Patient with multiple acyl-CoA dehydrogenase deficiency disease and ETFDH mutations benefits from riboflavin therapy: a case report.

BMC Med Genomics. 2018 Apr 03;11(1):37

Authors: Goh LL, Lee Y, Tan ES, Lim JSC, Lim CW, Dalan R

Abstract
BACKGROUND: Lipid storage myopathy (LSM) is a diverse group of lipid metabolic disorders with great variations in the clinical phenotype and age of onset. Classical multiple acyl-CoA dehydrogenase deficiency (MADD) is known to occur secondary to mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene. Whole exome sequencing (WES) with clinical correlations can be useful in identifying genomic alterations for targeted therapy.
CASE PRESENTATION: We report a patient presented with severe muscle weakness and exercise intolerance, suggestive of LSM. Diagnostic testing demonstrated lipid accumulation in muscle fibres and elevated plasma acyl carnitine levels. Exome sequencing of the proband and two of his unaffected siblings revealed compound heterozygous mutations, c.250G > A (p.Ala84Thr) and c.770A > G (p.Tyr257Cys) in the ETFDH gene as the probable causative mutations. In addition, a previously unreported variant c.1042C > T (p.Arg348Trp) in ACOT11 gene was found. This missense variant was predicted to be deleterious but its association with lipid storage in muscle is unclear. The diagnosis of MADD was established and the patient was treated with riboflavin which resulted in rapid clinical and biochemical improvement.
CONCLUSIONS: Our findings support the role of WES as an effective tool in the diagnosis of highly heterogeneous disease and this has important implications in the therapeutic strategy of LSM treatment.

PMID: 29615056 [PubMed - in process]

The MAKE Biomarker Discovery for Enhancing anTidepressant Treatment Effect and Response Study: Design and Methodology.

Psychiatry Investig. 2018 Apr 05;:

Authors: Kang HJ, Kim JW, Kim SY, Kim SW, Shin HY, Shin MG, Kim JM

Abstract
Objective: Depression is associated with a major disease burden, and many individuals suffer from depressive symptoms due to an insufficient response to ostensibly adequate antidepressant treatment. Therefore, it is important to identify reliable treatment response predictors for use in developing personalized treatment strategies.
Methods: The MAKE Biomarker discovery for Enhancing anTidepressant Treatment Effect and Response (MAKE BETTER) study was performed to identify predictors of antidepressant response using a 2-year naturalistic prospective design. Participants in the MAKE BETTER study were consecutively recruited from patients who visited the Psychiatry Department of Chonnam National University Hospital, Gwangju, South Korea for treatment of a depressive disorder. Data on demographic and clinical characteristics, genetic markers measured by whole-exome sequencing, and blood markers were obtained. The types and doses of antidepressants were determined based on the clinical judgment of the psychiatrist, and the treatment outcomes (e.g., depressive and other psychiatric symptoms and issues related to safety) were assessed.
Results: We will be able to use the data collected in this study to develop a treatment-response prediction index composed of biomarkers.
Conclusion: The MAKE BETTER study will provide an empirical basis for a personalized medicine approach to depression by enabling the prediction of antidepressant treatment response according the characteristics of each patient. It will thereby support evidence-based decision-making that decreases the use of a trial-and-error approach to the treatment of depressive disorders.

PMID: 29614851 [PubMed - as supplied by publisher]

Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis.

Clin Diabetes Endocrinol. 2018;4:6

Authors: Sahinoz M, Khairi S, Cuttitta A, Brady GF, Rupani A, Meral R, Tayeh MK, Thomas P, Riebschleger M, Camelo-Piragua S, Innis JW, Bishr Omary M, Michele DE, Oral EA

Abstract
Background: Juvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome.
Case presentation: A previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation.
Conclusions: This is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.

PMID: 29610677 [PubMed]

Exomechip Analyses Identify Genes Affecting Mortality after HLA-Matched Unrelated Donor Blood and Marrow Transplantation.

Blood. 2018 Apr 02;:

Authors: Zhu Q, Yan L, Liu Q, Zhang C, Wei L, Hu Q, Preus L, Clay-Gilmour AI, Onel K, Stram DO, Pooler L, Sheng X, Haiman CA, Zhu X, Spellman SR, Pasquini M, McCarthy PL, Liu S, Hahn T, Sucheston-Campbell LE

Abstract
While survival outcomes have significantly improved, up to 40% of patients die within 1-year after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2,473 AML, ALL, MDS patients and 2,221 10/10 HLA matched donors treated from 2000-2011. Single variant and gene-level analyses were performed with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of a testis expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, four (ALPP, EMID1, SLC44A5, LRP1), one (HHAT), and two (LYZL4, NT5E) genes were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures shows four of the associated variants impact the enzyme structure and likely decrease the enzyme's catalytic efficiency. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.

