Articles

Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR

It has been suggested that ultra-rare diseases should be recognized as distinct from more prevalent rare diseases, but how drugs developed to treat ultra-rare diseases (DURDs) might be distinguished from drugs...

Authors: Trevor Richter, Ghayath Janoudi, William Amegatse and Sandra Nester-Parr

Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease

Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human ...

Authors: Jennifer M. Kwon, Dietrich Matern, Joanne Kurtzberg, Lawrence Wrabetz, Michael H. Gelb, David A. Wenger, Can Ficicioglu, Amy T. Waldman, Barbara K. Burton, Patrick V. Hopkins and Joseph J. Orsini

Adolescence/adult onset MTHFR deficiency may manifest as isolated and treatable distinct neuro-psychiatric syndromes

5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a genetic disorder that can occur at any age and can be easily detected by increased homocysteinemia. In adolescence/adult onset forms, the clini...

Authors: Ana Gales, Marion Masingue, Stephanie Millecamps, Stephane Giraudier, Laure Grosliere, Claude Adam, Claudio Salim, Vincent Navarro and Yann Nadjar

Common drug review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand

Public payer reimbursement for non-oncology drugs in Canada, including orphan drugs, is based on recommendations by the Common Drug Review (CDR) (with the exception of Quebec). CDR has been criticized for nega...

Authors: John I. McCormick, L. Diana Berescu and Nabil Tadros

Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system

The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aime...

Authors: L. Marti-Sanchez, J. D. Ortigoza-Escobar, A. Darling, M. Villaronga, H. Baide, M. Molero-Luis, M. Batllori, M. I. Vanegas, J. Muchart, L. Aquino, R. Artuch, A. Macaya, M. A. Kurian and Pérez Dueñas

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of ...

Authors: Monika Słowińska, Sergiusz Jóźwiak, Angela Peron, Julita Borkowska, Dariusz Chmielewski, Krzysztof Sadowski, Elżbieta Jurkiewicz, Aglaia Vignoli, Francesca La Briola, Maria Paola Canevini and Katarzyna Kotulska-Jóźwiak

Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with seb...

Authors: Maja Di Rocco, Livia Pisciotta, Annalisa Madeo, Marta Bertamino and Stefano Bertolini

Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counse...

Authors: Katalin Komlosi, Stefan Diederich, Desiree Lucia Fend-Guella, Oliver Bartsch, Jennifer Winter, Ulrich Zechner, Michael Beck, Peter Meyer and Susann Schweiger

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease

Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration....

Authors: Thais Lampert Monte, Estela da Rosa Reckziegel, Marina Coutinho Augustin, Lucas D. Locks-Coelho, Amanda Senna P. Santos, Gabriel Vasata Furtado, Eduardo Preusser de Mattos, José Luiz Pedroso, Orlando Póvoas Barsottini, Fernando Regla Vargas, Maria-Luiza Saraiva-Pereira, Suzi Alves Camey, Vanessa Bielefeldt Leotti and Laura Bannach Jardim

PhenoDis: a comprehensive database for phenotypic characterization of rare cardiac diseases

Thoroughly annotated data resources are a key requirement in phenotype dependent analysis and diagnosis of diseases in the area of precision medicine. Recent work has shown that curation and systematic annotat...

Authors: Angela Adler, Pia Kirchmeier, Julian Reinhard, Barbara Brauner, Irmtraud Dunger, Gisela Fobo, Goar Frishman, Corinna Montrone, H.-Werner Mewes, Matthias Arnold and Andreas Ruepp

International practices in the dietary management of fructose 1-6 biphosphatase deficiency

In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an eme...

Authors: A. Pinto, M. Alfadhel, R. Akroyd, Y. Atik Altınok, S. M. Bernabei, L. Bernstein, G. Bruni, G. Caine, E. Cameron, R. Carruthers, B. Cochrane, A. Daly, F. de Boer, S. Delaunay, A. Dianin, M. Dixon…

The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome

Marfan syndrome (MFS) is a disorder of autosomal dominant inheritance, in which aortic root dilation is the main cause of morbidity and mortality. Fibrillin-1 (FBN-1) gene mutations are found in more than 90% ...

Authors: Víctor Manuel Becerra-Muñoz, Juan José Gómez-Doblas, Carlos Porras-Martín, Miguel Such-Martínez, María Generosa Crespo-Leiro, Roberto Barriales-Villa, Eduardo de Teresa-Galván, Manuel Jiménez-Navarro and Fernando Cabrera-Bueno

Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases

Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy...

