New HSP genotypes & phenotypes

Research from the Netherlands, China, Hungary, USA, Republic of Korea, Chile, Germany, Argentina, Japan, Peru, Spain, France and Brazil

 

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.

 

Ataxic gait first presentation in SPG7. Challenge to accurate diagnosis.

 

The overlap between spastic paraplegia and cerebellar ataxia suggests genetic testing in early presentations of ataxia should include HSP panels.

 

Abstract

A 43-year-old man presented with a slowly progressive fatigue and coordination problems, coupled with a radiological appearance of diffuse atrophy, especially in the cerebellar hemispheres. The diagnostic process was challenging because initially the additional investigations were focused on a cerebellar ataxia. In the following months, his ataxic gait developed in a more spastic pattern and whole exome sequencing revealed mutations in the SPG7 gene, confirming a diagnosis of hereditary spastic paraplegia. Therefore, the authors call for an extension of genetic panels in ataxia patients.

 

SOURCE: Case Rep Neurol. 2020 Oct 2;12(3):329-333. doi: 10.1159/000509346. eCollection Sep-Dec 2020. PMID: 33173492 Copyright © 2020 by S. Karger AG, Basel.

A Pyramidal Cause of a Cerebellar Ataxia: HSP-7

Tjerk Joppe Lagrand  1 , Gerard Hageman  2

  1. Department of Neurology, University Medical Centre Groningen, Groningen, The Netherlands.
  2. Department of Neurology, Medical Spectrum Twente, Enschede, The Netherlands.

 

ATP13A2 mutations associated with multiple conditions. A change in terminology is suggested.

 

Mutations in the ATP13A2 gene are associated with several neurodegenerative movement disorders including SPG78 type HSP, Parkinsonism, Kufor-Rakeb syndrome (PARK9), Spastic Ataxia, Supranuclear gaze palsy, Dementia and Motor Neurone Disease.

 

The study describes a combination of Parkinsonism and Spastic Paraplegia found in two people with mutations in this gene.

It is suggested that the term ATP13A2-associated disorder may better define a genetic entity with heterogeneous and overlapping clinical features.

 

SOURCE: Parkinsonism Relat Disord. 2020 Oct 6;81:45-47. doi: 10.1016/j.parkreldis.2020.10.004. Online ahead of print. PMID: 33049588

Intermediate phenotype of ATP13A2 mutation in two Chilean siblings: Towards a continuum between parkinsonism and hereditary spastic paraplegia

Marcelo Miranda  1 , Florian Harmuth  2 , M Leonor Bustamante  3 , Malco Rossi  4 , Marc Sturm  2 , Ólafur Th Magnusson  5 , Peter Bauer  6 , Thomas Klockgether  7 , Alfredo Ramirez  8

  1. Fundación Diagnosis, Santiago, Chile; Department of Neurology, Clinica Las Condes, Santiago, Chile.
  2. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
  3. Fundación Diagnosis, Santiago, Chile; Human Genetics Program, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, University of Chile, Santiago, Chile.
  4. Movement Disorders Section, Neuroscience Department, Fleni, Buenos Aires, Argentina; Argentine National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.
  5. deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.
  6. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Centogene AG, Am Strande 7, Rostock, Germany.
  7. Department of Neurology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  8. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany. Electronic address: [email protected].

 

 

More evidence of RNF170 as an HSP gene

 

Four members of one family with HSP carrying a new mutation in this gene.

 

Background: Spastic paraparesis and biallelic variants functionally characterized as deleterious in the RNF170 gene have recently been reported by Wagner et al. 2019, strongly supporting the involvement of this gene in hereditary spastic paraplegia.

Methods: Exome sequencing was performed on 6 hereditary spastic paraplegia families previously tested on an hereditary spastic paraplegia-specific panel.

Results: We describe here a novel hereditary spastic paraplegia family with 4 affected members carrying a homozygous p.(Tyr114*) stop gain variant in RNF170.

Conclusions: We confirm the involvement of biallelic truncating variants in RNF170 in a novel form of hereditary spastic paraplegia.

SOURCE: Mov Disord. 2020 Nov 9. doi: 10.1002/mds.28371. Online ahead of print. PMID: 33165979 © 2020 International Parkinson and Movement Disorder Society.