PMID: 29610366 [PubMed - as supplied by publisher]

Blue Diaper Syndrome and PCSK1 Mutations.

Pediatrics. 2018 Apr;141(Suppl 5):S501-S505

Authors: Distelmaier F, Herebian D, Atasever C, Beck-Woedl S, Mayatepek E, Strom TM, Haack TB

Abstract
Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations.

PMID: 29610180 [PubMed - in process]

Impact of clinical exomes in neurodevelopmental and neurometabolic disorders.

Mol Genet Metab. 2017 Aug;121(4):297-307

Authors: Evers C, Staufner C, Granzow M, Paramasivam N, Hinderhofer K, Kaufmann L, Fischer C, Thiel C, Opladen T, Kotzaeridou U, Wiemann S, Schlesner M, Eils R, Kölker S, Bartram CR, Hoffmann GF, Moog U

Abstract
Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias). In one family two coexisting autosomal recessive diseases caused by homozygous pathogenic variants in two different genes were diagnosed. In another family, a homozygous frameshift variant in STRADA was found to cause a severe NDD with early onset epilepsy, brain anomalies, hypotonia, heart defect, nephrocalcinosis, macrocephaly and distinctive facies so far designated as PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy) syndrome. In 7 of the 21 families with a molecular diagnosis the pathogenic variants were only identified by clinical follow-up, manual reevaluation of the literature, a change of filter setting, and/or reconsideration of inheritance pattern. Most importantly, clinical implications included management changes in 8 cases and impact on family planning in 20 families with a molecular diagnosis. This study shows that reevaluation and follow-up can improve the diagnostic rate and that WES results have important implications on medical management and family planning. Furthermore, we could confirm STRADA as a gene associated with syndromic ID but find it questionable if the current designation as PMSE depicts the most important clinical features.

PMID: 28688840 [PubMed - indexed for MEDLINE]

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

Mol Genet Metab. 2017 Aug;121(4):314-319

Authors: Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, Jhangiani SN, Gibbs RA, Elsea SH, Porter BE, Graham BH

Abstract
OBJECTIVE: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay.
METHODS: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects.
RESULTS: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain.
SIGNIFICANCE: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.

PMID: 28673551 [PubMed - indexed for MEDLINE]

Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial.

BMC Cancer. 2018 Apr 02;18(1):354

Authors: Tosco L, Laenen A, Gevaert T, Salmon I, Decaestecker C, Davicioni E, Buerki C, Claessens F, Swinnen J, Goffin K, Oyen R, Everaerts W, Moris L, De Meerleer G, Haustermans K, Joniau S, P.E.A.R.L. (ProstatE cAncer Research Leuven)

Abstract
BACKGROUND: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone.
OBJECTIVE: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints.
METHODS: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry.
DISCUSSION: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected.
TRIAL REGISTRATION: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

PMID: 29606109 [PubMed - in process]

Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.

Biol Psychiatry. 2017 Aug 01;82(3):224-232

Authors: Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ

Abstract
BACKGROUND: Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear.
METHODS: We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express NaV1.2.
RESULTS: In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability.
CONCLUSIONS: This functional characterization thus identifies SCN2A mutation and NaV1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.

PMID: 28256214 [PubMed - indexed for MEDLINE]

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

Lancet. 2018 Mar 28;:

Authors: Männikkö R, Wong L, Tester DJ, Thor MG, Sud R, Kullmann DM, Sweeney MG, Leu C, Sisodiya SM, FitzPatrick DR, Evans MJ, Jeffrey IJM, Tfelt-Hansen J, Cohen MC, Fleming PJ, Jaye A, Simpson MA, Ackerman MJ, Hanna MG, Behr ER, Matthews E

Abstract
BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.
METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.
FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057).
INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths.
FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

PMID: 29605429 [PubMed - as supplied by publisher]

Brief Report: Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases.

