58 research outputs found
Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies
Get PDFIntroduction : Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric neurodegenerative condition, which is usually fatal by mid-adolescence. Seizures are one of the most common early symptoms of CLN2 disease, but patients often experience language deficits, movement disorders, and behavioral problems. Diagnosis of CLN2 disease is challenging (particularly when differentiating between early-onset developmental, metabolic, or epileptic syndromes), and diagnostic delays often overlap with rapid disease progression. An enzyme replacement therapy (cerliponase alfa) is now available, adding CLN2 disease to the list of potentially treatable disorders requiring a prompt diagnosis. Areas covered : Although advances in enzymatic activity testing and genetic testing have facilitated diagnoses of CLN2 disease, our review highlights the presenting symptoms that are vital in directing clinicians to perform appropriate tests or seek expert opinion. We also describe common diagnostic challenges and some potential misdiagnoses that may occur during differential diagnosis. Expert opinion : An awareness of CLN2 disease as a potentially treatable disorder and increased understanding of the key presenting symptoms can support selection of appropriate tests and prompt diagnosis. The available enzyme replacement therapy heralds an even greater imperative for early diagnosis, and for clinicians to direct patients to appropriate diagnostic pathways
Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency
Get PDFMucolipidosis type II/III (ML II/III) and multiple sulfatase deficiency (MSD) share clinical features with the mucopolysaccharidoses. Both ML II/III and MSD result from enzymatic defects that affect the post-translational modification of lysosomal enzymes. In ML II/III the mannose-6-phosphate marker, essential for routing lysosomal enzymes towards the lysosomes, is lacking. This leads to the excretion of lysosomal enzymes in plasma where they are unable to execute their function. In MSD lysosomal sulfatases, as well as sulfatases from the endoplasmic reticulum and Golgi complex, cannot be activated due to the inability to modify a conserved cysteine residue at the active site. In mucolipidosis type IV (ML IV), lysosomal dysfunction is caused by the deficiency of transient receptor potential channel mucolipin-1 (TRPML1), a nonselective cation channel present in late endosomal and lysosomal membranes necessary for autophagy, vesicular trafficking, and mTOR and TFEB signaling. Neurological dysfunction and visual impairment are the most predominant clinical features; skeletal abnormalities are not seen in ML IV. Deficiency of the lysosomal enzymes cathepsin K (pycnodysostosis) and C (Papillon–Lefèvre or Haim–Munk syndrome) presents both with a very distinct clinical picture. Cathepsin K is important for bone resorption and extracellular matrix remodeling. Its deficiency results in stunted growth, facial dysmorphism, osteopetrosis, and dental abnormalities. In cathepsin C deficiency, premature loss of both deciduous and permanent teeth due to periodontitis in combination with palmoplantar keratosis is the main clinical feature.All disorders are ultra-rare and have autosomal recessive inheritance. Their clinical spectrum is not yet fully known, and patients are likely still underdiagnosed. No specific biomarkers are available that can lead to the diagnosis. All disorders have in common that no curative treatments are available and specialized multidisciplinary supportive care is needed to minimize the disease burden and provide an adequate quality of life
Extended Abstract: Deficiency of Sodium Taurocholate Cotransporting Polypeptide (SLC10A1): A New Inborn Error of Metabolism with an Attenuated Phenotype
No full textWe present the first patient with a defect in the Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP), which plays a key role in the enterohepatic circulation of bile salts. The clinical presentation of the child was mild and the child showed no signs of liver dysfunction or pruritus despite extremely elevated plasma bile salt levels (>100-fold upper-limit of normal). A homozygous point mutation was found in the SLC10A1 gene (resulting in amino acid change R252H) and functional studies confirmed the pathogenicity of the mutation. This confirms the role of NTCP as the major transporter of conjugated bile salts into the liver as part of the enterohepatic circulation and shows that other transporters partly can take over its function, resulting in a relatively mild phenotype. This work was published previously in [Vaz et al.: Hepatology 2015;61:260-267] and supplemented with some follow-up information of the patien
Inborn Errors of Metabolism
No full textUntil now, most studies on the pathophysiological mechanisms of inborn errors of metabolism have almost exclusively focused on the measurement of concentrations of different metabolites in plasma, urine, or cerebrospinal fluid. These static measurements cannot discriminate between increased or diminished metabolite production and utilization, which limits the interpretation of these studies with respect to the functional consequences of an enzymatic defect. Understanding the changes in dynamics of affected metabolic pathways is a prerequisite for understanding the pathophysiology of a metabolic disorder. Stable isotope infusion techniques have made it possible to study metabolic fluxes in humans in vivo. In this chapter, stable isotope techniques are described to study inborn errors of intermediary glucose, fat, and protein metabolism in vivo
Rectal Cancer Treatment Outside of the Screening Age in Australia and New Zealand: An Analysis of the Bi-National Colorectal Cancer Audit (BCCA)
No full textPoster Abstract - P-251.
Corrected by: Corrigendum to “Rectal Cancer Treatment Outside of the Screening Age in Australia and New Zealand: An Analysis of the Bi-National Colorectal Cancer Audit (BCCA)” [Eur J Surg Oncol 46/2 (2020) e106- e106]. https://doi.org/10.1016/j.ejso.2020.03.209, in Volume 46, Issue 6, June 2020, Page 1200. The authors regret that Dr. Nagendra Dudi-Venkata is missing from the author list and is actually a co-author of this abstract. The authors would like to apologise for any inconvenience caused.Abstract not availableMeike Van Harten, Emma Greenwood, Sergei Bedrikovetski, Nagendra Dudi-Venkata, Ronald Hunter, Hidde Kroon, Tarik Sammou
Hepatotoxicity due to chenodeoxycholic acid supplementation in an infant with cerebrotendinous xanthomatosis: implications for treatment
Get PDFWe present a two-week old girl who was diagnosed with cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, after a diagnostic workup for convulsions which were shown to be caused by a parechovirus encephalitis. The diagnosis of CTX was confirmed with CYP27A1 mutation analysis. She was started on chenodeoxycholic acid (CDCA) supplementation, which inhibits cholestanol production through a feedback mechanism, at the advised dosage of 15 mg/kg/day. Within 6 weeks, she developed jaundice with hepatomegaly. CDCA supplementation was stopped after which liver size and function rapidly normalised. CDCA supplementation was then restarted and maintained at 5 mg/kg/day. Cholestanol, liver enzymes and total bilirubin were frequently monitored in the patient, who is now 2.8 years of age, and have remained within normal range. Her psychomotor development has been normal. Conclusion: adequate metabolic control was achieved in an infant with CTX with CDCA supplementation at a dosage of 5 mg/kg/day and was well tolerated. CDCA supplementation at 15 mg/kg/day seems hepatotoxic in infants and should not be used. This is relevant in view of the possible inclusion of CTX in newborn screening programs in the near future.What is Known:• Cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, is a progressive neurological disorder.• Symptoms of CTX can be halted, and likely prevented, with chenodeoxycholic acid (CDCA) supplementation, making CTX a good candidate for newborn screening.What is New:• CDCA supplementation at the advised dosage of 15 mg/kg/day in children seems hepatoxic in infants with CTX.• Adequate metabolic control in an infant with CTX was achieved with CDCA supplementation at 5 mg/kg/day and well tolerated
Local aberration control to improve efficiency in multiphoton holographic projections
Get PDFOptical aberrations affect the quality of light propagating through a turbid medium, where refractive index is spatially inhomogeneous. In multiphoton optical applications, such as two-photon excitation fluorescence imaging and optogenetics, aberrations non-linearly impair the efficiency of excitation. We demonstrate a sensorless adaptive optics technique to compensate aberrations in holograms projected into turbid media. We use a spatial light modulator to project custom three dimensional holographic patterns and to correct for local (anisoplanatic) distortions. The method is tested on both synthetic and biological samples to counteract aberrations arising respectively from misalignment of the optical system and from samples inhomogeneities. In both cases the anisoplanatic correction improves the intensity of the stimulation pattern at least two-fold.ImPhys/Microscopy Instrumentation & Technique
Quantum Markov Semigroups and the Lindblad Master Equation: A generalisation to countably infinite dimensional Hilbert spaces of the Lindblad form for generators commuting with the modular automorphism group
No full textQuantum Markov Semigroups (QMS) describe the evolution of a quantum system by evolving a projection or density operator in time. QMS are generated by a generator obeying the well-known Lindblad equation. However, this is a difficult equation. Therefore, the result that the Lindblad form greatly simplifies in the case of the generator commuting with the modular automorphisms group, is useful. Unfortunately, the proof only works for finite dimensional Hilbert spaces, which is why the aim of this thesis is to generalise this result to countably infinite dimensional Hilbert spaces. To this end, the Lindblad equation is derived from both a mathematical and physical perspective. Where the former relies on rigorous proof and the latter relies on approximations. In the rigorous case the theory of unital completely positive maps is used. Furthermore, multiple topologies are considered which put less stringent conditions on the operators of interest than the norm topology. Additionally, the Haar measure is used on the unitaries of the bounded linear operators to construct the explicit Lindblad form. To derive the result by employing physical assumptions the interaction picture is used. The physical derivation starts from the Von Neumann equation and uses multiple assumptions to obtain the final Lindblad form. The most important physical assumptions are: the Born approximation, the Markov approximation and the rotating wave approximation. Furthermore, the main result is the generalisation of the simplified Lindblad form. This simplified form holds for generators commuting with the modular automorphisms group in case the Hilbert spaces are countably infinite dimensional. However, this requires the domain of the generator to be restricted to trace class operators with the identity operator artificially added. Additionally, the generator needs to map strongly convergent sequences to weakly convergent sequences. It also needs to be self-adjoint with respect to the Hilbert-Schmidt inner product. Lastly, the generator is assumed to be self-adjoint with respect to the Gelfand-Naimark-Segal (GNS) inner product <X, Y>=Tr(σ X*Y) for σ a density operator. This last assumption implies that the generator commutes with the modular automorphisms group, which is the symmetry we are considering. Hence, the two previous assumptions are the additional requirements needed to generalise the result, besides the restriction of the domain. Therefore, it is recommended for further research to generalise the result for the domain extended to the bounded operators B(H). It should be noted that the proof heavily relies on the Hilbert space structure induced by the Hilbert-Schmidt inner product. Consequently, the generalisation for the bounded operators would probably require a different approach. Another recommendation is to try and lift the sequence and self-adjoint requirements on the generator. In addition, it is interesting to investigate which physical systems actually have the symmetry of generators commuting with the modular automorphisms group. Applied Mathematic
Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand
No full textIn order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-H-2(2)] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5-3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: -31.9% vs. -17.9% (p=0.007), GGL: -66.2% vs. -50.8% (p=0.465) and GNG 6.8% vs. 19.5% (p=0.465). Plasma alanine levels were significantly lower (p=0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in childre
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