Research from China, Spain, USA, Canada, Czech Republic, Russia, Norway, South Korea, Slovenia
What are genotypes and phenotypes?
The distinction between genotype and phenotype is the difference between someone’s heredity, the set of genes they carry, i.e. their genotype and what that set of genes produces, i.e. their physical and other characteristics or phenotype.
Physical characteristics (phenotype) are determined by the set of genes (genotype) someone has.
Physical characteristics include appearance, development and behaviour. Examples include height; eye, skin and hair colour; body shape and size. Phenotype also includes characteristics that can be observed or measured such as levels of hormones, blood type and behaviour.
Phenotype is determined as well as by environmental influences on the genes. Identical twins, who have identical genotypes, eventually develop some differences because each twin will encounter different environmental influences as they develop and age.
New symptoms expand SPG7 phenotype
2 new variants found; Age-at-onset does not predict HSP type
Background: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts, and more than 80 HSP loci have been mapped to cause HSP. In this study, we aim to perform a genetic and clinical study of ten (6 male, 4 female) sporadic Chinese HSP patients.
Methods: Next-generation sequencing (NGS) gene panels combined with multiplex ligation-dependent probe amplification assay (MLPA) analysis and the trinucleotide repeat dynamic mutation detection are available for the ten patients.
Results: Among the 10 patients, one SPG7 patient, one SPG11 patient, and one pure SPG31 patient were detected. Two variants (deletion of exon 3-9 of SPG7 gene and the heterozygous mutation c.1861C > T/p.Q621* of SPG11 gene) were novel and three (c.1150_1150 + 1insCTAC/p.G384Afs*13 in SPG7 gene, c.3075dupA/p.E1026Rfs*4 in SPG11 gene, and c.478delA/p.R160Gfs*63 of REEP1 gene/SPG31) were previously reported.
The SPG11 patient presented mild intellectual with peripheral neuropathy and thin corpus callosum (TCC) with no white matter abnormalities (WMA). The SPG7 patient detected in this study is the third SPG7 family reported in China; he manifested peripheral neuropathy, scoliosis, and polydactyly which expand the phenotype spectrum of SPG7.
Conclusions: The age-at-onset (AAO) overlapped among each HSP subtype, which limited the ability to predict the subtype of HSP from AAO. Compared with non-Asian patients, the mutation frequency of SPG7 is relatively low in Asian populations. Considering the varieties of mutation types of HSP, we suggested targeted sequencing gene panels should be combined with MLPA for diagnosis of HSP.
SOURCE: Neurol Sci. 2022 Mar 28. doi: 10.1007/s10072-022-05921-3. Online ahead of print. PMID: 35348942 © 2022. Fondazione Società Italiana di Neurologia.
Expansion of the mutation and phenotypic spectrum of hereditary spastic paraplegia
1. Department of Neurosurgery, Changsha Central Hospital, University of South China, Changsha, Hunan, 410000, People’s Republic of China.
2. Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China.
Multinational study of SPG64 identifies 12 new variants
Spectrum of presentations broadened and metabolism of SPG64 neurons studied
Objective: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia (HSP) is associated with over 80 genes with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (MIM# 615683).
Methods: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterizations were performed.
Results: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described: c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs* 18), c.640del; p.(Gly216Glufs* 75), c.185T>G; p.(Leu62*), c.1531T>C; p.(*511Glnext* 100), c.967C>T; p.(Gln323*), c.414-2_414-1del, and c.146 A>G; p.(Tyr49Cys) including four recurrent variants c.1109T>A; p.(Leu370* ), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include: childhood-onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrates ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.
Interpretation: The ENTPD1 locus trait consists of childhood disease-onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1: i) expands previously described features of ENTPD1-related neurological disease, ii) highlights the importance of genotype-driven deep phenotyping, iii) documents the need for global collaborative efforts to characterize rare AR disease traits, and iv) provides insights into the disease trait neurobiology. This article is protected by copyright. All rights reserved.
SOURCE: Ann Neurol. 2022 Apr 26. doi: 10.1002/ana.26381. Online ahead of print. PMID: 35471564 This article is protected by copyright. All rights reserved.
Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia
Daniel G Calame # 1 2 3 , Isabella Herman # 1 2 3 , Reza Maroofian 4 , Aren E Marshall 5 , Karina Carvalho Donis 6 7 , Jawid M Fatih 2 , Tadahiro Mitani 2 , Haowei Du 2 , Christopher M Grochowski 2 , Sergio Sousa 8 , Charul Gijavanekar 2 , Somayeh Bakhtiari 9 10 , Yoko A Ito 5 , Clarissa Rocca 4 , Jill V Hunter 3 11 , V Reid Sutton 2 3 , Lisa T Emrick 1 2 3 , Kym M Boycott 5 , Alexander Lossos 12 , Yakov Fellig 13 , Eugenia Prus 14 , Yosef Kalish 14 , Vardiella Meiner 15 , Manon Suerink 16 , Claudia Ruivenkamp 16 , Kayla Muirhead 17 , Nebal W Saadi 18 , Maha S Zaki 19 , Arjan Bouman 20 , Tahsin Stefan Barakat 20 , David L Skidmore 21 , Matthew Osmond 4 , Thiago Oliveira Silva 7 22 , David Murphy 23 , Ehsan Ghayoor Karimiani 24 , Yalda Jamshidi 24 , Asaad Ghanim Jaddoa 25 , Homa Tajsharghi 26 , Sheng Chih Jin 27 , Mohammad Reza Abbaszadegan 28 29 , Reza Ebrahimzadeh-Vesal 29 , Susan Hosseini 29 , Shahryar Alavi 30 , Amir Bahreini 31 , Elahe Zarean 32 , Mohammad Mehdi Salehi 33 , Nouriya Abbas Al-Sannaa 34 , Giovanni Zifarelli 35 , Peter Bauer 35 , Simon Robson 36 , Zeynep Coban-Akdemir 2 37 , Lorena Travaglini 38 39 , Francesco Nicita 38 39 , Shalini N Jhangiani 40 , Richard A Gibbs 40 , Jennifer E Posey 2 , Michael C Kruer 9 10 , Kristin D Kernohan 5 41 , Jonas A Morales Saute 7 42 43 , Henry Houlden 4 , Adeline Vanderver 17 44 , Sarah H Elsea 2 , Davut Pehlivan 1 2 3 , Dana Marafi 2 45 , James R Lupski 2 3 40 46
1. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA.
2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.
3. Texas Children’s Hospital, Houston, Texas, 77030, USA.
4. Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
5. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
6. Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
7. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
8. Hospital Pediátrico de Coimbra, Portugal.
9. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, 85016, USA.
10. Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
11. Division of Neuroradiology, Edward B. Singleton Department of Radiology, Texas Children’s Hospital, Houston, Texas.
12. Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, 91120, Israel.
13. Department of Pathology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, 91120, Israel.
14. Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and the Hebrew University, POB 12000, 91120, Jerusalem, Israel.
15. Department of Genetics, Hadassah Medical Center and the Hebrew University, POB 12000, 91120, Jerusalem, Israel.
16. Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
17. Division of Neurology, Children’s Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA.
18. College of Medicine / University of Baghdad, Children Welfare Teaching Hospital, Unit of Pediatric Neurology, Medical City Complex, Baghdad, 10001, Iraq.
19. Clinical Genetics Department, Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, El-Tahrir Street, Dokki, Cairo, Egypt, 12311.
20. Department of Clinical Genetics, Erasmus MC University Medical Center, PO Box 2040, 3000, CA, Rotterdam, The Netherlands.
21. Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
22. Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
23. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.
24. Genetics Section, Molecular and Clinical Sciences Institute, St. George’s University of London, Cranmer Terrace, London, SW17 0RE, UK.
25. Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq.
26. School of Health Sciences, Division Biomedicine, University of Skovde, Skovde, Sweden.
27. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
28. Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
29. Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran.
30. Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
31. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA, USA.
32. Department of Perinatology, Isfahan University of Medical Sciences, Isfahan, Iran.
33. Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran.
34. John Hopkins Aramco Health Care, Pediatric Services, Dhahran, Saudi Arabia.
35. CENTOGENE, AG, Rostock, Germany.
36. Gastroenterology and Transplantation, Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
37. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
38. Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.
39. Laboratory of Molecular Medicine, Department of Neuroscience, IRCCS Bambino Gesù Children’s Hospital, 00146, Rome, Italy.
40. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
41. Newborn Screening Ontario, Ottawa, Canada, K1H 8L1, Canada.
42. Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
43. Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
44. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA.
45. Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
46. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
#. Contributed equally.
SPG6 possibly more common in China
Both pure and complicated forms of sporadic SPG6 identified, along with a new variant
Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable.
Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated.
Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one.
Conclusion: NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.
SOURCE: Front Genet. 2022 Apr 8;13:859688. doi: 10.3389/fgene.2022.859688. eCollection 2022. PMID: 35464835 Copyright © 2022 Fu, Ma, Li and Zhang.
Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6
Jun Fu 1 2 , Mingming Ma 2 , Gang Li 2 , Jiewen Zhang 1 2 3
1. Department of Neurological Diseases, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
2. Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, China.
3. Center of Neurological Rare Diseases of Henan Province, Zhengzhou, China.
2 cases of SPG83 described
Mitochondrial nature of this type of HSP confirmed
There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia.
Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.
SOURCE: Front Genet. 2022 Feb 9;13:780764. doi: 10.3389/fgene.2022.780764. eCollection 2022. PMID: 35222531 Copyright © 2022 Micule, Lace, Wright, Chrestian, Strautmanis, Diriks, Stavusis, Kidere, Kleina, Zdanovica, Laflamme, Rioux, Setty, Pajusalu, Droit, Lek, Rivest and Inashkina.
Case Report: Two Families With HPDL Related Neurodegeneration
Ieva Micule 1 2 , Baiba Lace 1 2 3 , Nathan T Wright 4 , Nicolas Chrestian 5 , Jurgis Strautmanis 2 , Mikus Diriks 2 , Janis Stavusis 1 , Dita Kidere 1 , Elfa Kleina 1 , Anna Zdanovica 1 , Nataly Laflamme 3 , Nadie Rioux 3 , Samarth Thonta Setty 3 , Sander Pajusalu 6 7 8 , Arnaud Droit 3 , Monkol Lek 8 , Serge Rivest 3 , Inna Inashkina 1
1. Latvian Biomedical Research and Study Centre, Riga, Latvia.
2. Children’s Clinical University Hospital, Riga, Latvia.
3. Centre de recherche CHU de Québec, Laval University, Québec, QC, Canada.
4. Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, VA, United States.
