[Deepening the idea of systems biology and promoting the development of pan-vascular medical science].

Zhonghua Xin Xue Guan Bing Za Zhi. 2016 May 24;44(5):373-4

Authors: Ge JB

PMID: 27220570 [PubMed - in process]

Drugs affecting glycosaminoglycan metabolism.

Drug Discov Today. 2016 May 20;

Authors: Ghiselli G, Maccarana M

Abstract
Glycosaminoglycans (GAGs) are charged polysaccharides ubiquitously present at the cell surface and in the extracellular matrix. GAGs are crucial for cellular homeostasis, and their metabolism is altered during pathological processes. However, little consideration has been given to the regulation of the GAG milieu through pharmacological interventions. In this review, we provide a classification of small molecules affecting GAG metabolism based on their mechanism of action. Furthermore, we present evidence to show that clinically approved drugs affect GAG metabolism and that this could contribute to their therapeutic benefit.

PMID: 27217160 [PubMed - as supplied by publisher]

Mood, stress and longevity: convergence on ANK3.

Mol Psychiatry. 2016 May 24;

Authors: Rangaraju S, Levey DF, Nho K, Jain N, Andrews KD, Le-Niculescu H, Salomon DR, Saykin AJ, Petrascheck M, Niculescu AB

Abstract
Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner's office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson-Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a "life switch" actively controlled by mood and stress.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.65.

PMID: 27217151 [PubMed - as supplied by publisher]

Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease.

Int J Antimicrob Agents. 2016 Apr 22;

Authors: Sbaraglini ML, Bellera CL, Fraccaroli L, Larocca L, Carrillo C, Talevi A, Alba Soto CD

Abstract
Despite current efforts worldwide to develop new medications against Chagas disease, only two drugs are available, nifurtimox and benznidazole. Both drugs require prolonged treatment and have multiple side effects and limited efficacy on adult patients chronically infected with Trypanosoma cruzi. Recently, computer-guided drug repositioning led to the discovery of the trypanocidal effects of clofazimine and benidipine. These compounds showed inhibitory effects on cruzipain, the major cysteine protease of T. cruzi, of different parasite stages and in a murine model of acute Chagas disease. The aim of this work was to determine the efficacy of these novel cruzipain inhibitors when administered in a murine model of chronic Chagas disease. Benidipine and clofazimine were able to reduce the parasite burden in cardiac and skeletal muscles of chronically infected mice compared with untreated mice as well as diminish the inflammatory process in these tissues. Further studies should be performed to study the synergism with benznidazole and nifurtimox in view of combined therapies.

PMID: 27216381 [PubMed - as supplied by publisher]

The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis.

Elife. 2016;5

Authors: Patterson S, Wyllie S, Norval S, Stojanovski L, Simeons FR, Auer JL, Osuna-Cabello M, Read KD, Fairlamb AH

Abstract
There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.

PMID: 27215734 [PubMed - in process]

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy.

Pharmacogenomics J. 2016 May 24;

Authors: Zur RM, Roy LM, Ito S, Beyene J, Carew C, Ungar WJ

Abstract
Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta-analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90.4% (79.1-99.4%) and 100.0% (99.9-100%), respectively. For individuals with deficient or intermediate activity, phenotype sensitivity and specificity was 91.3% (86.4-95.5%) and 92.6% (86.5-96.6%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively. Genotyping has higher sensitivity as long as TPMT*2 and TPMT*3 are tested. Both approaches display high specificity. Latent class meta-analysis is a useful method for synthesizing diagnostic test performance data for clinical practice guidelines.The Pharmacogenomics Journal advance online publication, 24 May 2016; doi:10.1038/tpj.2016.37.

PMID: 27217052 [PubMed - as supplied by publisher]

Clinical-pharmacogenetic predictive models for MTX discontinuation due to adverse events in rheumatoid arthritis.

Pharmacogenomics J. 2016 May 24;

Authors: Jenko B, Lusa L, Tomsic M, Praprotnik S, Dolzan V

Abstract
We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.The Pharmacogenomics Journal advance online publication, 24 May 2016; doi:10.1038/tpj.2016.36.

PMID: 27217051 [PubMed - as supplied by publisher]

Malignant Pyoderma Associated with Granulomatosis with Polyangiitis (Wegener Granulomatosis) as a Unique Indication for Facial Vascularized Composite Allotransplantation: Part I.

