New HSP genotypes and phenotypes

Research from The Netherlands, Sweden, Russia, USA, Italy, Brazil, UK, Japan, France, Switzerland, Germany, Tunisia, Iran, China, Turkey


High rate of KIF1A mutations in large study


Dominant rather than recessive inheritance


7% of people in a Dutch study of 347 with mostly ‘pure’, slowly progressive, autosomal dominant HSP were found to have mutations in the KIF1A gene outside the motor domain. Normally HSP-causing mutations in this gene are associated with autosomal recessive SPG30 as well as other neurodegenerative conditions.



Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia.

Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly ‘pure’ spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families.

The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization.

In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%).The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

SOURCE: Eur J Hum Genet. 2019 Sep 5. doi: 10.1038/s41431-019-0497-z. [Epub ahead of print] PMID: 31488895

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Pennings M1, Schouten MI1, van Gaalen J2, Meijer RPP1, de Bot ST3, Kriek M4, Saris CGJ2, van den Berg LH5, van Es MA5, Zuidgeest DMH6, Elting MW7, van de Kamp JM7, van Spaendonck-Zwarts KY8, Die-Smulders C9, Brilstra EH10, Verschuuren CC11, de Vries BBA1, Bruijn J12, Sofou K13, Duijkers FA8, Jaeger B14, Schieving JH15, van de Warrenburg BP2, Kamsteeg EJ16.

1 Department of Human Genetics, Radboud university medical centre, Nijmegen, The Netherlands.

2 Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical centre, Nijmegen, The Netherlands.

3 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

4 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

5 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

6 Department of Neurology, Ikazia hospital, Rotterdam, The Netherlands.

7 Department of Clinical Genetics, Amsterdam UMC, Vrije Universtiteit Amsterdam, Amsterdam, The Netherlands.

8 Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

9 Department of Human Genetics and research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands.

10 Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands.

11 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

12 Department of Pediatrics, Skaraborg Hospital, Skövde, Sweden.

13 Department of Pediatrics, The Queen Silvia Children’s Hospital, University of Gothenburg Sweden, Gothenburg, Sweden.

14 Department of Pediatric Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

15 Department of Pediatric Neurology, Radboud University Medical Center, Amalia Children’s Hospital and Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.

16 Department of Human Genetics, Radboud university medical centre, Nijmegen, The Netherlands.



14 new SPAST (SPG4) mutations were discovered in a large study of HSP population genetics in Russia


SPG4 accounted for 30% of the HSP detected overall (40% where there is family history) with SPG3 at 8%



Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders, it share common symptom – of progressive lower spastic paraparesis. The most common autosomal dominant (AD) forms of HSP are SPG4 (SPAST gene) and SPG3 (ATL1 gene).

In the current research we investigated for the first time the distribution of pathogenic mutations in SPAST and ATL1 genes within a large cohort of Russian HSP patients (122 probands; 69 famillial cases). We determined the frequencies of genetic abnormalities using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and Next Generation Sequencing (NGS) of targeted gene panels.

As a result, SPG4 was diagnosed in 30.3% (37/122) of HSP cases, where the familial cases represented 37.7% (26/69) of SPG4. In total 31 pathogenic and likely pathogenic variants were detected in SPAST, with 14 new mutations. Among all detected SPAST variants, 29% were gross deletions and duplications.

The proportion of SPG3 variants in Russian cohort was 8.2% (10/122) that were all familial cases. All 10 detected ATL1 mutations were missense substitutions, most of which were in the mutational hot spots of 4, 7, 8, 12 exons, with 2 novel mutations.

This work will be helpful for the populational genetics of HSP understanding.

SOURCE: Sci Rep. 2019 Oct 8;9(1):14412. doi: 10.1038/s41598-019-50911-9. PMID: 31594988

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia.

Kadnikova VA1, Rudenskaya GE2, Stepanova AA2, Sermyagina IG2, Ryzhkova OP2.

