New HSP genotypes and phenotypes

Research from Germany, UK, Taiwan, Sweden, Italy, Saudi Arabia, China, Czech Republic, Iran, USA, Austria, Belgium, the Netherlands, Egypt, Pakistan, France, Japan, Turkey, Russia, Ireland, India

What are genotypes and phenotypes?

The distinction between genotype and phenotype is the difference between an organism’s heredity (its genes or genotype) and what that heredity produces (the physical form and other characteristics, or phenotype).

The term “phenotype” refers to the observable physical properties of an organism, including people. These physical properties include appearance, development and behavior.

An organism’s phenotype is determined by its genotype, which is the set of genes the organism carries, as well as by environmental influences upon these genes. Due to the influence of environmental factors, organisms with identical genotypes, such as identical twins, ultimately express non-identical phenotypes because each organism encounters unique environmental influences as it develops.

Examples of phenotypes include height; eye, skin and hair color; shape and size. Phenotypes also include characteristics that can be observed or measured such as levels of hormones, blood type or behaviour.


SPG83 investigated in 34 people from 25 families

This study, which had 109 contributors from 19 countries spread around the world, found a syndrome varying from juvenile-onset pure HSP to infantile-onset spastic tetraplegia with developmental delay.

Abstract

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations.

Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

SOURCE:  Brain. 2021 May 10;awab041. doi: 10.1093/brain/awab041. Online ahead of print. PMID: 33970200 © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Manuela Wiessner  1 Reza Maroofian  2 Meng-Yuan Ni  3 Andrea Pedroni  4 Juliane S Müller  5   6 Rolf Stucka  1 Christian Beetz  7 Stephanie Efthymiou  2 Filippo M Santorelli  8 Ahmed A Alfares  9 Changlian Zhu  10   11   12 Anna Uhrova Meszarosova  13 Elham Alehabib  14 Somayeh Bakhtiari  15 Andreas R Janecke  16 Maria Gabriela Otero  17 Jin Yun Helen Chen  18 James T Peterson  19 Tim M Strom  20 Peter De Jonghe  21   22   23 Tine Deconinck  24 Willem De Ridder  21   22   23 Jonathan De Winter  21   22   23 Rossella Pasquariello  8 Ivana Ricca  8 Majid Alfadhel  25 Bart P van de Warrenburg  26   27 Ruben Portier  28 Carsten Bergmann  29 Saghar Ghasemi Firouzabadi  30 Sheng Chih Jin  31 Kaya Bilguvar  32   33 Sherifa Hamed  34 Mohammed Abdelhameed  34 Nourelhoda A Haridy  2   34 Shazia Maqbool  35 Fatima Rahman  35 Najwa Anwar  35 Jenny Carmichael  36 Alistair Pagnamenta  37 Nick W Wood  2   38 Frederic Tran Mau-Them  39 Tobias Haack  40 Genomics England Research Consortium, PREPARE networkMaja Di Rocco  41 Isabella Ceccherini  41 Michele Iacomino  41 Federico Zara  41   42 Vincenzo Salpietro  41   42 Marcello Scala  2 Marta Rusmini  41 Yiran Xu  10 Yinghong Wang  43 Yasuhiro Suzuki  44 Kishin Koh  45 Haitian Nan  45 Hiroyuki Ishiura  46 Shoji Tsuji  47 Laëtitia Lambert  48 Emmanuelle Schmitt  49 Elodie Lacaze  50 Hanna Küpper  51 David Dredge  18 Cara Skraban  52   53 Amy Goldstein  19   53 Mary J H Willis  54 Katheryn Grand  55 John M Graham  55 Richard A Lewis  56 Francisca Millan  57 Özgür Duman  58 Nihal Dündar  59 Gökhan Uyanik  60   61 Ludger Schöls  62   63 Peter Nürnberg  64 Gudrun Nürnberg  64 Andrea Catala Bordes  13 Pavel Seeman  13 Martin Kuchar  65 Hossein Darvish  66 Adriana Rebelo  67 Filipa Bouçanova  4 Jean-Jacques Medard  4 Roman Chrast  4 Michaela Auer-Grumbach  68 Fowzan S Alkuraya  69 Hanan Shamseldin  69 Saeed Al Tala  70 Jamileh Rezazadeh Varaghchi  71 Maryam Najafi  6   72 Selina Deschner  73 Dieter Gläser  73 Wolfgang Hüttel  74 Michael C Kruer  15 Erik-Jan Kamsteeg  27   72 Yoshihisa Takiyama  45 Stephan Züchner  67 Jonathan Baets  21   22   23 Matthis Synofzik  62   63 Rebecca Schüle  62   63 Rita Horvath  5   6 Henry Houlden  2 Luca Bartesaghi  4 Hwei-Jen Lee  3 Konstantinos Ampatzis  4 Tyler Mark Pierson  17   56   75   76 Jan Senderek  1

1. Friedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany.

2. Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.