Authors: Susan Stein, Elizabeth Bogard, Nicole Boice, Vivian Fernandez, Tessa Field, Alan Gilstrap, Susan R. Kahn, Jane Larkindale and Toni Mathieson

Primary hemophagocytic lymphohistiocytosis in adults: the utility of family surveys in a single-center study from China

This study investigated the clinical characteristics of primary hemophagocytic lymphohistiocytosis (HLH) in adults, including immunological markers, pedigree findings, and conditions of allogeneic hematopoieti...

Authors: Zhili Jin, Yini Wang, Jingshi Wang, Jia Zhang, Lin Wu, Zhuo Gao, Wenyuan Lai and Zhao Wang

An overview of the impact of rare disease characteristics on research methodology

About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders...

Authors: Danielle Whicher, Sarah Philbin and Naomi Aronson

Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm

Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irre...

Authors: Yoshiki Sekijima, Mitsuharu Ueda, Haruki Koike, Sonoko Misawa, Tomonori Ishii and Yukio Ando

Congenital anomalies in neurofibromatosis 1: a retrospective register-based total population study

Neurofibromatosis type 1 (NF1) is a dominantly inherited Rasopathy caused by mutations in the NF1 gene on chromosome 17. NF1 has been connected to congenital anomalies, e.g., in the skeletal and cardiovascular sy...

Authors: Jussi Leppävirta, Roope A. Kallionpää, Elina Uusitalo, Tero Vahlberg, Minna Pöyhönen, Juha Peltonen and Sirkku Peltonen

Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trial

Rett syndrome is caused by a pathogenic mutation in the MECP2 gene with major consequences for motor and cognitive development. One of the effects of impaired MECP2 function is reduced production of Brain Derived...

Authors: Jenny Downs, Jenny Rodger, Chen Li, Xuesong Tan, Nan Hu, Kingsley Wong, Nicholas de Klerk and Helen Leonard

Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation

TMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no inf...

Authors: Pietro Vajro, Katarzyna Zielinska, Bobby G. Ng, Marco Maccarana, Per Bengtson, Marco Poeta, Claudia Mandato, Elisa D’Acunto, Hudson H. Freeze and Erik A. Eklund

Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications

Rare diseases are often un- or misdiagnosed for extended periods, resulting in a long diagnostic delay that may significantly add to the burden of the disease. An early diagnosis is particularly essential if a...

Authors: Gé-Ann Kuiper, Olga L. M. Meijer, Eveline J. Langereis and Frits A. Wijburg

Compounded medication for patients with rare diseases

When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is impo...

Authors: Marc Dooms and Maria Carvalho

Disease-specific health related quality of life patient reported outcome measures in Genodermatoses: a systematic review and critical evaluation

Health Related Quality of Life (HR-QoL) Patient reported outcome measures (PROMs) have high utility in evaluation of new interventions in genodermatoses, however inconsistent standards of development and valid...

Authors: John W. Frew, Mark Davidson and Dedee F. Murrell

Exploring patient and family involvement in the lifecycle of an orphan drug: a scoping review

Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagn...

Authors: Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani and Tania Stafinski

Non-invasive test using palmitate in patients with suspected fatty acid oxidation defects: disease-specific acylcarnitine patterns can help to establish the diagnosis

The aim of the present study was to establish a non-invasive, fast and robust enzymatic assay to confirm fatty acid oxidation defects (FAOD) in humans following informative newborn-screening or for selective s...

Authors: Nils Janzen, Alejandro D. Hofmann, Gunnar Schmidt, Anibh M. Das and Sabine Illsinger

Receptor of ghrelin is expressed in cutaneous neurofibromas of individuals with neurofibromatosis 1

Multiple cutaneous neurofibromas are a hallmark of neurofibromatosis 1 (NF1). They begin to appear during puberty and increase in number and volume during pregnancy, suggesting a hormonal influence. Ghrelin is...

Authors: Rafaela E. Rozza-de-Menezes, Nicolle C. Gaglionone, Raquel M. Andrade-Losso, Orlando H. K. Siqueira, Lilian M. Almeida, Kamila da S. Peruzini, Marco A. C. Guimarães-Filho, Carolina I. Brum, Mauro Geller and Karin S. Cunha

Down-regulation of miR-9* in the peripheral leukocytes of Huntington’s disease patients

Huntington’s disease (HD), caused by expansion of a polyglutamine tract within HUNTINGTIN (HTT) protein, is an autosomal dominant neurodegenerative disease associated with a progressive neurodegeneration of st...

Authors: Kuo-Hsuan Chang, Yih-Ru Wu and Chiung-Mei Chen

KBG syndrome

KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings includ...

Authors: Dayna Morel Swols, Joseph Foster II and Mustafa Tekin

Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome

Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present...

Authors: Jianying Xi, Chong Yan, Wei-Wei Liu, Kai Qiao, Jie Lin, Xia Tian, Hui Wu, Jiahong Lu, Lee-Jun Wong, David Beeson and Chongbo Zhao

Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients

Mitochondrial dysfunction may represent a pathogenic factor in Huntington disease (HD). Physical exercise leads to enhanced mitochondrial function in healthy participants. However, data on effects of physical ...

Authors: Sandro Manuel Mueller, Saskia Maria Gehrig, Jens A. Petersen, Sebastian Frese, Violeta Mihaylova, Maria Ligon-Auer, Natalia Khmara, Jean-Marc Nuoffer, André Schaller, Carsten Lundby, Marco Toigo and Hans H. Jung

Morphoproteomics and biomedical analytics coincide with clinical outcomes in supporting a constant but variable role for the mTOR pathway in the biology of congenital hyperinsulinism of infancy

We first introduced the concept of the mTOR pathway’s involvement in congenital hyperinsulinism of infancy (CHI), based largely on morphoproteomic observations and clinical outcomes using sirolimus (rapamycin)...

Authors: Robert E. Brown, Senthil Senniappan, Khalid Hussain and Mary F. McGuire

Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in adult patients with Pompe disease

Pompe disease is a rare, progressive, metabolic disease, and the first treatable inheritable muscle disorder. Enzyme replacement therapy (ERT) with alglucosidase alfa is disease specific and the only medicinal...

Authors: Tim A. Kanters, Ans T. van der Ploeg, Michelle E. Kruijshaar, Dimitris Rizopoulos, W. Ken Redekop, Maureen P. M. H. Rutten-van Mӧlken and Leona Hakkaart-van Roijen

Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance

Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest unde...

Authors: Gabriel C. Dworschak, Nadine Zwink, Eberhard Schmiedeke, Kiarasch Mortazawi, Stefanie Märzheuser, Konrad Reinshagen, Johannes Leonhardt, Barbara Gómez, Patrick Volk, Anke Rißmann, Ekkehart Jenetzky and Heiko Reutter

A novel mutation of HOXA11 in a patient with septate uterus

The etiology of Müllerian duct anomalies (MDAs) is poorly understood at present. The HOXA11 gene is crucial for the development of the Müllerian duct. The objective of this study is to report a unique case of MDA...

Authors: Ying Zhu, Zhi Cheng, Jing Wang, Beihong Liu, Longfei Cheng, Beili Chen, Yunxia Cao and Binbin Wang

Health-related quality of life among adults with diverse rare disorders

Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-relate...

Authors: Kathleen R. Bogart and Veronica L. Irvin

A novel mutation in ST14 at a functionally significant amino acid residue expands the spectrum of ichthyosis-hypotrichosis syndrome

Mutations in the ST14 gene, encoding the serine protease matriptase, have been associated with ichthyosis-hypotrichosis syndrome (IHS), a Mendelian disorder with skin and hair manifestations which include, in add...

Authors: Leila Youssefian, Andrew Touati, Amir Hossein Saeidian, Omid Zargari, Sirous Zeinali, Hassan Vahidnezhad and Jouni Uitto

Indirect estimation of the prevalence of spinal muscular atrophy Type I, II, and III in the United States

Spinal muscular atrophy (SMA) is a progressive, devastating disease and a leading inherited cause of infant mortality. The limited population-based literature is confined to small regional studies. Estimates o...

Authors: Cathy Lally, Cynthia Jones, Wildon Farwell, Sandra P. Reyna, Suzanne F. Cook and W. Dana Flanders

Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome

Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment...

Authors: Laura Avagliano, Paolo Grazioli, Milena Mariani, Gaetano P. Bulfamante, Angelo Selicorni and Valentina Massa

Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness

Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosid...

Authors: Katherine Johnson, Ana Töpf, Marta Bertoli, Lauren Phillips, Kristl G. Claeys, Vidosava Rakocevic Stojanovic, Stojan Perić, Andreas Hahn, Paul Maddison, Ela Akay, Alexandra E. Bastian, Anna Łusakowska, Anna Kostera-Pruszczyk, Monkol Lek, Liwen Xu, Daniel G. MacArthur…

Measuring what matters to rare disease patients – reflections on the work by the IRDiRC taskforce on patient-centered outcome measures

Our ability to evaluate outcomes which genuinely reflect patients’ unmet needs, hopes and concerns is of pivotal importance. However, much current clinical research and practice falls short of this objective b...

Authors: Thomas Morel and Stefan J. Cano

Abstracts from the First European Meeting for ATTR Amyloidosis for Doctors and Patients

Authors:

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.

Authors: Conceição Bettencourt, Vincenzo Salpietro, Stephanie Efthymiou, Viorica Chelban, Deborah Hughes, Alan M. Pittman, Monica Federoff, Thomas Bourinaris, Martha Spilioti, Georgia Deretzi, Triantafyllia Kalantzakou, Henry Houlden, Andrew B. Singleton and Georgia Xiromerisiou

Erratum to: Quantification of gait in mitochondrial m.3243A > G patients: a validation study

Authors: Rob Ramakers, Saskia Koene, Jan T. Groothuis, Paul de Laat, Mirian C. H. Janssen and Jan Smeitink

Mimicking hypersensitivity pneumonitis as an uncommon initial presentation of chronic granulomatous disease in children

Dry cough, dyspenea and diffuse centrilobular nodules in both lungs of radiologic findings similar to hypersensitivity pneumonitis (HP) are rare initial presentation in chronic granulomatous disease (CGD). CGD...

Authors: Hui Liu, Jinrong Liu, Huimin Li, Yun Peng and Shunying Zhao

Mortality in patients with Sanfilippo syndrome

Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) is an inherited monogenic lysosomal storage disorder divided into subtypes A, B, C and D. Each subtype is characterized by deficiency of a differen...

Authors: Christine Lavery, Chris J. Hendriksz and Simon A. Jones

A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry

Hereditary recurrent fevers (HRF) are a group of rare monogenic diseases leading to recurrent inflammatory flares. A large number of variants has been described for the four genes associated with the best know...

Authors: Riccardo Papa, Matteo Doglio, Helen J. Lachmann, Seza Ozen, Joost Frenkel, Anna Simon, Bénédicte Neven, Jasmin Kuemmerle-Deschner, Huri Ozgodan, Roberta Caorsi, Silvia Federici, Martina Finetti, Maria Trachana, Jurgen Brunner, Liliana Bezrodnik, Mari Carmen Pinedo Gago…

Cognitive impairment profile in adult patients with Niemann pick type C disease

Cognitive impairment is one of the core symptoms of Niemann Pick type C (NPC) disease, but few data concerning the neuropsychological profile of NPC patients are available. The aim of our study was to characte...

Authors: Camille Heitz, Stéphane Epelbaum and Yann Nadjar

Unmet clinical needs and burden in Angelman syndrome: a review of the literature

Angelman syndrome (AS) is a rare disorder with a relatively well-defined phenotype. Despite this, very little is known regarding the unmet clinical needs and burden of this condition, especially with regard to...

Authors: Anne C. Wheeler, Patricia Sacco and Raquel Cabo

KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers

Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule u...

Authors: Saskia Koene, Edwin Spaans, Luc Van Bortel, Griet Van Lancker, Brant Delafontaine, Fabio Badilini, Julien Beyrath and Jan Smeitink

The complete European guidelines on phenylketonuria: diagnosis and treatment

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreate...

Authors: A. M. J. van Wegberg, A. MacDonald, K. Ahring, A. Bélanger-Quintana, N. Blau, A. M. Bosch, A. Burlina, J. Campistol, F. Feillet, M. Giżewska, S. C. Huijbregts, S. Kearney, V. Leuzzi, F. Maillot, A. C. Muntau, M. van Rijn…

Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: 3-year data from the hunter outcome survey (HOS)

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S). Treatment is available in the form of enzyme replace...

Authors: Joseph Muenzer, Roberto Giugliani, Maurizio Scarpa, Anna Tylki-Szymańska, Virginie Jego and Michael Beck