1 Federal State Budgetary Institution “Research Centre For Medical Genetics”, Moscow, 115478, Russia. [email protected].

2 Federal State Budgetary Institution “Research Centre For Medical Genetics”, Moscow, 115478, Russia.



RNF170 gene variant now associated with a form of AR-HSP


The mechanism described is also implicated in cerebellar ataxias and proposed as a target for therapy



Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia.

We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish.

Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

SOURCE: Nat Commun. 2019 Oct 21;10(1):4790. doi: 10.1038/s41467-019-12620-9.

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Wagner M1,2,3Osborn DPS4Gehweiler I5,6Nagel M5,6Ulmer U5,6Bakhtiari S7,8Amouri R9,10Boostani R11Hentati F9,10Hockley MM8Hölbling B5,6Schwarzmayr T3Karimiani EG4,12Kernstock C13Maroofian R4Müller-Felber W14Ozkan E4Padilla-Lopez S7,8Reich S5,6Reichbauer J5,6Darvish H15Shahmohammadibeni N15Tafakhori A16Vill K14Zuchner S17,18Kruer MC7,8Winkelmann J1,3,19Jamshidi Y4Schüle R20,21.

1 Institute of Human Genetics, Technische Universität München, Trogerstraße 32, 81675, Munich, Germany.

2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.

3 Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.

4 Genetics Centre, Molecular and Clinical Sciences Institute, St George’s University of London, London, UK.

5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

6 German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany.

7 Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, 85016, USA.

8 Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA.

9 Neurology Department, Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia.

10 Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia.

11 Department of Neurology, Mashhad, Iran.

12 Next Generation Genetic Clinic, Mashhad, Iran.

13 Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.

14 Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337, Munich, Germany.

15 Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.

16 Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

17 Dr. John T. Macdonald Foundation, Department of Human Genetics, FL33136, Miami, USA.

18 John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, FL33136, Miami, USA.

19 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

20 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

21 German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany.



New spontaneous mutation with no family history found in ADCY5 gene


Previously only associated with Parkinson-related disorders


This is the first time that a mutation in the ADCY5 gene has been associated with spastic paraplegia


The Undiagnosed Diseases Program at the University of Alabama at Birmingham recently found a previously unknown genetic variant that is believed to account for a severe movement disorder in a young woman. In a case study published in the Sept. 9, 2019 issue of Neurology, the journal of the American Academy of Neurology, the research team reports on the discovery of the variant, and describes the steps taken to unlock this medical mystery.

The patient, a woman in her 20’s, first began to develop impairment of her lower limbs at age 5. By adulthood, she could no longer walk, and had hand tremor, large spasms of her legs in the evenings, intermittent slurred speech and occasional tingling in her fingers and toes.

She underwent evaluation at UAB’s Undiagnosed Diseases Program, in the Department of Genetics, which is a court of last resort for those cases where a diagnosis has not been made despite extensive efforts by medical professionals.

The team considered—and ultimately ruled out—a wide variety of neurodegenerative and metabolic disorders.

Because of the discovery of this novel mutation, the case study also calls for the addition of ADCY5 to gene sequencing test panels for spastic paraparesis.

Read the full article . . .

SOURCE: Medical Xpress

Undiagnosed diseases program finds novel genetic variant

by Bob Shepard, University of Alabama at Birmingham SEPTEMBER 10, 2019



New HSP associated gene ATP1A1 identified


New mutation in the gene is the cause


Mutations in this gene have previously been associated with Charcot-Marie-Tooth disease (type CMT2DD). This is the first instance of the gene being associated with HSP, via a new mutation.



Dominant mutations in ATP1A1, encoding the alpha-1 isoform of the Na+ /K+ -ATPase, have been recently reported to cause an axonal to intermediate type of Charcot-Marie-Tooth disease (ie, CMT2DD) and a syndrome with hypomagnesemia, intractable seizures and severe intellectual disability.

