Publications by authors named "Charles Marques Lourenço"

59 Publications

Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Nature 2021 Feb 10. Epub 2021 Feb 10.

Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.
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http://dx.doi.org/10.1038/s41586-021-03208-9DOI Listing
February 2021

Metachromatic leukodystrophy: pediatric presentation and the challenges of early diagnosis.

Rev Assoc Med Bras (1992) 2020 Oct;66(10):1344-1350

Faculdade de Medicina - Centro Universitário Estácio de Ribeirão Preto, Ribeirão Preto, SP, Brasil.

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http://dx.doi.org/10.1590/1806-9282.66.10.1344DOI Listing
October 2020

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity.

Orphanet J Rare Dis 2020 11 1;15(1):309. Epub 2020 Nov 1.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Av., 3900 - HC Criança - off D506, Ribeirão Prêto, SP, 14049-900, Brazil.

Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing.

Results: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis.

Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.
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http://dx.doi.org/10.1186/s13023-020-01590-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603684PMC
November 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

TRAPγ-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms.

J Med Genet 2021 Mar 24;58(3):213-216. Epub 2020 Apr 24.

Department of Pediatrics, Universitätsklinikum Münster, Münster, Germany

Newly synthesised glycoproteins enter the rough endoplasmic reticulum through a translocation pore. The translocon associated protein (TRAP) complex is located close to the pore. In a patient with a homozygous start codon variant in TRAPγ (SSR3), absence of TRAPγ causes disruption of the TRAP complex, impairs protein translocation into the endoplasmic reticulum and affects transport, for example, into the brush-border membrane. Furthermore, we observed an unbalanced non-occupancy of N-glycosylation sites. The major clinical features are intrauterine growth retardation, facial dysmorphism, congenital diarrhoea, failure to thrive, pulmonary disease and severe psychomotor disability.
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http://dx.doi.org/10.1136/jmedgenet-2019-106279DOI Listing
March 2021

Novel clinical and genetic insight into CXorf56-associated intellectual disability.

Eur J Hum Genet 2020 03 10;28(3):367-372. Epub 2019 Dec 10.

Centogene AG, Rostock, Germany.

Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.
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http://dx.doi.org/10.1038/s41431-019-0558-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028711PMC
March 2020

Clinical findings in Brazilian patients with adult GM1 gangliosidosis.

JIMD Rep 2019 Sep 17;49(1):96-106. Epub 2019 Jul 17.

National Institute of Population Medical Genetics (INAGEMP) Porto Alegre Brazil.

GM1 gangliosidosis is a lysosomal storage disorder caused by β-galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross-sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4-34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.
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http://dx.doi.org/10.1002/jmd2.12067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718113PMC
September 2019

Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data.

Orphanet J Rare Dis 2019 07 8;14(1):168. Epub 2019 Jul 8.

Birmingham Children's Hospital, Birmingham, UK.

Background: Sanfilippo syndrome type B (Sanfilippo B) belongs to a group of rare lysosomal storage diseases characterized by progressive cognitive decline from an early age, acute hyperactivity, and concomitant somatic symptoms. Caregivers face a unique set of challenges related to the complex nature of Sanfilippo B, but the burden and impact on quality of life (QoL) of caregivers is poorly defined and best practice guidance for clinicians is lacking.

Methods: An international clinical advisors meeting was convened to discuss key aspects of caregiver burden associated with Sanfilippo B based on findings from qualitative and quantitative research undertaken to identify and quantify the nature and impact of the disease on patients and caregivers.

Results: Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties. Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress.

Conclusion: A Sanfilippo-specific QoL questionnaire is needed that is directed at caregiver needs and burden and best practice management of these domains.
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http://dx.doi.org/10.1186/s13023-019-1150-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615275PMC
July 2019

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Hum Mutat 2019 07 24;40(7):908-925. Epub 2019 Apr 24.

Metabolic Unit, Great Ormond Street Hospital NHS Trust, Institute for Child Health UCL, London, UK.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.
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http://dx.doi.org/10.1002/humu.23731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661012PMC
July 2019

Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS.