RNF170-Related Hereditary Spastic Paraplegia: Confirmation by a Novel Mutation

Jean-Madeleine de Sainte Agathe  1 , Sandra Mercier  2   3 , Jean-Yves Mahé  3   4 , Yann Péréon  3   5 , Julien Buratti  1 , Laurène Tissier  1 , Bophara Kol  1 , Samia Ait Said  1 , Éric Leguern  1   6 , Guillaume Banneau  1 , Giovanni Stévanin  6   7

  1. Assistance Publique – Hôpitaux de Paris, GH Sorbonne Université, Département de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
  2. Service de Génétique Médicale, CHU Nantes, Nantes, France.
  3. Centre de Référence des Maladies Neuromusculaires, AOC, Hôtel-Dieu, Nantes, France.
  4. Établissement de Santé pour Enfants et Adolescents de la région Nantaise, Nantes, France.
  5. Laboratoire d’Explorations Fonctionnelles, CHU de Nantes, Nantes, France.
  6. Institut du Cerveau, Sorbonne Université (INSERM 1127, CNRS 7225), Paris, France.
  7. Équipe de Neurogénétique, École Pratique des Hautes Etudes (EPHE), PSL Research University, Paris, France.

 

 

New mutation, expanded set of symptoms in KIF1A gene (SPG30). The authors of the study suggest that dysfunction in the KIF1A gene is better understood as a single neuromuscular disorder rather than separate disorders that happen to be associated with mutations in this gene.

 

As well as finding a new mutation in this gene that is part of the family responsible for transport functions in neurons, the study identified a new form of inheritance (germline mosaicism*) in 2 affected siblings of an unaffected mother. A number of symptoms not normally associated with SPG30 were also described.

 

Abstract

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability.

We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system.

We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

 

SOURCE: Hum Mutat. 2020 Sep 15. doi: 10.1002/humu.24118. Online ahead of print. PMID: 32935419 © 2020 Wiley Periodicals LLC.

Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases

Ximena Montenegro-Garreaud  1   2   3 , Adam W Hansen  3   4 , Michael M Khayat  3   4 , Varuna Chander  3   4 , Christopher M Grochowski  4 , Yunyun Jiang  3 , He Li  3 , Tadahiro Mitani  4 , Elena Kessler  5 , Joy Jayaseelan  3 , Hua Shen  3 , Alper Gezdirici  6 , Davut Pehlivan  4   7 , Qingchang Meng  3 , Jill A Rosenfeld  4 , Shalini N Jhangiani  3 , Suneeta Madan-Khetarpal  5 , Daryl A Scott  4   8 , Hugo Abarca-Barriga  1   9 , Milana Trubnykova  1   10 , Marie-Claude Gingras  3   4   11 , Donna M Muzny  3   4 , Jennifer E Posey  4 , Pengfei Liu  4   12 , James R Lupski  3   4   13   14 , Richard A Gibbs  3   4

  1. Servicio de Genética y Errores Innatos del Metabolismo, Instituto Nacional de Salud del Niño, Lima, Perú.
  2. División de Investigación, Instituto de Medicina Genética, Lima, Perú.
  3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  5. Division of Medical Genetics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  6. Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
  7. Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  8. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
  9. Facultad de Ciencias de la Salud, Medicina Humana, Universidad Científica del Sur, Lima, Perú.
  10. Area Preclínica, Facultad de Ciencias de la Salud, Universidad Peruana de Ciencias Aplicadas, Lima, Perú.
  11. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
  12. Baylor Genetics, Houston, Texas, USA.
  13. Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA.
  14. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

 

 

SPG15 should be suspected in patients with juvenile‐onset atypical parkinsonism responsive to levodopa. However when used chronically, the treatment induced motor complications.

 

The findings of the study provide support for overlap between SPG types 15 and 11. The study highlights the importance of identifying parkinsonian characteristics in people with HSP.