Here, we describe the first case of hereditary spastic paraplegia (HSP) caused by a novel de novo (p.L337P) variant in ATP1A1. We provide evidence for the causative role of this variant with functional and homology modelling studies.

This finding expands the phenotypic spectrum of the ATP1A1-related disorders, adds a piece to the larger genetic puzzle of HSP, and increases knowledge on the molecular mechanisms underlying inherited axonopathies (ie, CMT and HSP). This article is protected by copyright. All rights reserved.

SOURCE: Clin Genet. 2019 Nov 8. doi: 10.1111/cge.13668. [Epub ahead of print] This article is protected by copyright. All rights reserved. PMID: 31705535

Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation.

Stregapede F1,2, Travaglini L1, Rebelo AP3, Cintra VP4, Bellacchio E5, Bosco L1, Alfieri P6, Pro S7, Zuchner S3, Bertini E1, Nicita F1.

1 Unit of Neuromuscular and Neurodegenerative diseases, Department of Neurosciences, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy.

2 Department of Sciences, University of Roma Tre, Rome, Italy.

3 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.

4 Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.

5 Genetics and Rare Diseases Research Division, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy.

6 Unit of Child Neuropsychiatry, Department of Neurosciences, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy.

7 Unit of Neurophysiology, Department of Neurosciences, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy.



Atypical cases of SINO HSP in two studies  – KIDINS220 gene variants


Six new mutations discovered amongst 57 members of 15 Chinese families with HSP, including an atypical pure HSP for a new mutation in the KIDINS220 gene. 


BACKGROUND: Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown.

METHODS: A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted.

RESULTS: The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity.

CONCLUSION: Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.

SOURCE: Mol Diagn Ther. 2019 Oct 19. doi: 10.1007/s40291-019-00426-w. [Epub ahead of print] PMID: 31630374

Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia.

Zhao M1, Chen YJ1, Wang MW1, Lin XH1, Dong EL1, Chen WJ1,2, Wang N3,4, Lin X5,6.

1 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.

2 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.

3 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. [email protected].

4 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.

5 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. [email protected].

6 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.




A child with pathogenic mutations in both the KIDINS220 and CC2D2A genes has an atypical, milder disorder than either spastic paraplegia alone or Joubert syndrome, the conditions associated respectively with these two genes individually.



With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220.

He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.

SOURCE: Clin Dysmorphol. 2019 Oct 1. doi: 10.1097/MCD.0000000000000298. [Epub ahead of print] PMID: 31577543

Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants.

Lam Z1, Albaba S2, Study D3, Balasubramanian M4,5.

1 Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds.

2 Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield.

3 DDD Study, Wellcome Sanger Institute, Hinxton, Cambridge.

4 Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield.

5 Academic Unit of Child Health, University of Sheffield, United Kingdom.



UBAP1 mutation focus in two separate studies


Extending knowledge of the latest HSP type, SPG80


SPG80 HSP mechanism described and 3 new UBAP1 mutations identified


Research in Japan has extended knowledge of the newest form of HSP discovered earlier in 2019, SPG80, associated with mutations in the UBAP1 gene. This study identified three new mutations from four families. One of these mutations was introduced into laboratory mice where its normal role in endosomal dynamics was disrupted through a loss-of-function mechanism.



We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC).

Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80).

All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes.

Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.

SOURCE: J Hum Genet. 2019 Nov;64(11):1055-1065. doi: 10.1038/s10038-019-0670-9. Epub 2019 Sep 12. PMID: 31515522

UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

Nan H1, Ichinose Y1, Tanaka M2, Koh K1, Ishiura H3, Mitsui J4, Mizukami H5, Morimoto M6, Hamada S7, Ohtsuka T7, Tsuji S2,4, Takiyama Y8.

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

2 Institute of Medical Genomics, International University of Health and Welfare, Chiba, 286-8686, 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, Yokohama City Seibu Hospital, St. Marianna University School of Medicine, Yokohama, 241-0811, Japan.