J Thorac Oncol. 2018 Mar 28;:

Authors: Li Y, Liu B, Connolly ID, Kakusa BW, Pan W, Nagpal S, Montgomery SB, Gephart MH

Abstract
When compared to solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. LMD does not undergo surgical resection, limiting the tissue available for scientific research. Here we performed whole-exome sequencing (WES) on 8 LMD samples to identify somatic mutations and compared the results with 26 solid brain metastases. We found that TAS2R31 and PDE4DIP were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with retrospective chart review of an additional 44 NSCLC LMD patients, we discovered a surprisingly low number of KRAS mutations (n=4, 7.7%), but a high number of EGFR mutations (n=33, 63.5%). The median interval for developing LMD from NSCLC was shorter in EGFR-mutant (16.3 mo) than wild-type (23.9 mo) patients (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic toolkit, and correlations of EGFR in LMD and KRAS in solid metastases suggest molecular distinctions or systemic treatment pressure underpinning differences in growth patterns within the brain.

PMID: 29604399 [PubMed - as supplied by publisher]

Stem Cell modeling of Mitochondrial Parkinsonism reveals key functions of OPA1.

Ann Neurol. 2018 Mar 31;:

Authors: Jonikas M, Madill M, Mathy A, Zekoll T, Zois CE, Wigfield S, Kurzawa-Akanbi M, Browne C, Sims D, Chinnery PF, Cowley SA, Tofaris GK

Abstract
OBJECTIVE: Defective mitochondrial function due to OPA1 mutations causes primarily optic atrophy and less commonly neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some but not all patients is unknown. Here we used a tractable iPSC-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism.
METHODS: iPSC were generated from two patients with OPA1 haploinsufficiency and two controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long range PCR. Mitochondrial membrane potential was measured by TMRM uptake and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants.
RESULTS: OPA1 haploinsufficient iPSC differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation.
INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons at least in part by regulating the stability of Complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. This article is protected by copyright. All rights reserved.

PMID: 29604226 [PubMed - as supplied by publisher]

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.

Ann Neurol. 2018 Mar 31;:

Authors: Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Brüggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Münchau A, Shakkottai V, Klein C, Collins C, Lohmann K, van de Warrenburg BP, Burmeister M

Abstract
OBJECTIVE: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias and spastic paraplegia.
METHODS: In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures.
RESULTS: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all seven families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4, SCAR4. Linkage to chromosome 1p36 was found in this family with a LOD score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but two patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knock-down or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production.
INTERPRETATION: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. This article is protected by copyright. All rights reserved.

PMID: 29604224 [PubMed - as supplied by publisher]

SAM syndrome is characterized by extensive phenotypic heterogeneity.

Exp Dermatol. 2018 Mar 31;:

Authors: Taiber S, Samuelov L, Mohamad J, Cohen Barak E, Sarig O, Shalev SA, Lestringant G, Sprecher E

Abstract
Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life-threatening inherited condition caused by bi-allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome-causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasizes the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits. This article is protected by copyright. All rights reserved.

PMID: 29604126 [PubMed - as supplied by publisher]

Independent development of endometrial epithelium and stroma within the same endometriosis.

J Pathol. 2018 Mar 31;:

Authors: Noë M, Ayhan A, Wang TL, Shih IM

Abstract
The pathogenesis of endometriosis, a common benign but debilitating disease in women, remains elusive. The currently held stem cell theory posits that circulating progenitor/stem cells are deposited outside the uterus where they differentiate into endometrial stroma and glandular tissue to establish endometriosis. Fundamental to testing this hypothesis is to elucidate the evolution of both tissue types. Here, we applied droplet digital PCR to analyze synonymous and missense somatic passenger mutations, which are neutral with respect to clonal selection, among six non-superficial endometriotic lesions. We found that among 19 mutations sequenced, all were significantly enriched in epithelial but not in stromal components of every lesion examined. Our data indicate that the evolution of non-superficial endometriosis is complex, in that epithelium is clonal and its development is independent of stroma, providing new insight into the genesis of endometriosis.

PMID: 29604057 [PubMed - as supplied by publisher]

Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease.

Gastroenterology. 2018 Mar 27;:

Authors: Sribudiani Y, Chauhan RK, Alves MM, Petrova L, Brosens E, Harrison C, Wabbersen T, de Graaf BM, Rügenbrink T, Burzynski G, Brouwer RWW, IJcken WFJV, Maas SM, de Klein A, Osinga J, Eggen BJL, Burns AJ, Brooks AS, Shepherd IT, Hofstra RMW