 

Abstract

Hereditary spastic paraplegias (HSP) are a group of genetically and phenotypically heterogeneous disorders resulting from progressive degeneration of the corticospinal tract. 1 They may have autosomal dominant, autosomal recessive, x‐linked, or mitochondrial inheritance, and the main clinical features derive from lower limb spasticity. There are now more than 80 genes or loci associated with this condition, globally identified as spastic paraplegia genes (SPG). 1 , 2

The SPG15 subtype represents 2%–4% of the autosomal recessive inherited HSP and are associated to mutations in the ZFYVE26 gene that code for spastizin. It belongs to the group of autosomal recessive HSP with thin corpus callosum (AR HSP‐TCC), which includes a diverse genetic basis covering SPG11, SPG15, SPG21, SPG32, and SPG 47. 3 , 4

SPG15 is clinically characterized by progressive lower limbs spasticity that may be associated to a variable number of other manifestations such as cognitive impairment, retinal degeneration, motor neuropathy, dysarthria, and rarely parkinsonism, although the knowledge about its phenotypic spectrum is still limited. 5 Here, we report a case of a juvenile‐onset levodopa‐responsive parkinsonism associated to SPG 15 that developed motor complications under chronic levodopa therapy.

Case Report

A young Brazilian man, born from non‐consanguineous parents, with an apparent normal neuropsychomotor development, presented school difficulties initiating at childhood. In addition, at the age of 10, he developed progressive dysarthria, stiffness, and bradykinesia of the right limbs that gradually progressed to involve all four limbs, associated to gait slowing. At the age of 14, he was referred to our service for evaluation, being diagnosed as having juvenile‐onset asymmetric parkinsonism. He started levodopa as the first dopaminergic treatment with excellent response. However, there was a gradual need for dosage increase and pramipexole was associated to the treatment. The brain magnetic resonance imaging (MRI) showed thinning of the corpus callosum and the “sign of the ears of the lynx” (Fig. (Fig.1A,B),1A,B), which directed the genetic tests. Analysis of the ZFYVE26 gene revealed the presence of a known homozygous deletion (c.918delA), confirming the diagnosis of SPG15. Other complementary tests were normal (complete blood count, iron metabolism analysis, copper metabolism analysis, and serum ceruloplasmin). Nerve conduction studies and electroencephalography were also within the normal range. At the age of 17, he started to present motor complications related to dopaminergic treatment with wearing‐off, off‐dystonia, and peak‐dose dyskinesia. On clinical examination in the “off” state, there was marked global bradykinesia and dystonic posture of the right arm, Unified Parkinson’s disease rating scale motor scoring was 78 out of 108 points (video segment 2). The levodopa challenge test after administration of 250 mg of levodopa led to a 72% improvement in motor score (22 out of 108 points) and to the appearance of generalized severe choreic movements in the “on state” (video segment 1). At this time, the mini mental state examination (MMSE) revealed a score of 23 (lost 5 points in calculation, 1 point in day of the month, and 1 point in drawing). He was independent for basic and instrumental activities of daily living. Eye movement’s examination was normal, and there was mild spasticity of the lower limbs, no cerebellar signs, or other abnormal findings on neurological examination.

Discussion

Parkinsonism has already been reported in AR HSP‐TCC patients, initially SPG11 was proposed as a cause of atypical juvenile parkinsonism and later confirmed by other studies. 6 , 7 Shortly thereafter, mutations in Spastizin gene were found in three Turkish descent brothers and in a patient of Portuguese origin, characterizing the SPG15 phenotype. 8 , 9 They all had parkinsonism responsive to levodopa but the authors did not describe motor complications due to chronic dopaminergic treatment. More recently a 30‐year‐old woman with SPG15 presented a similar phenotype. 10

Our case strengthens the previous evidence that levodopa‐responsive parkinsonism, especially of juvenile‐onset, should be included in the SPG15 phenotype. It also describes, for the first time, the development of motor fluctuations and dyskinesia induced by chronic levodopa treatment in a patient with juvenile parkinsonism associated to SPG15. These findings not only extend the phenotypic spectrum of SPG15 but also provide support for phenotypic overlap between SPG15 and SPG11. We conclude that the benefit of dopaminergic therapy emphasizes the importance of identifying parkinsonian characteristics in HSP patients.

In conclusion, SPG15 should be suspected in patients with juvenile‐onset atypical parkinsonism responsive to levodopa presenting signs of spasticity, motor neuropathy, pigmentary maculopathy, cognitive impairment, family history suggestive of HSP, or the typical MRI brain findings (thin corpus callosum and the “sign of the ears of the lynx”).