3. Department of Biochemistry, National Defense Medical Center, Neihu, Taipei, Taiwan.

4. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

5. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

6. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

7. Centogene AG, Rostock, Germany.

8. Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

9. Department of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia.

10. Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

11. Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.

12. Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.

13. DNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

14. Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

15. Barrow Neurological Institute, Phoenix Children’s Hospital and University of Arizona College of Medicine, Phoenix, USA.

16. Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.

17. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA.

18. Neurology Department, Massachusetts General Hospital, Boston, USA.

19. Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia, Philadelphia, USA.

20. Institute of Human Genetics, Technische Universität München, Munich, Germany.

21. Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium.

22. Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

23. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.

24. Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerpen, Belgium.

25. Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.

26. Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.

27. Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

28. Polikliniek Neurologie Enschede, Medisch Spectrum Twente, Enschede, The Netherlands.

29. Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.

30. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

31. Department of Genetics, Washington University School of Medicine, St. Louis, USA.

32. Department of Genetics, Yale University School of Medicine, New Haven, USA.

33. Yale Center for Genome Analysis, Yale University, New Haven, USA.

34. Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt.

35. Development and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.

36. Oxford Regional Clinical Genetics Service, Northampton General Hospital, Northampton, UK.

37. NIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

38. The National Hospital for Neurology and Neurosurgery, London, UK.

39. Unité Fonctionnelle 6254 d’Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France.

40. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

41. IRCCS Istituto Giannina Gaslini, Genoa, Italy.

42. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

43. Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.

44. Department of Pediatric Neurology, Osaka Women’s and Children’s Hospital, Osaka, Japan.

45. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.

46. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

47. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan.

48. Department of Clinical Genetics, CHRU Nancy, Nancy, France.

49. Department of Neuroradiology, CHRU Nancy, Nancy, France.

50. Department of Medical Genetics, Le Havre Hospital, Le Havre, France.

51. Department of Pediatric Neurology, University Children’s Hospital Tübingen, Tübingen, Germany.

52. Roberts Individualized Medical Genetics Center, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, USA.

53. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

54. Department of Pediatrics, Naval Medical Center San Diego, San Diego, USA.

55  Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, USA.

56. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, USA.

57. GeneDx, Gaithersburg, USA.

58. Department of Pediatric Neurology, Akdeniz University Hospital, Antalya, Turkey.

59. Department of Pediatrics, Faculty of Medicine, Division of Pediatric Neurology, İzmir Kâtip Çelebi University, İzmir, Turkey.

60. Center for Medical Genetics, Hanusch Hospital, Vienna, Austria.

61. Medical School, Sigmund Freud Private University, Vienna, Austria.

62. Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.

63. German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.

64. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.

65. Department of Paediatric Neurology, Liberec Hospital, Liberec, Czech Republic.

66. Cancer Research Center and Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran.

67. Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.

68. Department of Orthopedics and Traumatology, Medical University of Vienna, Vienna, Austria.

69. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

70. Department of Pediatrics, Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia.

71. Hasti Genetic Counseling Center of Welfare Organization of Southern Khorasan, Birjand, Iran.

72. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

73. genetikum, Center for Human Genetics, Neu-Ulm, Germany.

74. Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freibug, Germany.

75. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA.

76. Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, USA.


Symptom profiles vary enormously in SPG5, even in siblings

Where liver disease occurs, the condition can be fatal. This study in China of a five-month-old baby girl describes the successful treatment of the liver condition with chenodeoxycholic acid. The girls brother had HSP symptoms from 13 years of age.

Background: Deficiency of oxysterol 7α-hydroxylase, encoded by CYP7B1, is associated with fatal infantile progressive intrahepatic cholestasis and hereditary spastic paraplegia type 5. Most reported patients with CYP7B1 mutations presenting with liver disease in infancy have died of liver failure. However, it was recently reported that two patients treated with chenodeoxycholic acid survived. Correlations between the phenotype and genotype of CYP7B1 deficiency have not been clearly established.

