for its central role during development and adulthood. Thus, the functions attributed to huntingtin so far are important cellular processes in the early stages of development and adulthood, and contribute as initial or secondary disease mechanisms to several neurodegenerative disorders. This might not be a coincidence!Finally, the scaffold nature of huntingtin might be important for histogenesis in general and explain the widespread abnormalities observed in Huntington disease. A high level of huntingtin is found in the testes and one of the peripheral manifestations of the disease is testicular pathology, with a reduced number of germ cells and abnormal seminiferous tubule morphology (van Raamsdonk et al, 2007). Testes require functional intracellular transport for their normal development, and asymmetrical division is particularly important for germline stem-cell maintenance. Thus, an abnormal developmental programme induced by defective huntingtin function would alter cells and, thereby, the homeostasis of the tissues expressing this protein.Several other disorders are caused by the toxic presence of an abormal polyglutamine expansion. These ‘polyglutamine diseases'' have this mutation in common; however, the mutated proteins are unrelated and the disorders are phenotypically distinct, affecting different brain regions and neurons. A defect in the function of the mutated proteins explains the separate mechanisms of neuronal degeneration observed. Huntington disease is a dominant disorder, but the vision of it as a gain-of-function disease with loss-of-function manifestations could be outdated. The situation seems to be more complicated, and most patients express not only one copy of the mutant huntingtin, but also half the amount of the wild-type protein. It is time to rethink the idea that studying huntingtin protein is irrelevant to Huntington disease. In the light of recent advances in the understanding of its function, one might even suggest that taking developmental biology into account could provide new insight into the pathological mechanisms of this so far incurable adult-onset disorder.     

Wilson's disease: a common liver disorder?

In two sibships 7 of 24 siblings were homozygous for Wilson''s disease. In family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of ceruloplasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D-penicillamine. None showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of D-penicillamine therapy the conditions of the two probands had improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson''s disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, it may be a more common cause of liver disease in young people than has been appreciated.     

Dubowitz syndrome: a cholesterol metabolism disorder?

Dubowitz syndrome (DS) (MIM#223370) (4) is a very rare genetic and developmental disorder involving multiple congenital anomalies including: 1) growth failure/short stature; 2) unusual but characteristic facial features; small triangular face, high sloping forehead, ptosis, short palpebral fissures, broad and flat nasal bridge; 3) microcephaly; 4) mild mental retardation; and 5) in at least 50% of the cases, eczema. Multiple organ systems are affected and the disorder is unpredictable and extremely variable in its expression. Here we describe a male Turkish patient who has typical and less common findings of DS with additionally persistently low serum lipid levels and an arachnoid cyst. The present patient is the second case of DS with persistently low cholesterol levels.     

Pre-eclampsia: a disorder of placental mitochondria?

Pre-eclampsia is a common, pregnancy-induced, multisystem disease leading to severe complications in the mother and foetus. The aetiology of pre-eclampsia remains a mystery, but a growing body of evidence suggests that a mitochondrial defect might cause the impairement of differentiation and invasion of the trophoblast that leads to this disorder. This hypothesis is the topic of ongoing studies that, if confirmed, would be highly relevant to preventative strategies for this disease.     

Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?

A major concern regarding psychostimulant medication (amphetamine and methylphenidate) in the treatment of children and adolescents with attention deficit/hyperactivity disorder (ADHD) are the potential adverse effects to the developing brain, particularly in regard to dopaminergic brain function. The present review focuses on the pharmacology of these psychostimulants, their mode of action in the human brain and their potential neurotoxic effects to the developing brain in animals, particularly concerning DA brain function. The potential clinical significance of these findings for the treatment of ADHD in children and adolescents is discussed. Studies on sensitization to psychostimulants’ rewarding effects, which is a process expected to increase the risk of substance abuse in humans, are not included. The available findings in non-human primates support the notion that the administration of amphetamine and methylphenidate with procedures simulating clinical treatment conditions does not lead to long-term adverse effects in regard to development, neurobiology or behaviour as related to the central dopaminergic system.     