 

SOURCE: Mov Disord Clin Pract. 2020 Oct; 7(7): 842–844. Published online 2020 Aug 26. doi: 10.1002/mdc3.13027 PMID: 33033739 Copyright © 2020 The Authors.

SPG15: A Rare Correlation with Atypical Juvenile Parkinsonism Responsive to Levodopa

Filipe Miranda Milagres Araujo  1 , Wilson Marques Junior  2 , Pedro José Tomaselli  2 , Ângela V Pimentel  1 , Manuelina C Macruz Brito  1 , Vitor Tumas  1

  1. Movement Disorders and Behavioral Neurology Section University of São Paulo Ribeirão Preto Brazil.
  2. Neurogenetics Section, Department of Neurosciences and Behavioral Sciences Ribeirão Preto Medical School Hospital, University of São Paulo (USP) Ribeirão Preto Brazil.

 

 

SPG56 found to overlap with PXE in some cases

 

Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries. Mutations in the CYP2U1 gene associated with SPG56 have been found in PXE patients who tested negative for mutations in the ABCC6 gene that is the main cause of PXE. 

 

Purpose: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients.

Methods: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.

Results: 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE.

Conclusion: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

 

SOURCE: J Intern Med. 2020 Oct 27. doi: 10.1111/joim.13193. Online ahead of print. PMID: 33107650

Pseudoxanthoma Elasticum overlaps Hereditary Spastic Paraplegia Type 56

Anne Legrand  1 , Claire Pujol  2 , Christelle M Durand  3 , Aurélie Mesnil  4 , Isabelle Rubera  5 , Christophe Duranton  5 , Stéphane Zuily  6 , Ana Berta Sousa  7 , Mathilde Renaud  8 , Jean-Luc Boucher  9 , Nicolas Pietrancosta  9 , Salma Adham  10 , Christophe Orssaud  11 , Cecilia Marelli  12 , Carlo Casali  13 , Lucia Ziccardi  14 , Nicolas Villain  15 , Claire Ewenczyk  16 , Alexandra Durr  16 , Cyril Mignot  17 , Giovanni Stevanin  18 , Clarisse Billon  1 , Marguerite Hureaux  19 , Xavier Jeunemaitre  1 , Cyril Goizet  3 , Juliette Albuisson  20

  1. Université de Paris, F-75005 Paris, France ; Inserm, U970, Paris Cardiovascular Research Centre, Paris (PARCC), F-75015 Paris, France ; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, F-75015 Paris, France.
  2. Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau, F-75013 Paris, France.
  3. Inserm, U1211, Laboratoire Maladies Rares: Génétique et Métabolisme, Univ. Bordeaux, F-33076 Bordeaux, France ; Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU Bordeaux, F-33076 Bordeaux, France.
  4. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Génétique, F-75015, Paris, France.
  5. Université Côte d’Azur, CNRS, UMR 7370, Laboratoire de Physiomédecine Moléculaire, LabEx ICST, F- 06107, Nice, France.
  6. Université de Lorraine, Inserm UMR_S 1116, F-54000 Nancy, France; CHRU de Nancy, Service de Médecine vasculaire, Centre de Compétences Régional des Maladies Vasculaires Rares, F-54000, Nancy, France.
  7. Service de Génétique, Département de Pédiatrie, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisboa, Portugal.
  8. CHRU de Nancy, Service de Neurologie, F-54000, Nancy, France.
  9. UMR 8601, CNRS, Université de Paris, F-75005, Paris, France.
  10. Université de Paris, F-75005 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, F-75015, Paris, France.
  11. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité fonctionnelle d’ophtalmologie, F-75015, Paris, France.
  12. Inserm U1198 MMDN, F-34000 Montpellier, France ; Gui de Chauliac University Hospital, Department of Neurology, Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic Diseases, F-34000, Montpellier, France.
  13. Department of SBMC, Sapienza University Rome, Rome, Italy.
  14. IRCCS- Fondazione Bietti, Neurophysiology of Vision and Neuroophthalmology Unit, IT-00198, Rome, Italy.
  15. Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau, F-75013 Paris, France; Sorbonne Université, GRC n° 21, Alzheimer Precision Medicine, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière; Département de Neurologie, Institut de la Mémoire et de la maladie d’Alzheimer, F-75013 Paris, France.
  16. Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau, F-75013 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France.
  17. Sorbonne Université, F-75013 Paris, France ; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France ; Institut du Cerveau, F-75013 Paris, France ; Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
  18. Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau, F-75013 Paris, France ; PSL research University, Ecole Pratique des Hautes Etudes, Neurogenetics team, F-75014 Paris, France.
  19. Université de Paris, F-75005 Paris, France ; Inserm, U970, Paris Cardiovascular Research Centre, Paris (PARCC), F-75015 Paris, France ; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Génétique, F-75015 Paris, France.
  20. Université de Paris, F-75005 Paris, France ; Inserm, U970, Paris Cardiovascular Research Centre, Paris (PARCC), F-75015 Paris, France ; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, F-75015 Paris; Département de Biologie et Pathologie des Tumeurs, Centre Georges François Leclerc, F- 21079, Dijon, France.

 

 

New ATP13A2 mutation causing SPG78 found

 

Progressive intellectual disability, psychiatric systems, rigidity and involuntary movements were all present before spastic paraparesis occurred.

 

Objective: To establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).

Methods: Physical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.

Results: The 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s-30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.

Conclusions: Our study further broadens the clinical spectrum associated with ATP13A2 mutations.

 

SOURCE: Neurol Genet. 2020 Sep 8;6(5):e514. doi: 10.1212/NXG.0000000000000514. eCollection 2020 Oct. PMID: 33134512 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia

Yasuko Odake  1 , Kishin Koh  1 , Yoshihisa Takiyama  1 , Hiroyuki Ishiura  1 , Shoji Tsuji  1 , Masahito Yamada  1 , Mitsuhiro Yoshita  1

  1. Department of Clinical Research (Y.O., M. Yoshita), National Hospital Organization, Hokuriku National Hospital, Nanto; Department of Neurology (K.K., Y.T.), Graduate School of Medical Science, University of Yamanashi,

 

 

3 new pathogenic variants in PNPLA6 discovered

 

Related to SPG39 and other conditions

 

Abstract

PNPLA6-related disorders include several phenotypes, such as Boucher-Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome.

In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases.

The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies.

Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain.

In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.

 

SOURCE: Exp Eye Res. 2020 Oct 22;108327. doi: 10.1016/j.exer.2020.108327. Online ahead of print. PMID: 33141049 Copyright © 2020 Elsevier Ltd. All rights reserved.

Novel variants in PNPLA6 causing syndromic retinal dystrophy

Shijing Wu  1 , Zixi Sun  1 , Tian Zhu  1 , Richard G Weleber  2 , Paul Yang  2 , Xing Wei  1 , Mark E Pennesi  3 , Ruifang Sui  4

  1. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
  2. Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.
  3. Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.
  4. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

 

 

3 new variants in SPG11 discovered

 

One further variant reclassified from being “of uncertain significance” to pathogenic or disease-causing. SPG11 was the most common cause of HSP in the 18 families from southern Spain surveyed. Almost half of all cases did not receive a genetic diagnosis.

 

Abstract

Spastic paraplegia (SPG) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations. Despite of the new molecular technologies, many patients remain yet undiagnosed. The purpose of this study was to describe the clinical presentation and molecular characteristics of a cohort of 27 patients from 18 different families with SPG in the south of Spain.

We used a targeted next-generation sequencing (NGS) approach to study a proband from each family. Variants in SPG11 gene were the most common cause of SPG in our area. We made a genetic diagnosis in 52% of cases, identified 3 novel variants and reclassified one uncertain variant in SPG11 gene as pathogenic variant. We identified a patient with two truncating mutations in the SPG11 gene and late onset disease and report another missense mutation outside of the motor domain of KIF1A gene in a family with pure SPG.

Our study contributes to the scientific knowledge of SPG. It is important to note the large group of cases (48%) that were not genetically diagnosed in our cohort. Therefore NGS approach is an efficient diagnostic tool, but the number of non-diagnosed subjects is still large, suggesting further genetic heterogeneity.