Case presentation: A 5-month-7-day-old Chinese baby from non-consanguineous parents was referred for progressive cholestasis and prolonged prothrombin time from one month of age. Genetic testing revealed compound heterozygous mutations c.187C > T(p.R63X)/c.334C > T(p.R112X) in CYP7B1, and fast atom bombardment mass spectrometry analysis of the urinary bile acid confirmed the presence of atypical hepatotoxic 3β-hydroxy-Δ5-bile acids.

While awaiting liver transplantation she was orally administered chenodeoxycholic acid. Her liver function rapidly improved, urine atypical bile acids normalized, and she thrived well until the last follow-up at 23 months of age. Her 15-year-old brother, with no history of infantile cholestasis but harboring the same mutations in CYP7B1, had gait abnormality from 13 years of age. Neurological examination revealed hyper-reflexia and spasticity of the lower limbs. Brain MRI revealed enlarged perivascular space in the bilateral basal ganglia and white matter of frontal parietal.

Conclusions: In summary, these findings highlight that the phenotype of CYP7B1 deficiency varies widely, even in siblings and that early administration of chenodeoxycholic acid may improve prognosis.

SOURCE:  BMC Gastroenterol. 2021 Apr 13;21(1):163. doi: 10.1186/s12876-021-01749-x. PMID: 33849447

Successful treatment of infantile oxysterol 7α-hydroxylase deficiency with oral chenodeoxycholic acid

Yun-Ping Tang  1   2 Jing-Yu Gong  1 Kenneth D R Setchell  3 Wujuan Zhang  3 Jing Zhao  4 Jian-She Wang  5

1. Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, 201508, China.

2. Department of Gastroenterology, Qilu Children’s Hospital of Shandong University, Jinan, 250022, Shandong, China.

3. Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA.

4. The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.

5. The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.


9 new mutations across 5 HSP genes found in 9 people

HSP types include SPG5A, SPG11, SPG7, SPG39 and SPG15 with highly variable symptom profiles.

Abstract

Spastic paraplegias (SPGs) are a group of clinically and genetically heterogeneous neurodegenerative diseases. Mutations in 78 genes have been identified in autosomal dominant hereditary SPG (AD-HSP) and autosomal recessive hereditary SPG (AR-HSP).

Compared to familial HSP, much less is known about the genetic and clinical profiles of sporadic SPGs. In this study, we have screened mutations for 18 sporadic SPGs or AR-HSP patients (mainly Northern Chinese) by whole-exome sequencing. We identified 12 mutations in five genes in 9 (50%) patients, including 9 novel ones: SPG5A/CYP7B1 (c.851C > A; c.122 + 2 T > G), SPG11/KIAA1840 (c.1735 + 3_ 1735 + 6del AAGT); SPG7/SPG7 (c.1454G > A; c.1892_ 1906dup GAGGACGGGCCTCGG); SPG39/PNPLA6 (c.1591G > A; c. 2990C > T); SPG15/ ZFYVE26 (c. 4804C > T; c. 4278 G > A).

Among all the mutations, 7 were detected in the SPG5A and SPG11. Age at onset was significantly younger in cases with mutations (15.45 ± 6.78 years) than those without mutations (25.56 ± 10.90 years) (P = 0.03). Except for two cases with the SPG5A mutations, all cases presented with complicated SPGs. Three cases carrying mutations in SPG7, SPG15, SPG39 showed symptoms and signs of ataxia. One case carrying the homozygous c.259 + 2 T > C mutation in CYP7B1 showed serum parameters indicating liver impairment. Magnetic resonance imaging showed significantly thinned corpus callosum in cases with SPG11 and SPG15, but not in those with SPG5A, SPG7 or SPG39. In contrast, cerebellar atrophy was prominent in the SPG7 and SPG39 cases. These findings expand the spectrum of genetic, clinical and imaging features of sporadic SPG and AR-HSP, and have important implications in genetic counselling, molecular mechanisms and precise diagnosis of the disease.

SOURCE:  Neurosci Lett. 2021 Jul 10;761:136108. doi: 10.1016/j.neulet.2021.136108. Online ahead of print. PMID: 34256108  Copyright © 2021 Elsevier B.V. All rights reserved.  