5. Department of Pediatric Neurology, Pediatric Neuromuscular Disorders, Centre Mère Enfant Soleil, Laval University, Québec, QC, Canada.
6. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
7. Department of Clinical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia.
8. Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.
More evidence for KPNA3 as an infantile-onset HSP-causing gene
Both previously identified and new variants found in KPNA3 in this study of genetic testing data of 400 people with HSP in Canada. The phenotype is shown to include complex HSP to include axonal neuropathy.
We read with interest the article by Schob and colleagues, who identified a novel gene associated with hereditary spastic paraplegia (HSP), KPNA3. Using a trio approach with whole exome sequencing (WES), the authors identified 4 index patients with HSP with de novo deleterious missense variants in KPNA3. The clinical symptoms were consistent among the patients, who had pure, mostly infantile-onset HSP.
To examine whether KPNA3 variants also occurred in the Canadian HSP (CanHSP) cohort (previously described in Refs. 2 and 3), we analyzed 400 patients with available WES data. We identified 2 additional de novo missense variants in KPNA3 (confirmed using Sanger sequencing) in 2 unrelated patients with HSP who did not have a prior genetic diagnosis. One of these variants, p. (Leu328Pro), carried by Patient 1, was also reported by Schob et al. The other variant, p.(Leu407Arg), carried by Patient 2, is a novel variant, also residing in the Armadillo repeat region of KPNA3.
Tables 1 and 2 detail the clinical findings in the 2 patients we identified and compare them to the findings reported by Schob et al. Consistent with their findings, our 2 patients also had infantile-onset HSP. Patient 2 presented with early-onset lower limb weakness and hyperreflexia, bilateral upgoing toes, muscle stiffness, unsteady gait, and attention deficit hyperactivity disorder (ADHD). Patient 1 presented with similar symptoms except for ADHD, along with additional manifestations, including distal muscle atrophy and motor axonal neuropathy. Her gait was narrow-based and unsteady since she first started ambulating and had not progressed over time. On sensory examination, she had decreased proprioception and vibration up to her knees bilaterally but otherwise normal. Nerve conduction studies car- ried out at age 13 years revealed motor axonal neuropathy of the lower extremities, with normal studies of the upper extremities and sensory nerves. Somatosensory evoked potentials of the posterior tibial nerve carried out at age 8 years were abnormal with low amplitudes and poorly formed cortical responses bilaterally. She lacked symptoms of cerebellar dysfunction, such as scanning speech, dysarthria, dysmetria, dysdiadochokinesis, and tremor. These features, along with her longstanding motor axonal neuropathy, could suggest an afferent ataxia. Speech delay seen in Patient 1 and ADHD in Patient 2 could be neurodevelopmental phenotypes caused by KPNA3 mutations.
Overall, our findings confirm the role of de novo KPNA3 variants in HSP and expand the phenotype beyond pure HSP to include axonal neuropathy.
SOURCE: Ann Neurol. 2022 May;91(5):730-732. doi: 10.1002/ana.26275. Epub 2021 Dec 14. PMID: 34825409
Heterozygous De Novo KPNA3 Mutations Cause Complex Hereditary Spastic Paraplegia
Mehrdad A Estiar 1 2 , Noor Lail 3 , David A Dyment 4 , Parizad Varghaei 2 5 , Taila Hartley 4 , Meredith K Gillespie 4 , Grace Yoon 3 6 , Kym M Boycott 4 , Guy A Rouleau 1 2 7 , Ziv Gan-Or 1 2 7
1. Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
2. The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Quebec, Canada.
3. Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
4. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
5. Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Quebec, Canada.
6. Division of Neurology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
7. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
New variant in SPG11 identified
No relationship between variant type and age of onset in SPG11
SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11.
The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygous for the c.5381T>C variant.
Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not find any relationship between the age of onset and the type of variant.
Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene in the Czech SPG11 patients. The c.3454-2A>G variant is novel.
SOURCE: Neurol Res. 2022 May;44(5):379-389. doi: 10.1080/01616412.2021.1975224. Epub 2022 Mar 7. PMID: 35254204
SPG11: clinical and genetic features of seven Czech patients and literature review
Kristyna Doleckova 1 , Jan Roth 1 , Julia Stellmachova 2 , Tomas Gescheidt 3 , Vladimir Sigut 4 , Pavel Houska 5 , Robert Jech 1 , Michael Zech 6 7 , Martin Vyhnalek 8 , Emilie Vyhnalkova 9 , Pavel Seeman 10 , Anna Uhrova Meszarosova 10
1. Department of Neurology and Center of Clinical Neuroscience First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague.
2. Department of Medical Genetics, University Hospital Olomouc, Olomouc, Czechia.
3. Department of Neurology, St. Anne´s University Hospital, Brno, Czechia.
4. Department of Neurology, Krnov Hospital, Krnov.
5. Department of Neurology, Strakonice Hospital, Strakonice, Czechia.
6. Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
7. Institute of Human Genetics, Technical University of Munich, Munich, Germany.
8. Department of Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague.
9. Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague.