Parkinsonism Relat Disord 2019 05 23;62:148-155. Epub 2018 Dec 23.

Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil.

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis.

Objective And Methods: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide.

Results: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel.

Conclusion: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.
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http://dx.doi.org/10.1016/j.parkreldis.2018.12.024DOI Listing
May 2019

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

Front Neurol 2018 4;9:981. Epub 2018 Dec 4.

Molecular Medicine, Pisa, Italy.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel () comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.
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http://dx.doi.org/10.3389/fneur.2018.00981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289125PMC
December 2018

SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response.

Mov Disord 2018 10 10;33(10):1650-1656. Epub 2018 Oct 10.

Department of Neurology, University of Campinas (UNICAMP), Campinas, Brazil.

Background: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias.

Objectives: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa.

Methods: Patients and controls underwent single-photon emission computed tomography imaging utilizing Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores.

Results: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial.

Conclusion: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.
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http://dx.doi.org/10.1002/mds.27491DOI Listing
October 2018

mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

Neuroimage Clin 2018 9;19:848-857. Epub 2018 Jun 9.

Department of Neurology, University of Campinas (UNICAMP), Campinas, Brazil. Electronic address:

mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. -related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.
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http://dx.doi.org/10.1016/j.nicl.2018.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008284PMC
January 2019

Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity.

Mol Cytogenet 2018 5;11:14. Epub 2018 Feb 5.

1Human Genome and Stem Cell Research Center (HUG-CELL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Rua do Matao no 277, Cidade Universitaria-Butanta, Sao Paulo, SP 05508-090 Brazil.

Background: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype.

Results: Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the  gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility . We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. , , , , , ), and also identified other potentially relevant candidates including , , and

Conclusion: Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.
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http://dx.doi.org/10.1186/s13039-018-0363-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800070PMC
February 2018

Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review.

Neurogenetics 2018 05 8;19(2):123-130. Epub 2018 Feb 8.

IRCCS Stella Maris, via dei Giacinti 2, 56128, Pisa, Calambrone, Italy.

Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.
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http://dx.doi.org/10.1007/s10048-018-0538-8DOI Listing
May 2018

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

JAMA Neurol 2018 04;75(4):495-502

Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.

Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.

Design, Setting, And Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.

Main Outcomes And Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.

Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions And Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
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http://dx.doi.org/10.1001/jamaneurol.2017.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933354PMC
April 2018

Epilepsy in mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 16;122S:55-61. Epub 2017 Oct 16.

Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina.

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, including short stature, musculoskeletal abnormalities, and cardiorespiratory dysfunction, and several primary and secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity and signaling, and release of inflammatory mediators. The amount of literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing and treating MPS.
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http://dx.doi.org/10.1016/j.ymgme.2017.10.006DOI Listing
December 2017

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.

Brain 2017 Dec;140(12):3112-3127

Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany.

Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
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http://dx.doi.org/10.1093/brain/awx273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841036PMC
December 2017

GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms.

Int J Biochem Cell Biol 2017 11 14;92:90-94. Epub 2017 Sep 14.

BRAIN Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Post Graduate Program in Genetics and Molecular Biology of Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Medical Genetics Service of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Electronic address:

Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278Kfs*3, p.H588Qfs*27, p.N642Lfs*10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant α⁄β-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis-Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity.
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http://dx.doi.org/10.1016/j.biocel.2017.09.006DOI Listing
November 2017

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

PLoS Genet 2017 03 27;13(3):e1006683. Epub 2017 Mar 27.

Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
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http://dx.doi.org/10.1371/journal.pgen.1006683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386295PMC
March 2017

Biomolecules damage and redox status abnormalities in Fabry patients before and during enzyme replacement therapy.

Clin Chim Acta 2016 Oct 22;461:41-6. Epub 2016 Jul 22.