Genetic, clinical and neuroimaging profiles of sporadic and autosomal recessive hereditary spastic paraplegia cases in Chinese

Yue Dong  1 Xu-Ying Li  1 Xian-Ling Wang  1 Fanxi Xu  1 Zhan-Jun Wang  1 Yang Song  1 Qibin Li  2 Ruichai Lin  2 Chaodong Wang  3

1. Department of Neurology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China.

2. Shenzhen Clabee Biotechnology Incorporation, Shenzhen 518057, China.

3. Department of Neurology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China.


New mutation found in each of SPG8, SPG12 and SPG31

SPG6, SPG8, SPG12 and SPG31 presented as ‘pure’ HSP, with SPG31 the mildest form. SPG9A and SPG17 presented as complicated forms.

Objective: To estimate the proportion and spectrum of infrequent autosomal dominant spastic paraplegias in a group of families with DNA-confirmed diagnosis and to investigate their molecular and clinical characteristics.

Material and methods: Ten families with 6 AD-SPG: SPG6 (n=1), SPG8 (n=2), SPG9A (n=1), SPG12 (n=1), SPG17 (n=3), SPG31 (n=2) were studied using clinical, genealogical, molecular-genetic (massive parallel sequencing, spastic paraplegia panel, whole-exome sequencing, multiplex ligation-dependent amplification, Sanger sequencing) and bioinformatic methods.

Results and conclusion: Nine heterozygous mutations were detected in 6 genes, including the common de novo mutation p.Gly106Arg in NIPA1 (SPG6), the earlier reported mutation p.Val626Phe in WASHC5 (SPG8) in isolated case and the novel p.Val695Ala in WASHC5 (SPG8) in a family with 4 patients, the novel mutation p.Thr301Arg in RTN2 (SPG12) in a family with 2 patients, the novel mutation c.105+4A>G in REEP1 (SPG31) in a family with 4 patients and the reported earlier p.Lys101Lys in REEP1 (SPG31) in a family with 3 patients, the known de novo mutation p.Arg252Gln in ALDH18A1 (SPG9A) in two monozygous twins; the common mutation p.Ser90Leu in BSCL2 (SPG17) in a family with 3 patients and in isolated case, reported mutation p.Leu363Pro in a family with 2 patients.

SPG6, SPG8, SPG12 and SPG31 presented ‘pure’ phenotypes, SPG31 had most benign course. Age of onset varied in SPG31 family and was atypically early in SPG6 case. Patients with SPG9A and SPG17 had ‘complicated’ paraplegias; amyotrophy of hands typical for SPG17 was absent in a child and in an adolescent from 2 families, but may develop later.

SOURCE:  Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(5):75-87. doi: 10.17116/jnevro202112105175. PMID: 34184482

Autosomal dominant spastic paraplegias

[Article in Russian]

G E Rudenskaya  1 V A Kadnikova  1 L A Bessonova  1 P A Sparber  1 S A Kurbatov  2 O L Mironovich  1 F A Konovalov  3 O P Ryzhkova  1

1. Bochkov Research Center for Medical Genetics, Moscow, Russia.

2. Voronezh Regional Clinical Consultative and Diagnostic Center, Vodonezh, Russia.

3. Genomed LLC, Laboratory of Clinical Bioinformatics, Moscow, Russia.


4 new variants found in three HSP types

Five families in central-southern China participated in the study covering SPG4, SPG11 and SPG26 HSP types.

Objective: Hereditary spastic paraplegias (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central-southern China.

Methods: Using targeted exome-sequencing technology, we investigated the genetic and clinical features in five HSP families. We reviewed the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analysis of an intron variant of SPAST in vitro.

Results: We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD-HSP) and four novel variants in two HSP families and a sporadic case. These identified four novel variants included a variant in SPG11 (p.Val1979Ter), two variants in B4GALNT1 (p.Ser475Phe and c.1002 + 2 T > G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the splicing variant in SPAST (c.1245+5G>A) revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying c.1245+5G>A variant in SPAST exhibited genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical features of early-onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated HSP.