10. Department of Paediatric Neurology, Neurogenetic Laboratory, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague.
Case of sporadic, infantile onset SPG4 described
Severe disabling spasticity and cognitive disturbance
A case of spastic paraplegia type 4 (SPG4) due to SPAST p.Arg499His mutation de novo in a child, aged 2 years 8 months, is presented. The differences of this first Russian case with the mutation and of a number of reported cases from typical SPG4 are very early onset, severe disabling spasticity and additional signs, cognitive disturbances in particular; SPAST mutations de novo are also infrequent. Specific patterns point to the relationship between genotype and phenotype. Methods of exome sequencing are particularly informative in atypical cases difficult for clinical diagnostics.
SOURCE: Zh Nevrol Psikhiatr Im S S Korsakova. 2022;122(3):117-120. doi: 10.17116/jnevro2022122031117. PMID: 35394730
Atypical spastic paraplegia type 4 due to p.Arg499His mutation in SPAST gene
[Article in Russian]
G E Rudenskaya 1 , E A Shestopalova 1 , V A Kadnikova 1 , O A Shchagina 1
1. Research Centre for Medical Genetics, Moscow, Russia.
New variant in SPG2 discovered in a female patient
This is extremely rare as SPG2 is an X-linked disease almost always found only in men. Pelizaeus–Merzbacher disease (PMD) is caused by variants in the same gene that causes SPG2 (PLP1).
Spastic paraplegia (SPG) is a genetically heterogeneous disease entity that comprises more than 70 subtypes based on the causative gene. SPG2 is one such subtype and it is associated with the mutation of the X-linked PLP1 gene that affects men. SPG2 mainly manifests as paraparesis with or without central nervous system (CNS) involvement. However, Pelizaeus–Merzbacher disease (PMD), a severe form of disease associated with the PLP1 gene, manifests with broad-spectrum symptoms, including early-onset nystagmus, hypotonia, cognitive impairment, and shortened life span.[1,2,3] Making a final diagnosis of PMD or SPG cannot be based solely on physical symptoms and requires genetic analysis. Here, we examine an unusual case of a female patient with spastic paraplegia and minimal CNS involvement. Using whole-exome sequencing (WES), we identified a novel heterozygous duplication mutation in PLP1, causing the condition.
We reported a novel PLP1 mutation associated with SPG2. The patient presented with relatively mild clinical features but a definite symptom of SPG, which has a heterozygous variant, resulting in premature truncation. Genetic analysis of more female SPG2 cases will help expand the genotype spectrum.
SOURCE: Ann Indian Acad Neurol. Nov-Dec 2021;24(6):958-960. doi: 10.4103/aian.AIAN_793_20. Epub 2021 Jun 29. PMID: 35359527
Symptomatic Female Spastic Paraplegia Patient with a Novel Heterozygous Variant of the PLP1 Gene
Ae Ryoung Kim 1 , Yun-Jeong Lee 2 , Mi Hee Kwack 3 , Jong-Mok Lee 4
1. Department of Rehabilitation Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
2. Department of Pediatrics, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
3. Department of Immunology, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
4. Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
New UBAP1 variant found in 33 year old female
Hotspot region in the gene identified
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases predominately presented with weakness and spasticity in lower extremities. HSPs have high clinical and genetic heterogeneity and over 80 genes or loci have been linked to HSP over the past two decades (Mackay‐Sim, 2021). Even so, approximately 50% of affected individuals are still not genetically diagnosed.
In 2019, two studies (Farazi Fard et al., 2019; Lin et al., 2019) identified pathological truncating variants within UBAP1 in autosomal dominant HSP pedigrees. These families are from Iran, USA, Germany, Canada, Bulgaria, Spain, and China, respectively, implying the diverse geographic origin for the UBAP1 variants. The phenotypes are predominantly pure early‐onset HSP in these families (MIM # 618418).
In this study, we reported a novel UBAP1 (NM_016525.5) truncating variant c.371dupT (p.Leu124Phefs*15) in a Chinese autosomal dominant HSP pedigree (Figure 1a). This study was approved by the Ethics Committee of Second Affiliated Hospital, Zhejiang University School of Medicine and written informed consents were obtained from the participants.
To date, 18 UBAP1 variants including the one identified here have been described (Bian et al., 2021; Bourinaris et al., 2020; Gu et al., 2020; Wang et al., 2020), and 17 of them occurred in Exon 4 of UBAP1 (Figure 1g), implying that Exon 4 is a potential hotspot region of UBAP1. In addition, all identified variants preserve the UMA domain but cause a loss of the SOUBA domain, implying that loss of ubiquitin binding would be detrimental. Further studies are required to elucidate the mechanism of SOUBA impairment causing HSP.
In summary, we identified a novel UBAP1 truncating variant in a Chinese autosomal dominant HSP pedigree. Our findings expanded variant spectrum of UBAP1 and further confirmed the pathogenicity of UBAP1 variants in HSP.