Drawing with a camera? Ethnographic film and transformative anthropology

Drawing has emerged as a recent focus of anthropological attention. Writers such as Ingold and Taussig have argued for its significance as a special kind of knowledge practice, linking it to a broader re‐imagining of the anthropological project itself. Underpinning their approach is an opposition between the pencil and the camera, between ‘making’ and ‘taking’, between restrictive and generative modes of inquiry. This essay challenges this assumption, arguing that these elements in drawing and filmmaking exist in a dialectical rather than a polarized relationship. It highlights particular insights that follow from a dialogue between written and film‐based anthropologies and links them to broader debates within the discipline – for example, debates about ways of knowing, skilled practice, improvisation and the imagination, and anthropology as a form of image‐making practice.     

Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders?

The fatty acid compositions of red blood cell (RBC) phospholipids from a patient with autistic spectrum disorder (ASD) had reduced percentages of highly unsaturated fatty acids (HUFA) compared to control samples. The percentage of HUFA in the RBC from the autistic patient was dramatically reduced (up to 70%) when the sample was stored for 6 weeks at -20 degrees C. However, only minor HUFA reductions were recorded in control samples stored similarly, or when the autistic sample was stored at -80 degrees C. A similar instability in RBC HUFA compositions upon storage at -20 degrees C has been recorded in schizophrenic patients. In a number of other neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and dyslexia, reduced concentrations of RBC HUFA have been recorded. The extent and nature of these aberrations require further assessment to determine a possible common biochemical origin of neurodevelopmental disorders in general. To facilitate this, a large scale assessment of RBC fatty acid compositions in patients with ASD, and related disorders, should be performed as a matter of urgency. Supplementing cells in culture with the tryptophan metabolite indole acrylic acid (IAA) affected the levels of cellular HUFA and prostaglandin production. Indole acroyl glycine (IAG), a metabolite of IAA excreted in urine, is found in high concentrations in patients with neurodevelopmental disorders including ASD, ADHD, dyslexia, Asperger's syndrome and obsessive compulsive disorder.     

Cerebro-Oculo-Facio-Skeletal Syndrome with a Nucleotide Excision–Repair Defect and a Mutated XPD Gene, with Prenatal Diagnosis in a Triplet Pregnancy

Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of DNA repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.     

Cohesin: a catenase with separate entry and exit gates?

Cohesin confers both intrachromatid and interchromatid cohesion through formation of a tripartite ring within which DNA is thought to be entrapped. Here, I discuss what is known about the four stages of the cohesin ring cycle using the ring model as an intellectual framework. I postulate that cohesin loading onto chromosomes, catalysed by a separate complex called kollerin, is mediated by the entry of DNA into cohesin rings, whereas dissociation, catalysed by Wapl and several other cohesin subunits (an activity that will be called releasin here), is mediated by the subsequent exit of DNA. I suggest that the ring's entry and exit gates may be separate, with the former and latter taking place at Smc1-Smc3 and Smc3-kleisin interfaces, respectively. Establishment of cohesion during S phase involves neutralization of releasin through acetylation of Smc3 at a site close to the putative exit gate of DNA, which locks rings shut until opened irreversibly by kleisin cleavage through the action of separase, an event that triggers the metaphase to anaphase transition.     

Is urine intercellular adhesion molecule-1 a marker of renal disorder in children with ureteropelvic junction obstruction?

Aim: We aimed to investigate whether urine intercellular adhesion molecule-1 (ICAM-1) might serve as a marker of renal disorder in children with ureteropelvic junction obstruction.

Material and methods: Twenty-nine children with severe hydronephrosis (HN) were compared with 23 participants with mild HN and with 19 healthy peers.

Results: Urine ICAM-1/uCre levels were significantly higher in HN children than healthy controls (P?<0.01), and in severe HN when compared with mild HN (p?<0.05).

Conclusions: It seemed to us that uICAM-1 is a biomarker of renal disorder, and might have the potential to predict which patients will require surgery.     

Germacranolides,a guaianolide with a β-lactone ring and further constituents from Grazielia species

An investigation of three Grazielia species afforded, in addition to known compounds, several new sesquiterpene lactones, eight germacranolides, two melampolides and one guaianolide as well as three diterpenes, two geranylgeraniol derivatives and a labda-diene. Three of the sesquiterpene lactones had an additional β-lactone ring, one an acid function, and two others unusual ester functions. The structures were elucidated by spectroscopic methods and some chemical transformations. The chemotaxonomic situation is discussed briefly.     