Conclusions: Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPAST, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

SOURCE:  Mol Genet Genomic Med. 2021 Feb 27;e1627. doi: 10.1002/mgg3.1627. Online ahead of print. PMID: 33638609 © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central-Southern China

Chen Wang  1 Yun-Jian Zhang  1 Ci-Hao Xu  2 Li De  3 Zhi-Jun Liu  1 Yan Wu  1

1. Department of Neurology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

2. Department of Radiology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

3. Biobank, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.


Five new variants found in AR-SPG7

Large study in Ireland of 32 cases

Only a small percentage of cases have spastic ataxia with peripheral neuropathy.

Background: Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype.

Methods: Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic.

Results: Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was 39.1 years (range 12-61), mean disease duration 17.8 years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families.

Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness.

Conclusions: Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia.

SOURCE:  J Neurol. 2021 Mar 27. doi: 10.1007/s00415-021-10507-8. Online ahead of print. PMID: 33774748

Neurophysiological and ophthalmological findings of SPG7-related spastic ataxia: a phenotype study in an Irish cohort

Petya Bogdanova-Mihaylova  1 Hongying Chen  2 Helena Maria Plapp  2 Ciara Gorman  3 Michael D Alexander  3   4 John C McHugh  3 Sharon Moran  5 Anne Early  6 Lorraine Cassidy  6 Timothy Lynch  7   8 Sinéad M Murphy #  5   4 Richard A Walsh #  5   7   4

1. National Ataxia Clinic, Department of Neurology, Tallaght University Hospital, Tallaght, Dublin 24, Ireland.

2. School of Medicine, Trinity College Dublin, Dublin, Ireland.

3. Department of Clinical Neurophysiology, Tallaght University Hospital, Dublin 24, Ireland.

4. Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland.

5. National Ataxia Clinic, Department of Neurology, Tallaght University Hospital, Tallaght, Dublin 24, Ireland.

6. Department of Ophthalmology, Tallaght University Hospital, Dublin 24, Ireland.

7. Dublin Neurological Institute at the Mater Hospital, University College Dublin, Dublin, Ireland.

8. Health Affairs, University College Dublin, Dublin, Ireland.

# Contributed equally.


8 new mutations & 3 new genes causing HSP

Next-generation sequencing in 17 people with clinically suspected HSP in this study in Turkey revealed 8 new mutations in 5 known HSP genes and in 3 genes not previously related to HSP.

Abstract

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of conditions that are characterized by lower limb spasticity and weakness. Considering the clinical overlap between metabolic causes, genetic diseases, and autosomal recessive HSP, differentiation between these types can be difficult based solely on their clinical characteristics.

This study aimed to investigate the genetic etiology of patients with clinically suspected HSP. The study group was composed of seven Turkish families who each had two affected children and three families who each had a single affected child (17 total patients). The 17 probands (14 males, 3 females) underwent whole exome sequencing. Five typical HSP genes (FA2H, AP4M1, AP4E1, CYP7B1, and MAG) and three genes not previously related to HSP (HACE1, GLRX5, ad ELP2) were identified in 14 probands. Eight novel variants were identified in seven families: c.653 T > C (p.Leu218Pro) in the FA2H gene, c.347G > A (p.Gly116Asp) in the GLRX5 gene, c.2581G > C (p.Ala861Pro) in the HACE1 gene, c.1580G > A (p.Arg527Gln) and c.1189-1G > A in the ELP2 gene, c.10C > T (p.Gln4*) and c.1025 + 1G > A in the AP4M1 gene, c.1291delG (p.Gly431Alafs*3) and c.3250delA (p.Ile1084*) in the AP4E1 gene, and c.475 T > G (p.Cys159Gly) in the MAG gene.

The growing use of next-generation sequencing improved diagnosis but also led to the continual identification of new causal genes for neurogenetic diseases associated with lower limb spasticity. The increasing number of HSP genes identified thus far highlights the extreme genetic heterogeneity of these disorders and their clinical and functional overlap with other neurological conditions. Our findings suggest that the HACE1, GLRX5, and ELP2 genes are genetic causes of HSP.

SOURCE:  Acta Neurol Belg. 2021 Apr 3. doi: 10.1007/s13760-021-01649-7. Online ahead of print. PMID: 33813722

HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies

Gunes Sager  1 Ayberk Turkyilmaz  2 Esra Arslan Ates  3 Busra Kutlubay  4

1. Department of Pediatric Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Semsi Denizer Avenue, Cevizli, 34890, Kartal, Istanbul, Turkey. [email protected]

2. Department of Medical Genetics, Erzurum City Hospital, Erzurum, Turkey.

3. Department of Medical Genetics, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey.

4. Department of Pediatric Neurology, Umraniye Training and Research Hospital, Istanbul, Turkey.


First ever case of pure HSP in SPG78

A newly discovered mutation in the ATP13A2 gene is associated with the first case of pure HSP ever described in SPG78.