SOURCE: Mol Genet Genomic Med. 2022 May;10(5):e1927. doi: 10.1002/mgg3.1927. Epub 2022 Mar 29. PMID: 35347897
A novel UBAP1 truncated variant in a Chinese family with hereditary spastic paraplegia
Qiao Wei 1 2 , Pei-Shan Wang 1 2 , Hai-Lin Dong 1 2 , Wen-Jiao Luo 1 2 , Zhi-Ying Wu 1 2 , Hong-Fu Li 1 2
1. Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. Key Laboratory of Medical Neurobiology of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Genotype and phenotype of SPG80 in a family described
Missing amino acid sequence in the UBAP1 gene found responsible for the spastic paraplegia
Hereditary spastic paraplegia (HSP) represents a group of rare inherited neurodegenerative conditions and is characterized by progressive lower limb spasticity. Ubiquitin-associated protein 1 (UBAP1)-related HSP is classified as spastic paraplegia-80 (SPG80), which is an autosomal-dominant (AD) juvenile-onset neurologic disorder and mainly affects the lower limbs.
We described the clinical and genetic features of two patients in the same family caused by heterozygous mutation of the UBAP1 gene. The proband was a 34-year-old woman with progressive spasticity and hyperreflexia in the lower limbs for 26 years. Her mother also had similar symptoms since the age of 6. The proband and her mother only had motor dysfunctions, such as unsteady gait, hypertonia, and hyperreflexia of lower limbs. Other system functions (sensory, urinary, visual, and cognitive impairments) were not involved.
WES disclosed a frameshift mutation (c.371dupT) in the UBAP1 gene, which was predicted to be “likely pathogenic” and was co-segregated in the pedigree. c.371dupT, encoding the truncated UBAP1 protein with 72.6% missing of the normal amino acid sequence, is responsible for the spastic paraplegia (SPG) in this family. In combination with clinical characteristics, genetic testing results, and co-segregation analysis, the diagnosis is considered to be pure spastic paraplegia-80 (SPG80), which is an AD disease.
By retrospectively analyzing the documented cases, we comprehensively review the phenotypic features and summarize the genotype spectrum of SPG80 to enhance earlier recognition and therapeutic strategies.
SOURCE: Front Neurol. 2022 Mar 7;13:820202. doi: 10.3389/fneur.2022.820202. eCollection 2022. PMID: 35321509 Copyright © 2022 Zhang, Zhu, Zhu, Ni, Liu, Zheng, Liu, Cao, Zhong and Tian.
Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review
Chao Zhang 1 2 , Xiaowei Zhu 1 2 , Zeyu Zhu 2 , Ruilong Ni 2 3 , Taotao Liu 2 3 , Haoran Zheng 2 3 , Shihua Liu 1 , Li Cao 1 2 , Ping Zhong 1 , Wotu Tian 2
1. Suzhou Hospital of Anhui Medical University Suzhou Municipal Hospital of Anhui Province, Suzou, China.
2. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China.
3. School of Medicine, Anhui University of Science and Technology, Huainan, China.
New variants in CAPN1 gene (SPG76) identified
Psychiatric symptoms can precede motor symptoms in HSP. Multiple genes may contribute to complex neuropsychiatric diseases.
CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain-1 function. Here we illustrate a translational approach to the case of an 18-year-old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP.
Exome sequencing showed compound-heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop-gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain-1 activity and dysregulated downstream signaling.
These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.
SOURCE: Ann Clin Transl Neurol. 2022 Apr;9(4):570-576. doi: 10.1002/acn3.51531. Epub 2022 Mar 16. PMID: 35297214 © 2022 The Authors.
Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early-onset psychosis
Julian E Alecu 1 , Afshin Saffari 1 , Hellen Jumo 1 2 , Marvin Ziegler 1 , Oleksandr Strelko 1 2 , Catherine A Brownstein 3 4 , Joseph Gonzalez-Heydrich 4 5 , Lance H Rodan 1 3 4 , Mark P Gorman 1 , Mustafa Sahin 1 2 6 , Darius Ebrahimi-Fakhari 1 4 6 7
1. Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2. Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, Massachusetts, USA.
3. Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Massachusetts, USA.
5. Department of Psychiatry and Behavioral Sciences, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6. Intellectual and Developmental Disabilities Research Center, Boston Children’s Hospital, Boston, Massachusetts, USA.
7. Movement Disorders Program, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2 new SPAST gene variants causing SPG4 discovered
The function of variants in the CPT1C and DNAJC16 genes in the 11 patients with pure HSP studied is unclear.
Background: Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 pure HSP patients in Yunnan Province.
Methods: Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.
Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception.
Conclusions: Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.
SOURCE: Ann Transl Med. 2022 Jan;10(2):67. doi: 10.21037/atm-21-6698. PMID: 35282124 2022 Annals of Translational Medicine. All rights reserved.
A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province
Tao Shen # 1 2 , Wen Zhang # 1 3 , Li Li 1 , Rong-Xia Zuo 1 2 , Zi-Jun Wang 4 , Tai Xiao 4 , Kun-Wen Zheng 4
1 Institute of Basic and Clinical Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, The First People’s Hospital of Yunnan Province, Kunming, China.
2. Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, Kunming, China.
3. Department of Digestive System, The First People’s Hospital of Yunnan Province, Kunming, China.
4. Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China.
#. Contributed equally.
New gene variant for SPG11 found
Mutations in SPG11 are the major causes of autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). Herein, we report a novel SPG11 mutation in a Chinese HSP-TCC family [Figure 1]a.