6 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.

7 Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

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



HSP and metabolic impairment in twins due to two disease-related mutations in each of the MTHFR and POLG genes, including a new mutation in MTHFR.



Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism.

We performed next-generation sequencing of 4,813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile).

MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain.

These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

SOURCE: J Hum Genet. 2019 Oct 23. doi: 10.1038/s10038-019-0689-y. [Epub ahead of print] PMID: 31645654

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

Wiedemann A1, Chery C1, Coelho D1, Flayac J1, Gueguen N2, Desquiret-Dumas V2, Feillet F1, Lavigne C3, Neau JP4, Fowler B5, Baumgartner MR5, Reynier P2, Guéant JL6, Oussalah A7.

1 INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.

2 Department of Biochemistry and Genetics, UMR CNRS 6214-INSERM 1083, University Hospital Centre, Angers, France.

3 Department of Internal Medicine and Vascular Medicine, University Hospital Centre, Angers, France.

4 Department of Neurology, University Hospital Centre, Poitiers, France.

5 Division of Metabolism and Children’s Research Centre, University Children’s Hospital, Zürich, Switzerland.

6 INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.

7 INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.



Child with two genetic diseases


HSP and congenital melanocytic nevus syndrome



Neurocutaneous disorders are caused by germline and/or somatic mutations and involve the integument and central nervous systems. Congenital melanocytic nevus syndrome is characterized by melanotic skin lesions caused by somatic mutations at codon 61 in NRAS. A large cutaneous lesion raises the risk of central nervous system involvement.

We report an 8-year-old girl with a congenital giant pigmented nevus that covered almost her entire back. Despite the absence of any radiological evidence of intracranial melanosis, the patient exhibited progressive limb spasticity with preserved intellectual ability. An extensive genetic analysis identified a specific class of heterozygous germline mutation in SPAST, p.(Arg499His), which is responsible for hereditary spastic paraplegia with infantile onset. In addition, a known heterozygous somatic mutation in NRAS, p.(Gln61Lys) was detected in the cutaneous lesion.

This observation recapitulates concomitant mosaicism and non-mosaicism within a single individual and suggests that the possibility of a dual genetic diagnosis should be considered when neurological decline is observed in a patient with a neurocutaneous disorder without any detectable intracranial lesions.

SOURCE: Eur J Med Genet. 2019 Nov 4:103803. doi: 10.1016/j.ejmg.2019.103803. [Epub ahead of print] Copyright © 2019 Elsevier Masson SAS. All rights reserved. PMID: 31698101

Hereditary spastic paraplegia masqueraded by congenital melanocytic nevus syndrome: Dual pathogenesis of germline non-mosaicism and somatic mosaicism.

Sakaguchi Y1, Uehara T2, Sasaki M1, Fujimura K1, Kishi K3, Kosaki K2, Takenouchi T4.

1 Neurocutaneous Center, Keio University Hospital, Tokyo, Japan; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

2 Neurocutaneous Center, Keio University Hospital, Tokyo, Japan; Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

3 Neurocutaneous Center, Keio University Hospital, Tokyo, Japan; Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo, Japan.

4 Neurocutaneous Center, Keio University Hospital, Tokyo, Japan; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.



2 sisters found to have a new mutation in the AP4S1 gene associated with SPG52


Sophisticated genetic testing on whole blood mRNA was employed in discovering the new mutation



We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant.

AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome.

In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.

SOURCE: Hum Mutat. 2019 Oct 29. doi: 10.1002/humu.23939. [Epub ahead of print] © 2019 Wiley Periodicals, Inc. PMID: 31660686

Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.

McCullough CG1, Szelinger S2, Belnap N2, Ramsey K2, Schrauwen I2, Claasen AM2, Burke LW3, Siniard AL2, Huentelman MJ2, Narayanan V2, Craig DW1.

1 Department of Translational Genomics, University of Southern California, Los Angeles, California.

2 Center for Rare Childhood Disorders, Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.

3 Department of Pediatrics, Larner College of Medicine, University of Vermont, Burlington, Vermont.



New mutation discovered in C19ORF12 gene associated with SPG43 in a family with a mitochondrial membrane neurodegenerative disease (MPAN)


Objective: To explore the clinical features and analyze the chromosome 19 open reading frame 12(C19ORF12) gene mutation of a family with mitochondrial membrane protein-associated neurodegeneration (MPAN).

Methods: The pedigree diagnosed as neurodegeneration with brain iron accumulation (NBIA) in Henan Provincial People’s Hospital in May 2018 was collected, and clinical data of the patients in this family was further analyzed. Furthermore, whole exome sequencing (WES) was employed to identify the disease-causing genes. Subsequently, the pathogenic mutation was validated by Sanger sequencing.

Results: We identified 3 brothers, born of consanguineous Chinese parents. These patients were thought to carry autosomal recessive genes. The age of the onset ranged from 8 to 10 years old. All of the patients exhibited a chronic course, then got worse progressively. Parkinsonism was the first symptom. Other clinical features included cognitive decline, ataxia, gait abnormality, dysarthria and spastic paraplegia. All cases showed hypo-intensity in bilateral substantia nigra and globus pallidus on T(2)WI, FLAIR and SWI of MRI. However, the “eye-of-the-tiger sign” , which was commonly found in pantothenate kinase-associated neurodegeneration (PKAN), was absent. Further findings included cerebellar atrophy (all 3 patients) and the atrophy of temporal lobe (only one brother of the proband). The homozygous mutation c.52G>T (p.Asp18Tyr) was found through WES and Sanger sequencing. The proband’s mother was heterozygous. This novel mutation was not reported in the mutation database. Consequently, the pathogenic mutation in C19ORF12 gene (exon2, c.2327C>T, p.P776L) was identified from the patients according to the American College of Medical Genetics and Genomics (ACMG) guideline. The final diagnosis of the family was MPAN.

Conclusions: We successfully identify a novel p.Asp18Tyr mutation in a family with MPAN. Our finding enriches the known MPAN mutation types and provides evidence for further research.

SOURCE: Zhonghua Yi Xue Za Zhi. 2019 Oct 8;99(37):2926-2931. doi: 10.3760/cma.j.issn.0376-2491.2019.37.011. PMID: 31607023

Pedigree analysis of C19ORF12 p.Asp18Tyr mutation in a family with mitochondrial membrane protein associated neurodegeneration

Li SJ1, Wang LLQin LZWang XJZhang JWLi W.

1 Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou 450003, China.



New mutation found in GJC2 gene associated with late-onset SPG44


Causing a phenotype with prominent ataxia, mild parkinsonism and a distinctive MRI pattern, along with spastic paraplegia.


OBJECTIVE: Recessive mutations in the Gap Junction Protein Gamma 2 (GJC2) gene cause Pelizaeus-Merzbacher-like disease type 1, a severe infantile-onset hypomyelinating leukodystrophy. Milder, late-onset phenotypes including complicated spastic paraplegia in one family (SPG44), and mild tremor in one case, were reported associated to GJC2 homozygous missense mutations. Here, we report a new family with two siblings carrying a different homozygous GJC2 mutation, presenting with late-onset ataxic and pyramidal disturbances, and parkinsonism in one of them.

METHODS: Two affected siblings were studied by neurological examination and brain MRI. Genetic analyses included genome-wide homozygosity mapping in both siblings, and whole exome sequencing in one sib. The resulting candidate gene variant was validated by Sanger sequencing.

RESULTS: The affected siblings share a novel homozygous GJC2 missense mutation (c.820G>C, p.Val274Leu), predicted as pathogenic by all used in-silico tools. Brain MRI showed hyperintense signal in T2-weighted images in the internal capsule and subcortical and periventricular white matter, consistent with hypomyelination.

CONCLUSIONS: Our findings confirm and further expand the late-onset phenotypes of GJC2 mutations, to include prominent ataxia, pyramidal disturbances and mild parkinsonism, and confirm the distinctive associated MRI pattern.

SOURCE: Parkinsonism Relat Disord. 2019 Sep;66:228-231. doi: 10.1016/j.parkreldis.2019.07.033. Epub 2019 Jul 31. Copyright © 2019 Elsevier Ltd. All rights reserved. PMID: 31431325

Late-onset phenotype associated with a homozygous GJC2 missense mutation in a Turkish family.

Kuipers DJS1, Tufekcioglu Z2, Bilgiç B2, Olgiati S1, Dremmen MHG3, van IJcken WFJ4, Breedveld GJ1, Mancini GMS1, Hanagasi HA2, Emre M2, Bonifati V5.

1 Erasmus MC, University Medical Center, Rotterdam, the Netherlands, Department of Clinical Genetics.

2 Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

3 Erasmus MC, University Medical Center, Rotterdam, the Netherlands, Department of Radiology.

4 Erasmus MC, University Medical Center, Rotterdam, the Netherlands, Center for Biomics.

5 Erasmus MC, University Medical Center, Rotterdam, the Netherlands, Department of Clinical Genetics.



Newly discovered mutation in SPG20


A newly discovered mutation in the gene associated with SPG20 (Troyer syndrome) was one of two compound heterozygous mutations causing the disease in two siblings with one of the mutations coming from the mother and the other from the father. This is the first reported such occurrence in SPG20.



Troyer syndrome is an autosomal recessive disease characterized by spastic paralysis, dysarthria, distal amyotrophy, and short stature. Recently, two siblings (an older brother and a younger sister) were admitted to our hospital for the chief complaints of “short stature and intellectual disability.” Through whole exome sequencing of the sister, who is the proband, it was found that her SPG20 gene had compound heterozygous mutations: c.364_365delAT (p.Met122Valfs* 2) and c.892delA (p.Thr298Glnfs* 30). Target testing revealed that the brother had the same genotype as the sister, and the former mutation originated from the father, while the latter mutation originated from the mother. In summary, this is the first report of Troyer syndrome in a family caused by SPG20 compound heterozygous mutations. A novel SPG20 mutation was found, namely c.892delA (p.Thr298Glnfs* 30). In addition, we also summarize these Troyer syndrome patients’ heights and their clinical characteristics, and provide a brief review of all known pathogenic mutations of SPG20.

SOURCE: Ann N Y Acad Sci. 2019 Sep 19. doi: 10.1111/nyas.14229. [Epub ahead of print] © 2019 New York Academy of Sciences. PMID: 31535723

Dwarfism in Troyer syndrome: a family with SPG20 compound heterozygous mutations and a literature review.

Liang H1, Miao H1, Yang H1, Gong F1, Chen S1, Wang L1, Zhu H1, Pan H1.

1 Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.



Dominantly-inherited IFIH1 gene mutation


Associated with sporadic HSP in first such report



Here, the pathogenesis of an IFIH1 gene mutation is discussed through the analysis of a sporadic case of hereditary spastic paraplegia. Next-generation sequencing was performed for the patient and his family members to detect mutations at the IFIH1 locus.

The patient and his father were found to carry the same heterozygous missense mutation (c.1093A > G; p.Gly495Arg) while the patient’s mother does not carry this mutation.

This is the first report of this heterozygous IFIH1 mutation and it is predicted to be disease-causing.

SOURCE: Hereditas. 2019 Aug 13;156:28. doi: 10.1186/s41065-019-0104-x. eCollection 2019. PMID: 31427910

Hereditary spastic paraplegia associated with a rare IFIH1 mutation: a case report and literature review.

Liu N1, Chen J1, Xu C1, Shi T1, Li J1.

1 Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province People’s Republic of China.


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