 

SOURCE: Int J Neurosci. 2020 Oct 15;1-12. doi: 10.1080/00207454.2020.1838514. Online ahead of print. PMID: 33059505

Clinical and molecular characterization of hereditary spastic paraplegia in a spanish southern region

P Carrasco Salas  1 , E Martínez Fernández  2 , C Méndez Del Barrio  2 , A Serrano Mira  1 , N Guerrero Moreno  3 , I Royo  4 , M Delgado  3 , J M Oropesa  2 , I Vázquez Rico  1

  1. Department of Human Genetics, Juan Ramon Jimenez Hospital (Huelva, Spain).
  2. Department of Neurology, Juan Ramon Jimenez Hospital (Huelva, Spain).
  3. Department of Pediatric Neurology, Juan Ramon Jimenez Hospital (Huelva, Spain).
  4. Department of Molecular Genetics, Reference Laboratory (Barcelona, Spain).

 

 

New SPG31 (REEP1) mutation found

 

Ankle contractures a common feature across three generations, suggesting that this feature may point to SPG31 HSP. Asymptomatic carriers within such families should also be considered.

 

Abstract

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic disorders characterized by lower-limb spastic paralysis. We report on a family with three generations of autosomal dominant inheritance of HSP caused by a novel heterozygous splice-site mutation (c.303 + 2 T > C) in REEP1 that was confirmed by RFLP analysis. Carriers of the mutation, including one asymptomatic individual, showed a mild HSP phenotype with a wide range of intrafamilial variation. All symptomatic carriers had ankle contractures in addition to other classical clinical symptoms of HSP. Clinicians should suspect REEP1-related HSP in patients who show ankle contractures with other symptoms of HSP and should consider that these patients have asymptomatic carriers within their family.

 

SOURCE: Gene. 2021 Jan 10;765:145129. doi: 10.1016/j.gene.2020.145129. Epub 2020 Sep 6.

PMID: 32905827 Copyright © 2020 Elsevier B.V. All rights reserved.

A novel REEP1 splicing mutation with broad clinical variability in a family with hereditary spastic paraplegia

Seong-Yong Park  1 , Jin-Mo Park  2 , Byeonghyeon Lee  1 , Un-Kyung Kim  3 , Jin-Sung Park  4

  1. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
  2. Department of Neurology, Dongguk University College of Medicine, Dongguk University Gyeongju Hospital, Gyeongju, Republic of Korea.
  3. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
  4. Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.

 

 

Yet another new SPAST mutation associated with SPG4 discovered.

 

Around 300 SPG4-causing mutations in the SPAST gene have now been identified.

 

Abstract

Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.

 

SOURCE: Case Rep Neurol Med. 2020 Aug 29;2020:7219514. doi: 10.1155/2020/7219514. eCollection 2020. PMID: 32908740 Copyright © 2020 Nathaniel M. Robbins et al.

A Novel SPAST/SPG4 Splice-Site Variant in a Family with Dominant Hereditary Spastic Paraplegia

Nathaniel M Robbins  1 , Jillian R Ozmore  2 , Thomas L Winder  3 , Pedro Gonzalez-Alegre  4 , Tanya M Bardakjian  4

  1. Department of Neurology, Geisel Dartmouth School of Medicine, Hanover, USA.
  2. Department of Medical Genetics, Dartmouth-Hitchcock Medical Center, Lebanon, USA.
  3. Invitae Corporation, San Francisco, USA.
  4. Department of Neurology, The University of Pennsylvania, Philadelphia, USA.

 

 

The results of this study suggest that the NEFL gene should be included in diagnostic testing strategies for people suspected of having HSP.

 

Mutations in the NEFL gene, known to cause Charcot-Marie-Tooth disease, were associated with a clinical picture dominated by spastic paraplegia in a study of a large number of cases in the Netherlands. Consequently, HSP is often suspected in these cases.

 

Introduction: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified.

Methods: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing.

Results: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed.

Discussion: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.