Abstract

SPG78 is a subtype of hereditary spastic paraplegia(HSP) caused by ATP13A2 gene mutations. SPG78 was reported as complicated HSP in several cases, but was never associated with pure HSP. Here we report the first Chinese patient carrying a novel homozygous nonsense mutation in ATP13A2 presenting with pure HSP.

SOURCE:  Parkinsonism Relat Disord. 2021 Mar 30;86:58-60. doi: 10.1016/j.parkreldis.2021.03.020. Online ahead of print. PMID: 33862550 Copyright © 2021 Elsevier Ltd. All rights reserved.

A novel homozygous mutation in ATP13A2 gene causing pure hereditary spastic paraplegia

Rui Ban  1 Chuanqiang Pu  2 Fang Fang  3 Qiang Shi  4

1. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, China.

2. Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.

3. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, China.

4. Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.


New variant associated with SPG50 found

Loss of function mutation in AP4M1 gene responsible, with two affected brothers having symptom profiles with significant overlap and also significant differences.

Background: Spastic paraplegia 50 (SPG50) is a rare autosomal recessive inherited disorder characterized by spasticity, severe intellectual disability and delayed or absent speech. Loss-of-function pathogenic mutations in the AP4M1 gene cause SPG50.

Methods: In this study, we investigated the clinical and genetic characteristics of a consanguineous family with two male siblings who had infantile hypotonia that progressed to spasticity, paraplegia in one and quadriplegia in the other patient. In addition, the patients also exhibited neurodevelopmental phenotypes including severe intellectual disability, developmental delay, microcephaly and dysmorphism.

Results: In order to identify the genetic cause, we performed cytogenetics, whole-exome sequencing and Sanger sequencing. Whole-exome sequencing of the affected siblings and unaffected parents revealed a novel exonic frameshift insertion of eight nucleotides (c.341_342insTGAAGTGC) on exon 4 of the AP4M1 gene.

Conclusion: Insertion of these eight nucleotides in the AP4M1 gene is predicted to result in a premature protein product of 132 amino acids. The truncated protein product lacks a signal binding domain which is essential for protein-protein interactions and the transport of cargo proteins to the membrane. Thus, the identified variant is pathogenic and our study expands the knowledge of clinical and genetic features of SPG50.

SOURCE:  Neurol Sci. 2021 Apr 21. doi: 10.1007/s10072-021-05262-7. Online ahead of print. PMID: 33884525

A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic paraplegia 50

Anikha Bellad  1   2 Satish Chandra Girimaji  3 Babylakshmi Muthusamy  4   5

1. Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.

2. Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.

3. Department of Child and Adolescent Psychiatry, NIMHANS, Hosur Road, Bangalore, 560029, India. [email protected]

4. Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India. [email protected]

5. Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.


3 new mutations found in 3 different AR-HSP genes

Whole exome sequencing (WES) was used to identify new mutations in the genes associated with SPG5A, SPG15 and the ultra-rare SPG64.

Abstract

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP.

Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation.

Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.

SOURCE:  J Neurogenet. 2021 Mar 26;1-11. doi: 10.1080/01677063.2021.1895146. Online ahead of print. PMID: 33771085

Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families

Mahdieh Pashaei  1 Atefeh Davarzani  1 Reza Hajati  1 Babak Zamani  2 Shahriar Nafissi  3 Farzaneh Larti  1 Yalda Nilipour  4 Mohammad Rohani  5 Afagh Alavi  1

1. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

2. Neurology Department, Firoozgar hospital, Iran University of Medical Sciences, Tehran, Iran.

3. Department of Neurology, Shariati Hospital., Tehran University of Medical Sciences, Tehran, Iran.

4. Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5. Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran.


Broader symptom profiles in SPG57 described

Symptom profile and severity may be associated with specific mutations

Abstract

In recent years, the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia, named spastic paraplegia type 57 (SPG57).