Complete remission in a patient with acute myelogenous leukemia treated with leukocyte α-interferon and cimetidine

Summary A 76-year-old woman with acute myelogenous leukemia with approximately 65% myeloblasts on bone marrow examination was treated daily with a combination of 4 megaU of leukocyte interferon IM and 1,000 mg cimetidine PO. During therapy there was a gradual decrease of bone marrow myeloblasts down to 9% and a normalization of peripheral white blood cells. The treatment was discontinued after 6 weeks because of increasing fatigue and anorexia. The general condition improved greatly during the following weeks and the patient entered complete remission, which has continued for 6 months so far. In the course of therapy there was a gradual appearance of antibodies showing a selective binding capacity to autochthonous leukemic cells with no tendency to increased binding to remission cells. The aim of this report is to stimulate a further evaluation of this form of therapy in additional AML patients whenever this might be justified as an alternative to conventional chemotherapy.     

TROSY NMR with a 52 kDa sugar transport protein and the binding of a small-molecule inhibitor

Using the sugar transport protein, GalP, from Escherichia coli, which is a homologue of human GLUT transporters, we have overcome the challenges for achieving high-resolution [¹⁵N-¹H]- and [¹³C-¹H]-methyl-TROSY NMR spectra with a 52?kDa membrane protein that putatively has 12 transmembrane-spanning α-helices and used the spectra to detect inhibitor binding. The protein reconstituted in DDM detergent micelles retained structural and functional integrity for at least 48?h at a temperature of 25?°C as demonstrated by circular dichroism spectroscopy and fluorescence measurements of ligand binding, respectively. Selective labelling of tryptophan residues reproducibly gave 12 resolved signals for tryptophan ¹⁵N backbone positions and also resolved signals for ¹⁵N side-chain positions. For improved sensitivity isoleucine, leucine and valine (ILV) methyl-labelled protein was prepared, which produced unexpectedly well resolved [¹³C-¹H]-methyl-TROSY spectra showing clear signals for the majority of methyl groups. The GalP/GLUT inhibitor forskolin was added to the ILV-labelled sample inducing a pronounced chemical shift change in one Ile residue and more subtle changes in other methyl groups. This work demonstrates that high-resolution TROSY NMR spectra can be achieved with large complex α-helical membrane proteins without the use of elevated temperatures. This is a prerequisite to applying further labelling strategies and NMR experiments for measurement of dynamics, structure elucidation and use of the spectra to screen ligand binding.     

Zinc-finger hydrolase: Computational selection of a linker and a sequence towards metal activation with a synthetic αββ protein

The zinc-finger protein is targeted for computational redesign as a hydrolase enzyme. Successful in having zinc activated for hydrolase function, the study validates the stepwise approach to having the protein tuned in main-chain structure stereochemically and over side chains chemically. A leucine homopolypeptide, harboring histidines to tri coordinate zinc and d-amino-acid-nucleated α-helix and β-hairpin building blocks of an αββ protein, is taken up for modeling, first with cyana, in a mixed-chirality linker between the building blocks, and then with IDeAS, in a sequence over side chains. The designed mixed-chirality polypeptide structure is proven to order as an intended αββ fold and capture zinc to activate its role as a hydrolase catalyst. The design approach to have protein folds defined stereochemically and receptor and catalysis functions defined chemically is presented, and illustrates L- and D-α-amino-acid structures as the alphabet integrating chemical- and stereochemical-structure variables as its letters.     

Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder?

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although no clear cause of LCH has been identified, it has been postulated that LCH might be the consequence of an immune dysregulation, causing Langerhans cells to migrate to and accumulate at various sites. Production of cytokines and chemokines is a central feature of immune regulation. Cytokines are abundantly present within LCH lesions. We review here the potential role of cytokines and chemokines in the pathogenesis of LCH. The type, distribution, and number of different cytokines released within lesions can provide clues to the possible aetiology of LCH and, ultimately, might offer therapeutic possibilities using recombinant cytokines or antagonists for this disorder.