Abstract
BACKGROUND & AIMS: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multi-generational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide.
METHODS: We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3. However, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons.
RESULTS: Within the linkage region, we identified 1 putative splice variant in the LPS responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on mRNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the indian hedgehog gene (IHH) and its mediator, the transcription factor GLI family zinc finger 3 (GLI3). When expressed in cells, the RET-P399L variant disrupted protein glycosylation and had altered phosphorylation following activation by GDNF. The deletion in GDNF prevented secretion of its gene product, reducing RET activation, and the IHH-Q51K variant reduced expression of the transcription factor GLI1. Injection of morpholinos that target ihh reduced the number of enteric neurons to 13%±1.4% of control zebrafish.
CONCLUSIONS: In a study of a large family with history of HSCR, we identified variants in LRBA, RET, the gene encoding the RET ligand (GDNF), IHH, and a gene encoding a mediator of IHH signaling (GLI3). These variants altered functions of the gene products when expressed in cells and knockout of ihh reduced the number of enteric neurons in the zebrafish gut.

PMID: 29601828 [PubMed - as supplied by publisher]

SCN1A variants associated with sudden infant death syndrome.

Epilepsia. 2018 Mar 30;:

Authors: Brownstein CA, Goldstein RD, Thompson CH, Haynes RL, Giles E, Sheidley B, Bainbridge M, Haas EA, Mena OJ, Lucas J, Schaber B, Holm IA, George AL, Kinney HC, Poduri AH

Abstract
We identified SCN1A variants in 2 infants who died of sudden infant death syndrome (SIDS) with hippocampal abnormalities from an exome sequencing study of 10 cases of SIDS but no history of seizures. One harbored SCN1A G682V, and the other had 2 SCN1A variants in cis: L1296M and E1308D, a variant previously associated with epilepsy. Functional evaluation in a heterologous expression system demonstrated partial loss of function for both G682V and the compound variant L1296M/E1308D. Our cases represent a novel association between SCN1A and SIDS, extending the SCN1A spectrum from epilepsy to SIDS. Our findings provide insights into SIDS and support genetic evaluation focused on epilepsy genes in SIDS.

PMID: 29601086 [PubMed - as supplied by publisher]

Whole exome sequencing in a multi-generation family from India reveals a genetic variation c.10C>T (p.Gln4Ter) in keratin 5 gene associated with Dowling-Degos disease.

Indian J Dermatol Venereol Leprol. 2018 Mar 29;:

Authors: Virmani N, Vellarikkal SK, Verma A, Jayarajan R, Sakhiya J, Desai C, Sivasubbu S, Scaria V

PMID: 29600799 [PubMed - as supplied by publisher]

Diagnostic odyssey of patients with mitochondrial disease: Results of a survey.

Neurol Genet. 2018 Apr;4(2):e230

Authors: Grier J, Hirano M, Karaa A, Shepard E, Thompson JLP

Abstract
Objective: To document the complex "diagnostic odyssey" of patients with mitochondrial disease.
Methods: We analyzed data from 210 Rare Diseases Clinical Research Network Contact Registry participants who were patients with a biochemical deficiency or self-reported diagnosis of mitochondrial disease, or their caregivers.
Results: Participants saw an average of 8.19 clinicians (SD 8.0, median 5). The first clinician consulted about symptoms was typically a primary care physician (56.7%), although 35.2% of participants initially sought a specialist. Of note, 55.2% of participants received their diagnosis from a neurologist, 18.2% from a clinical geneticist, and 11.8% from a metabolic disease specialist. A majority of the participants (54.6%) received 1 or more nonmitochondrial diagnoses before their final mitochondrial diagnosis. In their pursuit of a diagnosis, 84.8% of participants received blood tests, 71% a muscle biopsy, 60.5% MRI, and 38.6% urine organic acids. In addition, 39.5% of the participants underwent mitochondrial DNA sequencing, 19% sequencing of nuclear gene(s), and 11.4% whole-exome sequencing.
Conclusions: The diagnostic odyssey of patients with mitochondrial disease is complex and burdensome. It features multiple consultations and tests, and, often, conflicting diagnoses. These reflect disease variety, diagnostic uncertainty, and clinician unfamiliarity. The current survey provides an important benchmark. Its replication at appropriate intervals will assist in tracking changes that may accompany increased popularity of exome testing, more rigorous diagnostic criteria, increased patient reported outcome activity, and trials for promising therapies.

PMID: 29600276 [PubMed]

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features.

Front Neurol. 2018;9:147

Authors: Niu Z, Pontifex CS, Berini S, Hamilton LE, Naddaf E, Wieben E, Aleff RA, Martens K, Gruber A, Engel AG, Pfeffer G, Milone M

Abstract
Objective: The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.
Patients and methods: Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.
Results: Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.
Conclusion: The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.

PMID: 29599744 [PubMed]