Until now, four pathogenic homozygous variants of the TFG gene have been reported associated with SPG57. Two consanguineous Iranian families (1 and 2), the first one with two affected members and the second one with one, all with an early-onset progressive muscle weakness, spasticity, and several neurological symptoms were examined via the whole-exome sequencing. Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) have been found in the related families. The candidate variants were confirmed by Sanger sequencing and found to co-segregate with the disease in families. The bioinformatics analysis showed the deleterious effects of these nucleotide changes and the variants were classified as pathogenic according to ACMG guidelines.

A comparison of the clinical presentation of the patients harboring c.41A>G (p.Lys14Arg) with previously reported SPG57 revealed variability in the severity state and unreported clinical presentation, including, facial atrophy, nystagmus, hyperelastic skin, cryptorchidism, hirsutism, kyphoscoliosis, and pectus excavatum. The affected member of the second family carried a previously reported homozygous c.316C>T (p.Arg106Cys) variant and displayed a complex HSP including optic atrophy.

Remarkable clinical differences were observed between the family 1 and 2 harboring the c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) variants, which could be attributed to the distinct affected domains (PB1 domains and coiled-coil domains), and therefore, SPG57 might have been representing phenotype vs. variant position correlation.

SOURCE:  J Hum Genet. 2021 Mar 25. doi: 10.1038/s10038-021-00919-9. Online ahead of print. PMID: 33767317

Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature

Mehdi Khorrami  1 Mohammad Amin Tabatabaiefar  1 Erfan Khorram  1 Omid Yaghini  2 Mojgan Rezaei  3 Arash Hejazifar  4 Maryam Riahinezhad  5 Majid Kheirollahi  6

1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

2. Department of Pediatrics, School of Medicine, Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

3. Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.

4. Department of Biology, School of Sciences, The University of Isfahan, Isfahan, Iran.

5. Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran.

6. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.


New mutation causing SINO syndrome

Molecular studies suggest the cause of obesity in this form of complex HSP

Abstract

Nonsense variants in KIDINS220/ARMS were identified as the main cause of spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome, a rare disease with birth defects in brachycephaly, neurological disorder, and obesity. The cause of neural cell dysfunction by KIDINS220/ARMS were extensively studied while the cause of obesity in SINO syndrome remains elusive.

Here, we identified KIDINS220/ARMS as an adipocyte differentiation-regulating gene. A Chinese family, mother and her two sons, all showed severe symptoms of SINO syndrome. G-banding karyotyping, chromosome microarray analysis, and whole exome sequencing revealed a novel amber mutation, c.3934G>T (p. E1312X), which was close to the C-terminal region of KIDINS220/ARMS and resulted in the premature of the protein. Both the mRNA and protein levels of KIDINS220/ARMS gradually decreased during adipocyte differentiation. Knockdown of KINDINS220/ARMS could prompt adipocyte differentiation and lipid accumulation while overexpression of KIDINS220/ARMS decrease the rate of matured adipocytes. Furthermore, we demonstrated that KIDINS220/ARMS inhibits adipocyte maturation through sustained extracellular signal-regulated kinase signaling.

In conclusion, this is the first report about a vertical heredity of severe dominant pathogenic mutation of KIDINS220/ARMS, suggested that KIDINS220/ARMS played a negative role in adipocyte maturation, explained the cause of obesity in SINO syndrome and could highlight the importance of adipocyte differentiation in neuron functions.

SOURCE:  Front Cell Dev Biol. 2021 Mar 4;9:619475. doi: 10.3389/fcell.2021.619475. eCollection 2021. PMID: 33763417 Copyright © 2021 Zhang, Sun, Liu, Lv, Hou, Lin, Xu, Zhao, Gai, Zhao and Yuan.

SINO Syndrome Causative KIDINS220/ARMS Gene Regulates Adipocyte Differentiation

Kaihui Zhang  1   2   3 Wenxing Sun  4 Yi Liu  2 Yuqiang Lv  2 Daisen Hou  1   3 Yan Lin  1   3   5 Wei Xu  1   3   5 Jianyuan Zhao  1   3   5 Zhongtao Gai  2 Shimin Zhao  1   3   5 Yiyuan Yuan  1   3

1. The Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.

2. Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Ji’nan, China.

3. State Key Lab of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China.

4. Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, China.

5. Key Laboratory of Reproduction Regulation of NPFPC, Institutes of Biomedical Sciences and Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.