A 12-year-old boy (II: 2, the proband) was admitted to the hospital due to tremor in the upper limbs, weakness, and spasticity in the lower limbs, and declined academic performance, which first appeared at about 8 years of age and slowly progressed. Cognitive dysfunction, cerebellar ataxia, lower limb spasticity, and bilateral Babinski signs were observed during the examination. His brain magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) revealed a TCC accompanied by periventricular white matter abnormal changes. The “ears of the lynx” sign was seen in the anterior forceps of the corpus callosum which appeared to be hyperintense on fluid-attenuated inversion recovery (FLAIR) and hypointense on T1 images [Figure 1]b,[Figure 1]c,[Figure 1]d,[Figure 1]e,[Figure 1]f. Therefore, this patient was considered to have HSP-TCC. The father (I: 1) and the mother (I: 2) were unrelated, and examinations of them and the brother (II: 1) were normal. All participants were of Han nationality from Shandong province, China. Informed consent was obtained. By whole-exome sequencing, we identified a novel homozygous mutation c. 4744-1G → A in SPG11 in the proband [Figure 1]h. The father, mother, and brother were heterozygous [Figure 1]i. The mutation was absent in 200 normal chromosomes.
HSP-TCC is characterized by progressive spastic paraparesis and cognitive impairment. In the present study, the proband presented cognitive impairment, cerebellar ataxia, and lower limb spasticity. A TCC was seen, and the “ears of the lynx” sign, which is highly specific for SPG11, was observed on his brain MR images, suggesting that brain MR is essential to diagnose HSP-TCC and helpful to differentiate HSP subtypes.,,, Mutation in SPG11 accounts for 21% of AR HSP cases. In our study, the novel mutation c. 4744-1G → A was identified at the conserved splice acceptor site of exon 28 of SPG11, suggesting a splice-site mutation. The mutation might cause skipping of exon 28 or activation of the potential acceptor splice site at c. 4752-4753AG. A concomitant frameshift may occur and encode a truncated and dysfunctional spatacsin protein. In 2020, another frameshift deletion mutation c. 4746delT in exon 28 of SPG11, close to the site in our study, was detected in an Iranian patient with HSP-TCC, suggesting that mutations in this area are not rare. Spatacsin is pivotal for autophagic lysosome reformation, a pathway that generates new lysosomes. Regeneration dysfunction of lysosomes from autolysosomes and impaired autophagic clearance were found in spatacsin knockout mice, suggesting that autophagy/lysosomal dysfunction was involved in the pathogenesis of SPG11. Our study expands the mutation spectrum of SPG11 and might help to determine the molecular mechanism of HSP-TCC.
SOURCE: Neurol India. Jan-Feb 2022;70(1):424-426. doi: 10.4103/0028-3886.338730. PMID: 35263936
Novel SPG11 Mutation in Hereditary Spastic Paraplegia with Thin Corpus Callosum
Shuang Li 1 , Lili Sun 1 , Guohua Zhao 2 , Xiaomin Liu 1
1. Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
2. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
New SPG7 variant discovered
SPG7 can present with childhood optic nerve atrophy, preceding the characteristic SPG7 symptoms
Purpose: To describe a case of hereditary spastic ataxia (HSP) presenting with childhood optic nerve atrophy and report a novel homozygous variant in the SPG7 gene.
Observations: A 57-year-old man suffering from progressive optic nerve atrophy since childhood eventually underwent genetic testing. A targeted whole exome gene sequencing panel for optic neuropathy identified a novel homozygous variant in the SPG7 gene, c.2T > G, p.(Met?), which likely abolished production of paraplegin, an inner mitochondrial membrane protein. Subsequent neurologic examination revealed subtle signs of spastic paraplegia and ataxia in keeping with the genetic diagnosis of SPG7.
Conclusion and importance: Spastic paraplegia 7 (SPG7) is an autosomal recessive form of the neurodegenerative disorder HSP. Pure HSP is characterized by spastic paraparesis in the lower limbs, whereas complicated HSP presents additional neurological manifestations. This case report adds to the evidence that SPG7 can present with childhood optic nerve atrophy, preceding the characteristic SPG7 manifestations. SPG7 should be considered in the workup of suspected hereditary optic neuropathy.
SOURCE: Am J Ophthalmol Case Rep. 2022 Feb 16;26:101400. doi: 10.1016/j.ajoc.2022.101400. eCollection 2022 Jun. PMID: 35243150 © 2022 The Authors.
A novel homozygous variant in the SPG7 gene presenting with childhood optic nerve atrophy
Kathrine O Eriksen 1 , Andreas Reidar Wigers 1 , Iselin Marie Wedding 2 , Anne Kjersti Erichsen 1 , Tuva Barøy 3 , Kristoffer Søberg 3 , Øystein Kalsnes Jørstad 1 4
1. Department of Ophthalmology, Oslo University Hospital, Norway.
2. Department of Neurology, Oslo University Hospital, Norway.
3. Department of Medical Genetics, Oslo University Hospital, Norway.
4. Faculty of Medicine, University of Oslo, Norway.
New variant in the PCYT2 gene causing SPG82 identified
Axonal polyneuropathy, diagnosed in both brothers, has not previously been reported and expands the known phenotype.
Background and objectives: To expand the phenotype and genotype associated with PCYT2-related disorder.