 

SOURCE: Parkinsonism Relat Disord. 2020 Sep 12;80:98-101. doi: 10.1016/j.parkreldis.2020.09.016. Online ahead of print. PMID: 32979786 Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene

Karlien Mul  1 , Meyke I Schouten  2 , Erica van der Looij  3 , Dennis Dooijes  4 , Frederic A M Hennekam  5 , Nicolette C Notermans  6 , Peter Praamstra  7 , Judith van Gaalen  8 , Erik-Jan Kamsteeg  9 , Nienke E Verbeek  10 , Bart P C van de Warrenburg  11

  1. Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
  2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  4. Department of Genetics, Utrecht University Medical Center, Utrecht, the Netherlands.
  5. Department of Genetics, Utrecht University Medical Center, Utrecht, the Netherlands.
  6. Department of Neurology, Utrecht University Medical Center, Utrecht, the Netherlands.
  7. Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
  8. Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
  9. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  10. Department of Genetics, Utrecht University Medical Center, Utrecht, the Netherlands.
  11. Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.

 

 

Large study of SPG76 in China. Females with SPG76 were much more likely to have complicated symptoms compared with SPG76 males.

 

Three new mutations found in the CAPN1 gene responsible, with 33 different mutations in the gene identified in the study.

 

Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity.

Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases.

Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs* 103, c.759+1G>A, and p.R285* ), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W).

Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015).

Interpretation: Our study supports the clinically heterogeneous inter- and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

 

SOURCE: Ann Clin Transl Neurol. 2020 Oct;7(10):1862-1869. doi: 10.1002/acn3.51169. Epub 2020 Aug 29. PMID: 32860341 © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lu-Lu Lai  1 , Yi-Jun Chen  1 , Yun-Lu Li  1 , Xiao-Hong Lin  1 , Meng-Wen Wang  1 , En-Lin Dong  1 , Ning Wang  1   2 , Wan-Jin Chen  1   2 , Xiang Lin  1   2

  1. Department of Neurology and Institute of Neurology, First Affiliated Hospital, Institute of Neuroscience, Fujian Medical University, Fuzhou, 350005, China.
  2. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.

 

 

Rare case of SPG9B associated with 2 mutations, one of them being new.

 

Background: The ALDH18A1 gene is located at 10q24.1 and encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), a mitochondrial bifunctional enzyme that catalyzes the first two steps in de novo biosynthesis of proline, ornithine, citrulline, and arginine. ALDH18A1-related disorders have been classified into four groups, such as autosomal dominant and recessive hereditary spastic paraplegia (SPG9A and SPG9B, respectively), as well as autosomal dominant and recessive cutis laxa (ADCL3 and ARCL3A, respectively). Neurodegeneration is a characteristic feature of all groups.

Case report: Here, we report a girl with compound heterozygous disease-causing variants (c.-28-2A>G and c.383G>A, p.Arg128His) in the ALDH18A1 gene, revealed by whole exome sequencing. The c.-28-2A>G variant in intron 1, inherited from the mother, is a novel mutation, while the c.383G>A variant in exon 4, inherited from the father, has already been reported. The patient presented with vigorous infantile tremor preceding progressive spastic paraplegia. Dysmorphic features included elongated face, deep-set ears, upturned nose, long philtrum and pointed chin. Intrauterine and postnatal growth retardation, microcephaly, global developmental delay and profound intellectual disability were also noticed. Blood fasting ammonia level, plasma proline, ornithine and arginine levels were normal, while citrulline level was slightly decreased. Brain MRI revealed moderate hypoplasia of the corpus callosum and reduction of white matter volume.

Conclusions: The patient represents SPG9B, a rare form of autosomal recessive hereditary spastic paraplegias. The early onset tremor, preceding lower limb spasticity appears to be a unique early manifestation of neurodegeneration in this case.

 

SOURCE: Brain Dev. 2020 Aug 11;S0387-7604(20)30198-4. doi: 10.1016/j.braindev.2020.07.015. Online ahead of print. PMID: 32798076 Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Tremor as an early sign of hereditary spastic paraplegia due to mutations in ALDH18A1

Tibor Kalmár  1 , Zoltán Maróti  1 , Alíz Zimmermann  1 , László Sztriha  2

  1. Department of Pediatrics, University of Szeged, Szeged, Hungary.
  2. Department of Pediatrics, University of Szeged, Szeged, Hungary.

 

2 comments

  1. Thank you very much for sharing the disease status of HSP. My son was diagnosed as SPG30, now he is three years old. Is there any more research on SPG30 or any recent news? My son has not been able to walk on his own since he was born. What is this type of progress like? In the infantile period can it progress very slowly or not progress, can he walk independently through rehabilitation possibly? Hope you reply!

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