New mutations found in AP4-associated HSPs

Large Russian study of 118 families found over 4% were AP4-associated HSPs, the 5th most common HSP type. Whole exome gene sequencing (WES) was used

Objective: In the course of studies of spastic paraplegias in Russian patients to detect AP4-associated forms, estimate their proportion in the total SPG group and analyze clinical and molecular characteristics.

Material and methods: Five families of Russian ethnicity: four with SPG47, one with SPG51 (4 girls and a boy aged 2.5-9 years) were studied. Clinical and genealogical methods, whole-exome sequencing (WES) and verification by familial Sanger sequencing were used.

Results: In our total group, including 118 families with 21 different forms, SPG AP4-associated forms accounted for 4.2% owing mainly to SPG47 (3.4%, 5th place in SPG structure; 20% and 2nd place in AE subgroup.) In non-consanguineous, unrelated SPG47 families three patients had identical genotypes: homozygosity for an earlier reported mutation c.1160_1161 delCA (p.Thr387ArgfsTer30) in AP4B1 exon 6; the 4th patient was compound-heterozygous for the same mutation and novel c.1240C>T (p.Gln414Ter) in exon 7. Frequency of c.1160_1161 delCA may be caused by founder effect in Slavic populations though the idea needs additional studies. The SPG51 patient was compound heterozygous for novel AP4E1 mutations c.2604delA (p.Ser868fs) and c.3346A>G (p.Arg1116Gly). Parent’s heterozygosity in all cases was confirmed by Sanger sequencing. Phenotypes were typical: early development delay, muscle hypotony transforming into sever spasticity, mental deficiency, microceplaly (in all SPG47 cases), epilepsy (in 3 SPG47 and SPG51 cases), MRI changes, mainly hydrocephalus and/or hypoplasia of corpus callosum (in 3 SPG47 cases) and few extraneural signs.

Conclusion: AP4-associated SPG should be taken into consideration in patients with early-onset severe nervous diseases mimicking non-genetic organic CNS disorders and massive exome sequencing (WES or other variants) should be performed.

SOURCE:  Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(2):71-78. doi: 10.17116/jnevro202112102171. PMID: 33728854

AP4-assocated hereditary spastic paraplegias [Article in Russian]

G E Rudenskaya  1 D M Guseva  1 O L Mironovich  1 V A Kadnikova  1 E L Dadali  1 I F Komar’kov  2 O G Novoselova  2 O P Ryzhkova  1

1. Research Centre for Medical Genetics, Moscow, Russia.

2. Genomed Ltd, Moscow, Russia.


New SPG15 mutation found in Taiwanese study

One SPG15 case identified out of 195 people with HSP tested.

Background/purpose: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort.

Methods: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected.

Results: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the “ears of lynx” sign.

Conclusion: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15.

SOURCE:  J Formos Med Assoc. 2021 Feb 24;S0929-6646(21)00062-0. doi: 10.1016/j.jfma.2021.02.005. Online ahead of print. PMID: 33637369 Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.

Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Shao-Lun Hsu  1 Yi-Jiun Lu  2 Yu-Shuen Tsai  3 Hua-Chuan Chao  4 Jong-Ling Fuh  5 Yi-Chu Liao  5 Yi-Chung Lee  6

1. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

2. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.

3. Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan.

4. Division of Neurology, Department of Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

5. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.

6. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.


Mutational hotspot associated with both SPG9A and CMT1A

A Japanese family includes five members with HSP type SPG9A and five members with Charcot-Marie-Tooth disease type 1A. The ALDH18A1 gene involved might easily undergo mutation with the HSP causing mutation newly occurring in the fourth-generation, with the particular mutation type having been found before in other families.

Background: ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A.

Case presentation: A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine.

Conclusions: Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.

SOURCE:  BMC Neurol. 2021 Feb 11;21(1):64. doi: 10.1186/s12883-021-02087-x. PMID: 33573605

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

Kishin Koh  1 Ryusuke Takaki  1   2 Hiroyuki Ishiura  3 Shoji Tsuji  4   5 Yoshihisa Takiyama  6

1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

2. Department of Neurology, Iida Hospital, Nagano, 395-8505, Japan.

3. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

4. Department of Molecular Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, 113-8655, Japan.

5. Department of Neurology, International University of Health and Welfare, Chiba, 286-8686, Japan.

6. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.


Your email address will not be published. Required fields are marked *