Methods: Exome sequencing data from a patient with molecularly undiagnosed complex spastic paraplegia and axonal motor and sensory polyneuropathy were analyzed. Clinical data and nerve conduction studies of the patient and his affected brother were collected, and their phenotype and genotype were compared with previously reported patients with PCYT2-related disorder.
Results: A novel homozygous missense variant in PCYT2 (NM_001184917.2) c.88T>G; p.(Cys30Gly) was identified. This variant is located in a highly conserved tyrosine kinase site and is predicted damaging by several variant annotation tools. Both patients reported here and the previously published patients share several phenotypic features, including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline. Axonal polyneuropathy, diagnosed in both brothers, was not previously reported.
Discussion: This family with a novel PCYT2 variant expands the clinical spectrum of PCYT2-related disorder to include axonal motor and sensory polyneuropathy and the genetic spectrum to include the variant located in the first catalytic domain, whereas all previously reported variants are located in the second catalytic domain. Further research is required to disentangle the underlying pathophysiologic mechanisms, leading to the complex phenotype of PCYT2-related disorder.
SOURCE: Neurol Genet. 2022 Mar 1;8(2):e658. doi: 10.1212/NXG.0000000000000658. eCollection 2022 Apr. PMID: 35243002 Copyright © 2022 The Author(s).
Axonal Polyneuropathy in 2 Brothers With a Homozygous Missense Variant in the First Catalytic Domain of PCYT2
Lea Leonardis 1 , Marusa Skrjanec Pusenjak 1 , Ales Maver 1 , Helena Jaklic 1 , Ana Ozura Brecko 1 , Blaz Koritnik 1 , Borut Peterlin 1 , Karin Writzl 1
1. Institute of Clinical Neurophysiology (L.L., B.K.), University Medical Center Ljubljana; Department of Neurology (L.L., B.K.), Faculty of Medicine, University of Ljubljana; Clinical Institute of Genomic Medicine (M.S.P., A.M., H.J., B.P., K.W.), University Medical Centre Ljubljana; Medical Faculty (A.M., K.W.), University of Ljubljana; and Division of Neurology (A.O.B.), University Medical Centre Ljubljana, Slovenia.
High diagnostic yield with new model
Enables discovery of new disease-causing genes
Background and objectives: Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes.
Methods: A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient.
Results: We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD.
Discussion: Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.
SOURCE: Neurology. 2022 Mar 1;98(9):e912-e923. doi: 10.1212/WNL.0000000000013278. Epub 2022 Jan 10. PMID: 35012964 Copyright © 2022 The Author(s).
Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization
Agatha Schlüter 1 , Agustí Rodríguez-Palmero 1 , Edgard Verdura 1 , Valentina Vélez-Santamaría 1 , Montserrat Ruiz 1 , Stéphane Fourcade 1 , Laura Planas-Serra 1 , Juan José Martínez 1 , Cristina Guilera 1 , Marisa Girós 1 , Rafael Artuch 1 , María Eugenia Yoldi 1 , Mar O’Callaghan 1 , Angels García-Cazorla 1 , Judith Armstrong 1 , Itxaso Marti 1 , Elisabet Mondragón Rezola 1 , Claire Redin 1 , Jean Louis Mandel 1 , David Conejo 1 , Concepción Sierra-Córcoles 1 , Sergi Beltrán 1 , Marta Gut 1 , Elida Vázquez 1 , Mireia Del Toro 1 , Mónica Troncoso 1 , Luis A Pérez-Jurado 1 , Luis G Gutiérrez-Solana 1 , Adolfo López de Munain 1 , Carlos Casasnovas 1 , Sergio Aguilera-Albesa 1 , Alfons Macaya 1 , Aurora Pujol 2 , GWMD working group
GWMD working group: Hugo A Arroyo, Andr Es Barrios, Andrea Campo, Tamara Castillo, Rosario Cazorla, Mar Ia Asunci On Garc Ia, Ainhoa Garc Ia, Antonio Hedrera, Juan Hern Andez, Nathalie Launay, Maria Lorenzo, Concepci On Miranda, Ferm In Moreno, Amaia Muñoz, Juan Narbona, MaSocorro P Erez, Maria Antonia Ramos, Miquel Raspall- Chaure, Manel Roig-Quilis, Miguel Angel Urtasun, Mar Ia Esther V Azquez, Juan Francisco V Azquez
1. From the Neurometabolic Diseases Laboratory (A.S., A.R.-P., E. Verdura, V.V.-S., M.R., S.F., L.P.-S., J.J.M., C.G., C.C., A.P.), Bellvitge Biomedical Research Institute (IDIBELL); Instituto de Salud Carlos III (ISCIII) (A.S., A.R.-P., E. Verdura, M.R., S.F., L.P.-S., J.J.M., C.G., R.A., M.O., A.G.-C., J.A., M.d.T., L.A.P.-J., A.M., A.P.) and Secció d’Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M. Girós), Center for Biomedical Research on Rare Diseases (CIBERER); Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol (A.R.-P.), and Pediatric Neurology Research Group, Vall d’Hebron Research Institute (A.M.), and Pediatric Neurology Department, Vall d’Hebron University Hospital (M.d.T., A.M.), Universitat Autònoma de Barcelona; Neuromuscular Unit, Neurology Department (V.V.