Programa de Pós-Graduação em Ciências Biológicas:Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address:

Fabry disease (FD) is caused by deficient activity of the lysosomal enzyme α-galactosidase A. Its substrates, mainly globotriaosylceramide (Gb3), accumulate and seem to induce other pathophysiological findings of FD. Once enzyme replacement therapy (ERT) is not completely efficient on preventing disease progress in FD patients, elucidating the underlying mechanisms in FD pathophysiology is essential to the development of additional therapeutic strategies. We investigated 58 Fabry patients (23 male and 35 female) subdivided into two groups (at diagnosis and during long-term ERT) and compared them to healthy individuals. Fabry patients at diagnosis presented altered glutathione (GSH) metabolism (higher GSH levels, lower glutathione peroxidase - GPx - and normal glutathione reductase - GR - activities), higher lipid peroxidation levels (thiobarbituric acid reactive species - TBARS - and malondialdehyde - MDA), nitric oxide (NO(.)) equivalents and urinary Gb3. Fabry patients on ERT presented GSH metabolism similar to controls, although lipid peroxidation and urinary levels of NO(.) equivalents remained higher whereas Gb3 levels were lower than at diagnosis but still higher than controls. These data demonstrated that redox impairment occurs in Fabry patients before and after ERT, probably as a consequence of Gb3 accumulation, providing targets to future therapy approaches using antioxidants in combination with ERT in FD.
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http://dx.doi.org/10.1016/j.cca.2016.07.016DOI Listing
October 2016

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Brain 2016 Mar;139(Pt 3):765-81

1 Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK 6 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK 48 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.
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http://dx.doi.org/10.1093/brain/awv393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766378PMC
March 2016

De novo DNM1 mutations in two cases of epileptic encephalopathy.

Epilepsia 2016 Jan 27;57(1):e18-23. Epub 2015 Nov 27.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin-mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox-Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.
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http://dx.doi.org/10.1111/epi.13257DOI Listing
January 2016

KIAA0586 is Mutated in Joubert Syndrome.

Hum Mutat 2015 Sep 2;36(9):831-5. Epub 2015 Jul 2.

Department of Pediatrics, University of Washington, Seattle, Washington.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.
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http://dx.doi.org/10.1002/humu.22821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537327PMC
September 2015

Psychiatric disorders, spinocerebellar ataxia type 3 and CAG expansion.

J Neurol 2015 Jul 13;262(7):1777-9. Epub 2015 Jun 13.

Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Avenida dos Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14048-900, Brazil.

Few studies have investigated the association between spinocerebellar ataxia type 3 (SCA3) and psychiatric disorders, using mainly screening scales to assess signs and symptoms of depression and anxiety. With these limitations in mind, we assessed the prevalence of DSM-IV Axis I psychiatric disorders in SCA3 patients and their possible associations with the length of CAG repeats and socio-demographic characteristics, highlighting potential risk factors. DNA samples were collected from 59 adults diagnosed with SCA3 for the quantification of CAG repeats. Next, the patients were assessed in respect to the presence of psychiatric disorders with the Structured Clinical Interview for DSM-IV. Approximately half of the sample had at least one psychiatric disorder (mood disorders 45.2 %), mainly dysthymia and current depression. There were no statistically significant differences in the length of CAG repeats between subjects with and without psychiatric disorders. The perception that SCA3 has a negative impact on life and the subjective assessment of current health status as poor emerged as risk factors for the occurrence of psychiatric disorders in the sample. There is a higher prevalence of psychiatric disorders in SCA3 patients compared to the general population. The lack of association between CAG repeats and occurrence of psychiatric disorders lends support to the hypothesis that psychiatric disorders in this group are associated with adaptive emotional responses to becoming ill.
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http://dx.doi.org/10.1007/s00415-015-7807-3DOI Listing
July 2015

Erratum to: Respiratory dysfunction in Charcot-Marie-Tooth disease type 1A.

J Neurol 2015 May;262(5):1172

Department of Neurosciences and Behaviour Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.

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http://dx.doi.org/10.1007/s00415-015-7733-4DOI Listing
May 2015

Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.

Eur J Hum Genet 2016 Jan 25;24(1):66-72. Epub 2015 Mar 25.

Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
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http://dx.doi.org/10.1038/ejhg.2015.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795215PMC
January 2016

Analyses of disease-related GNPTAB mutations define a novel GlcNAc-1-phosphotransferase interaction domain and an alternative site-1 protease cleavage site.

Hum Mol Genet 2015 Jun 18;24(12):3497-505. Epub 2015 Mar 18.

Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany,

Mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the α/β-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. This enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. Upon arrival in the Golgi apparatus, the newly synthesized α/β-subunit precursor is catalytically activated by site-1 protease (S1P). Here we performed comprehensive expression studies of GNPTAB mutations, including two novel mutations T644M and T1223del, identified in Brazilian MLII/MLIII alpha/beta patients. We show that the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum (ER) due to loss of cytosolic ER exit motifs consistent with a severe clinical phenotype in homozygosity. The luminal missense mutations, C505Y, G575R and T644M, partially impaired ER exit and proteolytic activation in accordance with less severe MLIII alpha/beta disease symptoms. Analogous to the previously characterized S399F mutant, we found that the missense mutation I403T led to retention in the ER and loss of catalytic activity. Substitution of further conserved residues in stealth domain 2 (I346 and W357) revealed similar biochemical properties and allowed us to define a putative binding site for accessory proteins required for ER exit of α/β-subunit precursors. Interestingly, the analysis of the Y937_M972del mutant revealed partial Golgi localization and formation of abnormal inactive β-subunits generated by S1P which correlate with a clinical MLII phenotype. Expression analyses of mutations identified in patients underline genotype-phenotype correlations in MLII/MLIII alpha/beta and provide novel insights into structural requirements of proper GlcNAc-1-phosphotransferase activity.
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http://dx.doi.org/10.1093/hmg/ddv100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498157PMC
June 2015

Respiratory dysfunction in Charcot-Marie-Tooth disease type 1A.

J Neurol 2015 May 13;262(5):1164-71. Epub 2015 Mar 13.

We aimed to investigate the relationship between neurological compromise, respiratory parameters in wakefulness and in sleep, physiology, and morphology of phrenic nerves in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Sixteen patients with CMT1A were evaluated by spirometry, maximal expiratory and maximal inspiratory pressures (MEP, MIP), polysomnography, phrenic nerve compound muscle action potential (CMAP), and ultrasonography (roots C3,C4,C5 and phrenic nerves). Clinical disability was measured with Charcot-Marie-Tooth neuropathy score (CMT-NS; range 0-36). Two control groups, comprising 30 individuals matched for age, sex, and body mass index, were used for comparison. Ten patients were female (62%), mean age was 37.88 years (range 24-76); and CMT-NS range was 7-34. MIP was reduced in five (31%) and MEP in 12 patients (75%), although only one had restrictive respiratory dysfunction in spirometry. Apnoea-hypopnea index (AHI) was significantly higher in patients (12.01 ± 11.57/h × 5.89 ± 8.36/h; p value = 0.05) and increased in REM sleep compared with NREM (9.94 ± 10.96/h × 19.13 ± 19.93/h; p value = 0.01). There were significant correlations between CMT-NS and AHI (Pearson = 0.69; p value = 0.03); CMT-NS and MIP (Pearson = -0.691, p value = 0.003); and CMT-NS and MEP (Pearson = -0.603, p value = 0.013). Also, AHI showed negative correlation with MIP (Pearson = -0.52, p value = 0.036) and MEP (Pearson = -0.55, p value = 0.026). Phrenic nerves were enlarged in ultrasonography in all patients and presented significant correlations with CMAPs (right: Pearson = -0.554, p value = 0.026; left: Pearson = -0.558, p value = 0.025). We suggest that axonal degeneration of nerves directed to muscles of respiration might explain the high prevalence of respiratory weakness in patients with CMT1A. Clinical manifestations are frequent during sleep, where the diaphragm alone can only partially surpass the overload in breathing apparatus.
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http://dx.doi.org/10.1007/s00415-015-7677-8DOI Listing
May 2015