Identification of disease genes in rare neurological conditions

This thesis is about improving diagnosis and treatment to persons affected by rare diseases. Diagnosis before treatment is a principle often told to medical students. But what if a diagnosis can’t be made with the resources and knowledge at hand? The number of disorders where the genetic background and the molecular mechanisms are known is increasing rapidly with the advent of massive parallel sequencing, but there are still many disorders awaiting genetic and biological characterization. In my PhD project I have tried to contribute to characterization of new rare diseases, and in two cases this was successful all the way to finding the causative mutations. The success owes a great deal to two things, the access to massive parallel sequencing platforms and to the extensive resources available through my workplace, Centre for Inherited Metabolic Disorders, CMMS.

Paper I is the detailed description of a rare muscle disease, Sarcoplasmic body myopathy. The first description of a family from Sweden affected by this condition was published by our group 40 years ago and paper II provides comprehensive clinical investigations of nine individuals. Paper II is about the genetic and molecular characterization of the disorder, leading to the finding of the responsible gene, MB encoding myoglobin, and description of an additional five families. In paper II we also claim that the damage to muscle cells is caused by oxidative damage. Paper III provides a detailed clinical description of the first two Swedish families affected by spinocerebellar ataxia type 4, SCA4. Besides ataxia and polyneuropathy striking autonomic dysfunction was found, expanding the phenotype significantly. By linkage analysis, custom capture and sequencing we could narrow down the genomic region of interest. Further studies are ongoing in order to identify the causative gene.

Paper IV involves the clinical, biochemical and genetic characterization of a novel inborn error of metabolism, adenosine kinase deficiency, ADK. The two Swedish siblings affected by this disorder had an unusual biochemical abnormality, elevated methionine. After excluding all known causes of hypermethioninemia we could show that the siblings, as well as four additional patients from two unrelated families, were suffering from a previously unknown metabolic defect in the methionine cycle. Paper V constitutes a proof-of-concept study on how rapid diagnosis can be established in acutely ill infants in the neonatal intensive care unit, using customized, rapid whole genome sequencing. Babies with metabolic disorders often respond to treatment provided that diagnosis can be made before permanent damage to the central nervous system and other organs. In this study we provide evidence that a genetic diagnosis can be made in 15-18 hours.

List of scientific papers

I. Engvall M, Ahlberg G, Hedberg B, Edström L, Ansved T. Sarcoplasmic body myopathy--a rare hereditary myopathy with characteristic inclusions. Acta Neurol Scand. 2005;112(4):223-7.
https://doi.org/10.1111/j.1600-0404.2005.00475.x

II. Montse Olivé*, Martin Engvall*, Gianina Ravenscroft*, Macarena Cabrera-Serrano, Hong Jiao,Carlo Augusto Bortolotti, Marcello Pignataro, Matteo Lambrughi, Haibo Jiang, Alistair R.R. Forrest, Núria Benseny-Cases, Stefan Hofbauer, Christian Obinger, Gianantonio Battistuzzi, Marzia Bellei, Marco Borsari, Giulia Di Rocco, Helena M. Viola, Livia C. Hool, Josep Cladera, Kristina Lagerstedt-Robinson, Fengqing Xiang, Anna Wredenberg, Francesc Miralles, Juan José Baiges, Edoardo Malfatti, Norma B. Romero, Nathalie Streichenberger, Christophe Vial, Kristl G. Claeys, Chiara S.M. Straathof, An Goris, Christoph Freyer, Martin Lammens, Guillaume Bassez, Juha Kere, Paula Clemente, Thomas Sejersen, Bjarne Udd, Noemí Vidal, Isidre Ferrer, Lars Edström, Anna WedellÞ & Nigel G. LaingÞ. Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions. Nat Commun. 2019;10(1):1396-1409. *Shared first authors, ÞJoint last authors.
https://doi.org/10.1038/s41467-019-09111-2

III. M. Paucar*, M. Engvall*, C. Söderhäll, M. Skorpil, P. Fazio, K. Lagerstedt-Robinson, G. Solders, T. Skoog, X. Zhang, C. Freyer, A. Wredenberg, C. Halldin, M. Angeria, A. Varrone, I. Nennesmo, M. Risling, H. Jiao, A. WedellÞ and P. SvenningssonÞ. Ataxia, polyneuropathy, autonomic dysfunction and widespread neurodegeneration associated with spinocerebellar ataxia type 4. *Shared first authors, ÞJoint last authors. [Manuscript]

IV. Bjursell MK, Blom HJ, Cayuela JA, Engvall M, Lesko N, Balasubramaniam S, Göran Brandberg, Maria Halldin, Maria Falkenberg, Cornelis Jakobs, Desiree Smith, Eduard Struys, Ulrika von Döbeln, Claes M. Gustafsson, Joakim Lundeberg, and Anna Wedell. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet. 2011;89(4):507-15.
https://doi.org/10.1016/j.ajhg.2011.09.004

V. Stranneheim H, Engvall M, Naess K, Lesko N, Larsson P, Dahlberg M, Robin Andeer, Anna Wredenberg, Chris Freyer, Michela Barbaro, Helene Bruhn, Tesfail Emahazion, Måns Magnusson, Rolf Wibom, Rolf H Zetterström, Valtteri Wirta, Ulrika von Döbeln and Anna Wedell. Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism. BMC Genomics. 2014;15:1090.
https://doi.org/10.1186/1471-2164-15-1090