Plast Reconstr Surg. 2016 Jun;137(6):1007e-1015e

Authors: Gastman B, Hashem AM, Djohan R, Bernard S, Hendrickson M, Schwarz G, Gharb BB, Rampazzo A, Fernandez A, Zins J, Hoffman GS, Doumit G, Siemionow M, Papay F

Abstract
BACKGROUND: Granulomatosis with polyangiitis (Wegener granulomatosis) is a rare disease that commonly starts in the craniofacial region and can lead to considerable facial disfigurement. Granulomas and vasculitis, however, can involve many other tissues (especially pulmonary and renal). Dermatologic and subcutaneous components can lead to malignant pyoderma.
METHODS: The authors describe a unique pathologic condition, where significant Le Fort type trauma was associated with subsequent development of granulomatosis with polyangiitis and malignant pyoderma. Successive operations to excise necrotic tissue and reconstruct the defects were followed by worsening inflammation and tissue erosions. Trauma and surgery in proximity to the eye and sinuses masked the initial clinical presentation and led to delay in diagnosis and disease progression. The resultant facial disfigurement and tissue loss were substantial.
RESULTS: Despite multiple confounding factors, accurate diagnosis was eventually established. This was based on persistence of sinus inflammations in the absence of infective agents, proven sterility of lung lesions, and antineutrophil cytoplasmic antibody positivity with proteinase 3 specificity. Skin lesion biopsy specimens were identified as pyoderma gangrenosum and later as malignant pyoderma. Institution of immunosuppressive therapy allowed successful control of the disease and wound healing. The resulting craniofacial destruction, however, necessitated facial vascularized composite allotransplantation.
CONCLUSION: Recognition of this rare pathologic association is essential, to prevent delays in diagnosis and treatment that can lead to major craniofacial tissue loss.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

PMID: 27219252 [PubMed - as supplied by publisher]

[Peutz-Jeghers syndrome manifested as massive melæna at CHU-JRA Madagascar hospital: a case report].

Pan Afr Med J. 2016;23:78

Authors: Martinetti AF, Andriantsoa RM, Andriambelo RT, Nicole RR, Enintsoa RN

Abstract
Peutz-Jeghers syndrome (SPJ) is characterized by intestinal hamartomatous polyps in association with mucocutaneous lentiginosis. Patients are exposed to mechanical and bleeding complications. It is a cancer predisposition syndrome. Our study highlights the diagnostic criteria for Peutz-Jeghers syndrome (SPJ), the complications and the therapeutic progresses in patient care. We report the case of a 32-year-old male presenting with a massive melaena. It was hospitalized in the surgical intensive care unit with hypovolemic shock difficult to control. This required surgical intervention to stop bleeding. We found a hamartomatous polyps in the small intestine which caused bleeding. Peutz Jeghers Syndrome was diagnosed on the basis of labial lentigines during childhood. Clinical and paraclinical explorations did not reveal the presence of cancer. In Madagascar, this disease is still poorly understood. In the literature, the diagnosis of Peutz Jeghers syndrome is based on clinical findings or on the presence of complications such as haemorrhage, invagination or bowel obstruction. In our case, the disease was complicated by gastrointestinal bleeding with hypovolemic shock. Endoscopic polypectomy using double-balloon enteroscopy can reduce emergency small bowel surgery. Peutz-Jeghers syndrome is a rare disease. Despite this, it is important for clinicians to know it and to take it into consideration in case of gastrointestinal bleeding.

PMID: 27217901 [PubMed - in process]

Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus: 30-year experience with 16 patients at a single institute in the People's Republic of China.

Onco Targets Ther. 2016;9:2193-201

Authors: Chen YY, Li SQ, Liu HS, Qin YZ, Li L, Huang C, Bi YL, Meng YX, He J, Zhou XY, Ma DJ

Abstract
BACKGROUND AND PURPOSE: Thymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease.
METHODS: From June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed.
RESULTS: The median age was 32.5 years (range: 13-47 years), and the median disease duration was 8.5 months (range: 1-150 months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing's syndrome. Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2 weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41 months (95% CI: 30.3-51.7 months), and the progression-free survival was 28 months (95% CI: 21.6-34.3 months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection.
CONCLUSION: TNEC is an extremely aggressive disease that should be considered when treating patients with Cushing's syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However, additional patients and a longer follow-up will be needed to determine the variables that are predictive of survival and to improve patient prognosis.

PMID: 27217765 [PubMed]

Clear Cell Mypepithelial Carcinoma of the Base Tongue Managed by the Mandible Preserving Pull-Through Oropharyngectomy Approach.

Indian J Surg Oncol. 2015 Sep;6(3):263-6

Authors: Krishnamurthy A

Abstract
Myoepithelial carcinoma (MC) is rare disease that comprises of only about 2 % of all salivary gland carcinomas and MC that focally or predominantly displays clear cell-type tumor cells are considered as CCMC. We recently got to treat a rare case of a base tongue clear cell myoepithelial carcinoma. (CCMC) Our patient, to the best of our knowledge is the second case of base tongue CCMC and the first with metastatic involvement of the cervical lymph nodes. We successfully managed the tumor using the "mandible preserving pull-through oropharyngectomy approach" Knowledge of the different surgical approaches and techniques is thus vital for better oncologic, functional and aesthetic outcomes following surgery for tumors especially in challenging sub sites like the oropharynx.

PMID: 27217675 [PubMed]

[A Case of Inflammatory Myofibroblastic Tumor of Urinary Bladder].

Hinyokika Kiyo. 2016 Apr;62(4):201-4

Authors: Tanaka K, Ikeda A, Miyakawa T, Komine M, Tsutsumi M, Ishikawa S, Kawai K, Nishiyama H

Abstract
A 61-year-old man presenting with voiding pain was diagnosed with a bladder tumor by ultrasound in another hospital, and was subsequently referred to our hospital. Cystoscopy showed a nodular tumor and surrounding edematous mucosa in the right wall of the bladder. Initially, we suspected bladder invasion of gastrointestinal malignancy, but abdominal computed tomography, magnetic resonance imaging, and a series of tumor marker tests revealed no abonormalities. We performed transurethral resection of the bladder tumor under the clinical diagnosis of a submucosal tumor originating from the bladder wall. Histopathological examination revealed spindle cell proliferation, which was positively stained with anti-anaplastic lymphoma kinase (ALK) antibody. Based on the findings, the diagnosis of an inflammatory myofibroblastic tumor (IMT) was made. Therefore, we performed partial cystectomy to reduce the risk of local recurrence. The pathological diagnosis was IMT, and the surgical margins were negative. Bladder IMT is a rare disease, and surgical resection is the only recommended treatment. In the literature, if completely resected, the prognosis of patients with bladder IMT is excellent. Also, in the present case, no recurrence has been detected for over 6 months.

PMID: 27217015 [PubMed - in process]

Evidence of pathogenicity of a mutation in 3' untranslated region causing mild haemophilia A.

Haemophilia. 2016 May 24;

Authors: Pezeshkpoor B, Berkemeier AC, Czogalla KJ, Oldenburg J, El-Maarri O

Abstract
INTRODUCTION: Despite the high mutation detection rate, in a small group of haemophilia A patients, using current screening methods, no causal mutation in F8 can be detected. In such cases, the causal mutation might be in the non-coding sequences of F8.
AIM: Rarely, mutations in non-coding sequences reveal a pivotal role. Here, we analysed a mild haemophilia A patient harbouring a mutation in the 3' untranslated region (UTR) of F8 and elucidated the molecular mechanism leading to haemophilia phenotype.
METHODS: To find the causal mutation, the complete F8 genomic region was analysed by next generation sequencing. The effect of the identified alteration on F8 expression was evaluated in silico and analysed for the splicing effect at mRNA level. Moreover, in vitro studies using a luciferase reporter system were performed to functionally analyse the mutation.
RESULTS: We identified an alteration in the 3' UTR (c.*56G>T) as the only change in F8 gene. Pedigree analysis showed a segregation pattern for three affected members for the presumptive mutation. Moreover, the variant was predicted in silico to create a new donor splice site, which was also detected at mRNA level, resulting in a 159 bp deletion in 3' UTR of F8. Finally, the variant showed reduced expression of the gene reporter firefly luciferase in cell line expression analysis.
CONCLUSION: Our results advocate the patient specific c.*56G>T base change in the 3' UTR to be a disease-associated mutation leading to alternative splicing explaining the mild haemophilia A phenotype.

PMID: 27216882 [PubMed - as supplied by publisher]

Combined immunodeficiency in a patient with mosaic monosomy 21.

Immunol Res. 2016 May 24;

Authors: Rechavi E, Levy-Mendelovich S, Stauber T, Shamash J, Reinstein S, Vernitsky H, Adam D, Simon AJ, Lev A, Raas-Rothschild A, Somech R

Abstract
Monosomy 21 is an extremely rare genetic disorder presenting with a wide array of symptoms. Recurrent infections, some life threatening, have been reported in several monosomy 21 patients and attributed to an, as of yet, undefined immunodeficiency. Here we report on a 3-year-old boy with mosaic monosomy 21 who presented with clinical and laboratory evidence of immunodeficiency. Despite suffering from infections highly suggestive of a cell-mediated immune defect, the patient's T cells displayed normal counts, subsets and proliferation capability. T cell receptor repertoire was diverse, and de novo T cell production was intact. Consistent with earlier case reports, our patient displayed mildly low B cell counts with hypogammaglobulinemia. B cell subsets demonstrated mainly naïve and marginal zone B cells that have not undergone class switch. Subsequently, IgG, IgA and IgE levels were near absent, whereas IgM level was normal. De novo B cell production and B cell receptor diversity were normal. Together, these results are indicative of a defect in immunoglobulin class switching as the principal cause of immunodeficiency in monosomy 21. A better understanding of the immunodeficiency in this syndrome will enable targeted treatment and prevention of infections in order to prevent morbidity and mortality in these patients.

PMID: 27216863 [PubMed - as supplied by publisher]

Towards rational drug treatment of Lesch-Nyhan disease.

Mol Genet Metab. 2016 May 9;

Authors: Seifert R

Abstract
Lesch-Nyhan disease (LND) is a rare X-chromosomal purine metabolism disorder. LND is characterized by self-injurious behavior (SIB) for which there is no drug treatment. This commentary places a recent clinical study by Khasnavis et al. (Mol. Genetic. Metab., in press) on drug treatment of SIB into a broader context. Although the study by Khasnavis et al. was no break-through in terms of "positive" results, nonetheless, it presents an excellent model of how clinical studies in general and clinical studies on rare diseases should be conducted.

PMID: 27216368 [PubMed - as supplied by publisher]

Takayasu arteritis presenting with malignant hypertension; a rare manifestation of a rare disease: a case report and review of the literature.

Trop Doct. 2016 May 22;

Authors: Patel B, Tiwari A, Dubey SR, Bhatt GC, Tiwari P, Bhan BD

Abstract
Takayasu arteritis (TA) is a chronic inflammatory and obliterative disease of large vessels, which mainly affects the aorta and its major branches. TA can lead to renal failure and renovascular hypertension in 60% of patients; it is rare in children aged <10 years and, more rarely, it presents with malignant hypertension in the paediatric age group. Here we present a case of 9-year-old boy with TA who presented with malignant hypertension and required surgical intervention to control the blood pressure. Subsequently, his medications were titrated using 24 h ambulatory blood pressure monitoring (ABPM) and is doing well on follow-up.

PMID: 27216226 [PubMed - as supplied by publisher]

Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments.

World J Surg Oncol. 2016;14(1):151

Authors: Kassahun WT

Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.

PMID: 27215576 [PubMed - in process]

Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome.

Brain. 2016 Jan;139(Pt 1):31-8

Authors: Ortigoza-Escobar JD, Molero-Luis M, Arias A, Oyarzabal A, Darín N, Serrano M, Garcia-Cazorla A, Tondo M, Hernández M, Garcia-Villoria J, Casado M, Gort L, Mayr JA, Rodríguez-Pombo P, Ribes A, Artuch R, Pérez-Dueñas B

Abstract
Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.

PMID: 26657515 [PubMed - indexed for MEDLINE]

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

Brain. 2016 Jan;139(Pt 1):62-72

Authors: Sevilla T, Lupo V, Martínez-Rubio D, Sancho P, Sivera R, Chumillas MJ, García-Romero M, Pascual-Pascual SI, Muelas N, Dopazo J, Vílchez JJ, Palau F, Espinós C

Abstract
Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

PMID: 26497905 [PubMed - indexed for MEDLINE]

Distinct cardiac phenotype between two homozygotes born in a village with accumulation of a genetic deficiency of adipose triglyceride lipase.

Int J Cardiol. 2015 Aug 1;192:30-2

Authors: Higashi M, Hirano K, Kobayashi K, Ikeda Y, Issiki A, Otsuka T, Suzuki A, Yamaguchi S, Zaima N, Hamada S, Hanada H, Suzuki C, Nakamura H, Nagasaka H, Miyata T, Miyamoto Y, Kobayashi K, Naito H, Toda T

PMID: 25985012 [PubMed - indexed for MEDLINE]