-S., C.C.), Hospital Universitari de Bellvitge and Hospitalet de Llobregat, Universitat de Barcelona; Institut de Recerca Pediàtrica (R.A., M.O., A.G.-C.) and Molecular and Genetics Medicine Section (J.A.), Hospital Sant Joan de Déu (IRP-HSJD), Barcelona; Pediatric Neurology Unit, Department of Pediatrics (M.E.Y., S.A.-A.), Navarra Health Service, Navarrabiomed Research Foundation; Departments of Neuropediatrics (I.M.) and Neurology (E.M.R., A.L.d.M.), Hospital Universitario Donostia; Biodonostia Health Research Institute (Biodonostia HRI) (I.M., E.M.R., A.L.d.M.); University of the Basque Country (UPV-EHU) (I.M., A.L.d.M.), San Sebastian; Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED) (I.M., E.M.R., A.L.d.M.), Carlos III Health Institute, Madrid, Spain; Département de Médecine Translationnelle et Neurogénétique (C.R., J.L.M.), IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch; Laboratoire de Diagnostic Génétique (J.L.M.), Hôpitaux Universitaires de Strasbourg; Chaire de Génétique Humaine (J.L.M.), Collège de France, Illkirch; Complejo Asistencial Universitario de Burgos (D.C.); Department of Paediatric Neurology (C.S.-C.), Complejo Hospitalario Jaén; CNAG-CRG, Centre for Genomic Regulation (CRG) (S.B., M. Gut), Barcelona Institute of Science and Technology (BIST); Department of Pediatric Radiology (E. Vázquez), Hospital Materno-Infantil Vall d’Hebrón, Barcelona, Spain; Pediatric Neurology (M.T.), Hospital Clínico San Borja Arriarán, Central Campus Universidad de Chile; Genetics Service (L.A.P.-J.), Hospital del Mar Research Institute (IMIM); Department of Experimental and Health Sciences (L.A.P.-J.), Universitat Pompeu Fabra, Barcelona; Department of Paediatric Neurology (L.G.G.-S.), Children’s University Hospital Niño Jesús, Madrid; and Catalan Institution of Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain.
2. From the Neurometabolic Diseases Laboratory (A.S., A.R.-P., E. Verdura, V.V.-S., M.R., S.F., L.P.-S., J.J.M., C.G., C.C., A.P.), Bellvitge Biomedical Research Institute (IDIBELL); Instituto de Salud Carlos III (ISCIII) (A.S., A.R.-P., E. Verdura, M.R., S.F., L.P.-S., J.J.M., C.G., R.A., M.O., A.G.-C., J.A., M.d.T., L.A.P.-J., A.M., A.P.) and Secció d’Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (M. Girós), Center for Biomedical Research on Rare Diseases (CIBERER); Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol (A.R.-P.), and Pediatric Neurology Research Group, Vall d’Hebron Research Institute (A.M.), and Pediatric Neurology Department, Vall d’Hebron University Hospital (M.d.T., A.M.), Universitat Autònoma de Barcelona; Neuromuscular Unit, Neurology Department (V.V.-S., C.C.), Hospital Universitari de Bellvitge and Hospitalet de Llobregat, Universitat de Barcelona; Institut de Recerca Pediàtrica (R.A., M.O., A.G.-C.) and Molecular and Genetics Medicine Section (J.A.), Hospital Sant Joan de Déu (IRP-HSJD), Barcelona; Pediatric Neurology Unit, Department of Pediatrics (M.E.Y., S.A.-A.), Navarra Health Service, Navarrabiomed Research Foundation; Departments of Neuropediatrics (I.M.) and Neurology (E.M.R., A.L.d.M.), Hospital Universitario Donostia; Biodonostia Health Research Institute (Biodonostia HRI) (I.M., E.M.R., A.L.d.M.); University of the Basque Country (UPV-EHU) (I.M., A.L.d.M.), San Sebastian; Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED) (I.M., E.M.R., A.L.d.M.), Carlos III Health Institute, Madrid, Spain; Département de Médecine Translationnelle et Neurogénétique (C.R., J.L.M.), IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch; Laboratoire de Diagnostic Génétique (J.L.M.), Hôpitaux Universitaires de Strasbourg; Chaire de Génétique Humaine (J.L.M.), Collège de France, Illkirch; Complejo Asistencial Universitario de Burgos (D.C.); Department of Paediatric Neurology (C.S.-C.), Complejo Hospitalario Jaén; CNAG-CRG, Centre for Genomic Regulation (CRG) (S.B., M. Gut), Barcelona Institute of Science and Technology (BIST); Department of Pediatric Radiology (E. Vázquez), Hospital Materno-Infantil Vall d’Hebrón, Barcelona, Spain; Pediatric Neurology (M.T.), Hospital Clínico San Borja Arriarán, Central Campus Universidad de Chile; Genetics Service (L.A.P.-J.), Hospital del Mar Research Institute (IMIM); Department of Experimental and Health Sciences (L.A.P.-J.), Universitat Pompeu Fabra, Barcelona; Department of Paediatric Neurology (L.G.G.-S.), Children’s University Hospital Niño Jesús, Madrid; and Catalan Institution of Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain.