New HSP genotypes and phenotypes

From Canada, USA, Pakistan, France, Japan, Czech Republic and Belgium

Here is a summary of the latest discoveries in HSP gene mutations and in symptom profiles (phenotypes) associated with the different forms of HSP.

SPAST mutation plus pathogenic variants – causing HSP with autism spectrum disorder

Here we report a 12 year old male with an extreme presentation of spastic paraplegia along with autism and dysmorphisms. Whole exome sequencing identified a predicted pathogenic pair of missense variants in SPAST at the same chromosomal location, each with a different alternative allele, while a chromosome microarray identified a 1.73 Mb paternally inherited copy gain of 1q21.1q21.2 resulting in a blended phenotype of both Spastic paraplegia 4 and 1q21.1 microduplication syndrome.

We believe that the extreme phenotype observed is likely caused by the presence of cells which contain only mutant SPAST, but that the viability of the patient is possible due mosaicism of mutant alleles observed in different proportions across tissues.

A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder.

Matthews AM1, Tarailo-Graovac M2, Price EM2, Blydt-Hansen I3, Ghani A4, Drögemöller BI5, Robinson WP2, Ross CJ6, Wasserman WW1, Siden H7, van Karnebeek CD8.

1 Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada.

2 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada.

3 BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada.

4 Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada.

5 Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

6 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

7 BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada; Canuck Place Children’s Hospice, Vancouver, BC, Canada.

8 Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children’s Hospital, Vancouver, BC, Canada; Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, University of Amsterdam, The Netherlands.

New mutation associated with complicated HSP – neuropathy and deafness occurring

OBJECTIVE:

To identify the underlying genetic cause in 2 sisters affected with progressive lower extremity spasticity, neuropathy, and early-onset deafness.

METHODS:

Whole-exome sequencing was performed, and segregation testing of variants was investigated using targeted Sanger sequencing. An inherited paternal mosaic mutation was further evaluated through quantitative analysis of the ratio of mutant vs wild-type allele in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva.

RESULTS:

A novel heterozygous nonsense mutation (c.1140C>A; p.Y380X) in SOX10 was identified in the affected sisters. Paternal mosaicism was suspected based on a small chromatogram peak, which was less than the heterozygous peak of the mutated allele. Consistent with mosaicism, the mosaic paternal samples had notable variability in the ratio of mutant vs wild-type allele in various tissues (compared with the fully heterozygous daughter), with the highest paternal mutant levels in saliva (32.7%) and lowest in dermal fibroblasts (13.9%). Targeted clinical re-examination of the father revealed a sensorimotor neuropathy that was previously clinically unrecognized.

CONCLUSIONS:

These findings expand the phenotypic spectrum of SOX10-related neurocristopathy. Mutations in SOX10 should be considered in patients presenting with a complicated form of hereditary spastic paraplegia that includes neuropathy and deafness. Diagnostic workup may be complicated, as SOX10 mutations can present in a mosaic state, with a mild clinical manifestation.

SOURCE: Neurol Genet. 2017 May 15;3(3):e151. doi: 10.1212/NXG.0000000000000151. eCollection 2017 Jun. PMID: 28534044

HSP and deafness: Neurocristopathy caused by a novel mosaic SOX10 mutation.

Donkervoort S1, Bharucha-Goebel D1, Yun P1, Hu Y1, Mohassel P1, Hoke A1, Zein WM1, Ezzo D1, Atherton AM1, Modrcin AC1, Dasouki M1, Foley AR1, Bönnemann CG1.

1 Neuromuscular and Neurogenetic Disorders of Childhood Section (S.D., D.B.-G., P.Y., Y.H., P.M., D.E., A.R.F., C.G.B.), and National Eye Institute (W.M.Z.), National Institutes of Health, Bethesda, MD; Children’s National Medical Center (D.B.-G.), Washington, DC; Department of Neurology (A.H.), The Johns Hopkins University School of Medicine, Baltimore, MD; Children’s Mercy Hospital (A.M.A., A.C.M.), Kansas City, MO; and Department of Neurology (M.D.), University of Kansas Medical Center, Kansas City, KS.

New family found with SPG26 HSP – fever-induced ataxia and myokymia

A family in Pakistan has been added to the 12 families reported to date with SPG26 HSP. In this family, they also experience fever-induced ataxia with eyelid twitching (myokymia).

Hereditary spastic paraplegias (SPGs) are among the genetically most diverse neurologic disorders with over 70 loci identified.1,2 The recessively inherited SPG26 is caused by mutations in B4GALNT1, encoding the β-1-4-N-acetyl-galactosaminyl transferase which functions in the biosynthesis of complex glycosphingolipids.

To date, 12 families have been reported in 3 publications, with a broad phenotypic spectrum within and between families (table 1). We add a new family to the literature with 3 affected members and a remarkable phenotype of purely fever-induced ataxia with myokymia. We also review all published cases3,–5 to encapsulate the current knowledge of the neurologic features and spectrum of this disease.

SOURCE: Neurol Genet. 2017 Jun; 3(3): e156. Published online 2017 May 23. doi: 10.1212/NXG.0000000000000156 PMCID: PMC5458666

Febrile ataxia and myokymia broaden the SPG26 hereditary spastic paraplegia phenotype

Rubina Dad, MPhil, Susan Walker, PhD, Stephen W. Scherer, PhD, Muhammad Jawad Hassan, PhD, Mohammad Domaia Alghamdi, MD, Berge A. Minassian, MD, and Reem A. Alkhater, MD, FRCP (C)

From the Atta-ur Rahman School of Applied Biosciences (R.D., M.J.H.), National University of Sciences and Technology (NUST), Pakistan; Program in Genetics and Genome Biology (R.D., B.A.M.), Division of Neurology (B.A.M.), Department of Paediatrics, and The Centre for Applied Genomics, Genetics and Genome Biology (S.W., S.W.S.), The Hospital for Sick Children; Department of Molecular Genetics (S.W.S.), and McLaughlin Centre (S.W.S.), University of Toronto, Ontario, Canada; and Department of Pediatrics (M.D.A., R.A.A.), Division of Neurology, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.

Three new mutations in atypical HSP – associated with motor neuron disease

Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP).

A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway.

Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.

SOURCE: Neurobiol Aging. 2017 Jun 24. pii: S0197-4580(17)30214-2. doi: 10.1016/j.neurobiolaging.2017.06.018. [Epub ahead of print] Copyright © 2017 Elsevier Inc. All rights reserved. PMID: 28716533

Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.

Teyssou E1, Chartier L1, Amador MD2, Lam R1, Lautrette G3, Nicol M3, Machat S3, Da Barroca S1, Moigneu C1, Mairey M4, Larmonier T5, Saker S5, Dussert C1, Forlani S1, Fontaine B6, Seilhean D7, Bohl D1, Boillée S1, Meininger V8, Couratier P3, Salachas F6, Stevanin G9, Millecamps S10.

1 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

2 Département de Neurologie, Assistance Publique Hôpitaux de Paris (APHP), Centre de ressources et de compétences SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, France.

3 Service de Neurologie, Centre de ressources et de compétences SLA, CHU Dupuytren, Limoges, France.

4 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Ecole Pratique des Hautes Etudes, EPHE, Université de recherche Paris Sciences et Lettres, Paris, France.

5 Banque d’ADN et de cellules du Généthon, Evry, France.

6 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Département de Neurologie, Assistance Publique Hôpitaux de Paris (APHP), Centre de ressources et de compétences SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, France.

7 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Département de Neuropathologie, APHP, Hôpital Pitié-Salpêtrière, Paris, France.

8 Département de Neurologie, Assistance Publique Hôpitaux de Paris (APHP), Centre de ressources et de compétences SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, France; Hôpital des Peupliers, Ramsay Générale de Santé, Paris, France.

9 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Ecole Pratique des Hautes Etudes, EPHE, Université de recherche Paris Sciences et Lettres, Paris, France; Centre de Référence de Neurogénétique, Fédération de Génétique, APHP, Hôpital Pitié-Salpêtrière, Paris, France.

10 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Three Moroccan siblings with new SPG20 mutation – resulting in complicated HSP

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13.

Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.

SOURCE: Cold Spring Harb Mol Case Stud. 2017 Jul 5;3(4). pii: a001537. doi: 10.1101/mcs.a001537. Print 2017 Jul. © 2017 Dardour et al.; Published by Cold Spring Harbor Laboratory Press. PMID: 28679690

SPG20 mutation in three siblings with familial hereditary spastic paraplegia.

Dardour L1, Roelens F2, Race V1, Souche E1, Holvoet M1, Devriendt K1.

1 Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.

2 AZ Delta, 8800 Roeselare, Belgium.

New compound mutations in SPG56 gene – causing complicated HSP with delayed myelination.

Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging. As a rare clinical feature, delayed myelination has previously been reported in only two patients with CYP2U1 mutations.

Here, we report a patient with SPG56 with novel compound heterozygous mutations in CYP2U1 which were identified by whole exome sequencing. Our patient exhibited complex features together with delayed myelination, broadening the phenotypic spectrum of SPG56, and implying that CYP2U1 should be screened in HSP with delayed myelination.

SOURCE: J Hum Genet. 2017 Jul 20. doi: 10.1038/jhg.2017.77. [Epub ahead of print] PMID: 28725025

An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination.

Minase G1,2, Miyatake S1, Nabatame S3, Arai H4, Koshimizu E1, Mizuguchi T1, Nakashima M1, Miyake N1, Saitsu H5, Miyamoto T2, Sengoku K2, Matsumoto N1.

1 Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

2 Department of Obstetrics and Gynecology, Asahikawa Medical University, Hokkaido, Japan.

3 Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

4 Department of Pediatric Neurology, Morinomiya Hospital, Osaka, Japan.

5 Department of Biochemistry, Hamamatsu University School of Medicine, Sizuoka, Japan.

Large Czech study of ATL1 (SPG3A) finds two new mutations – but SPG3A found to be less frequent than reported elsewhere

Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP.

We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results.

ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations.

Disease-Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients.

Mészárosová AU1, Grečmalová D2, Brázdilová M3, Dvořáčková N2, Kalina Z4, Čermáková M5, Vávrová D5, Smetanová I5, Staněk D1, Seeman P1,5.

1 DNA Laboratory, Department of Child Neurology, Charles University 2nd Medical School and University Hospital Motol, Prague, Czech Republic.

2 Department of Medical Genetics, Faculty Hospital Ostrava, Ostrava, Czech Republic.

3 Department of Child Neurology, Charles University 2nd Medical School and University Hospital Motol, Prague, Czech Republic.

4 Department of Medical Genetics, Faculty Hospital Brno, Brno, Czech Republic.

5 Centre for Medical Genetics and Reproductive Medicine GENNET, Prague, Czech Republic.