New HSP genotypes and phenotypes

Research from Iran, USA, Italy, Germany, Spain, Bulgaria, Canada, Austria, Saudi Arabia, China, Ireland and Finland


UBAP1 gene (SPG80 HSP) identified in 10 families globally



The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide.

Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1).

HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing.

We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations.

We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency.

UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.


SOURCE: Am J Hum Genet. 2019 Apr 4;104(4):767-773. doi: 10.1016/j.ajhg.2019.03.001. Epub 2019 Mar 28. PMID: 30929741 Copyright © 2019. Published by Elsevier Inc.

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.

Farazi Fard MA1, Rebelo AP2, Buglo E2, Nemati H3, Dastsooz H4, Gehweiler I5, Reich S5, Reichbauer J5, Quintáns B6, Ordóñez-Ugalde A6, Cortese A2, Courel S2, Abreu L2, Powell E7, Danzi MC2, Martuscelli NB8, Bis-Brewer DM2, Tao F2, Zarei F3, Habibzadeh P9, Yavarian M1, Modarresi F10, Silawi M1, Tabatabaei Z1, Yousefi M1, Farpour HR3, Kessler C5, Mangold E11, Kobeleva X12, Tournev I13, Chamova T14, Mueller AJ15, Haack TB15, Tarnopolsky M16, Gan-Or Z17, Rouleau GA17, Synofzik M5, Sobrido MJ6, Jordanova A18, Schüle R5, Zuchner S2, Faghihi MA19.

1 Persian BayanGene Research and Training Center, Shiraz, Iran.

2 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA.

3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

4 Persian BayanGene Research and Training Center, Shiraz, Iran; Italian Institute for Genomic Medicine, University of Turin, Turin 10126 Italy.

5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany; German Center for Neurodegenerative Diseases, Tübingen 72706, Germany.

6 Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain.

7 The Genesis Project foundation Miami, FL 33136, USA.

8 Department of Biology University of Miami, Miami, FL 33136, USA.

9 Persian BayanGene Research and Training Center, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.

10 Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA.

11 Institute of Human Genetics University of Bonn, Bonn 53113, Germany.

12 Department of Neurology, University of Bonn, Bonn 53113, Germany.

13 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia 1618, Bulgaria.

14 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria.

15 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen 72706, Germany.

16 Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 4L8, Canada.

17 Department of Human Genetics, McGill University, Montréal, Quebec H3A 0G4, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

18 Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2610, Belgium; Molecular Medicine Center Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia 1431, Bulgaria.

19 Persian BayanGene Research and Training Center, Shiraz, Iran; Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA.



SPG78 gene linked to 3 other conditions

Juvenile onset ALS now added


Mutations in the ATP13A2 gene, associated with SPG78 HSP and two other diseases, have now been linked with juvenile onset ALS (a form of motor neurone disease). Mutations in the same gene also cause a neurodegenerative condition in Australian cattle dogs



BACKGROUND: Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.


RESULTS: We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study.


CONCLUSIONS: We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.


SOURCE: Hum Genomics. 2019 Apr 16;13(1):19. doi: 10.1186/s40246-019-0203-9. PMID: 30992063

Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion.

Spataro R1, Kousi M2,3,4, Farhan SMK5,6,7, Willer JR2, Ross JP8,9, Dion PA8,9, Rouleau GA8,9, Daly MJ5,7,10, Neale BM5,6,7, La Bella V11, Katsanis N12.

1 IRCCS Centro Neurolesi Bonino Pulejo, Palermo, Italy.

2 Center for Human Disease Modeling, Duke University Medical Center, Carmichael Building, 300 North Duke Street, Suite 48-118, Durham, NC, 27701, USA.

3 MIT Computer Science and Artificial Intelligence Laboratory (CSAIL), Cambridge, MA, USA.

4 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

5 Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

6 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

7 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

8 Montreal Neurological Institute, and Hospital, McGill University, Montréal, QC, Canada.

9 Department of Human Genetics, McGill University, Montreal, QC, Canada.

10 Institute for Molecular Medicine Finland, Helsinki, Finland.

11 ALS Clinical Research Center, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, via G La Loggia 1, 90129, Palermo, Italy. [email protected].

12 Center for Human Disease Modeling, Duke University Medical Center, Carmichael Building, 300 North Duke Street, Suite 48-118, Durham, NC, 27701, USA.



New SPG4 mutation found

Frequent urination first sign of HSP


This is the first time that frequent urination has been reported as the initial symptom of HSP. A new mutation in the SPAST gene associated with SPG4 was identified.



OBJECTIVE: Hereditary spastic paraplegia type-IV (HSP4) is the most common of the autosomal-dominant HSPs. Though urinary dysfunction is a frequent phenotypic feature, long-term pollakisuria (frequent urination) as the initial manifestation of HSP4 has not been reported.


CASE REPORT: The patient is a 56yo female with an uneventful history until age 46y, when she developed pollakisuria. After another 6y she developed a coordination disorder, recognized as difficulties with running and climbing stairs. Since 6 months prior to presentation, she recognized mild dysphagia. The further history was positive for strabismus, varicosity, hepatopathy, thiamin-deficiency, niacin-deficiency, lumbago, cutaneous borelliosis, abortive psoriasis, lumbar spondylosis, osteochondrosis L5/S1, and HLA-B27-positive rheumatoid arthritis.

Clinical exam revealed mild weakness for left foot extension (M5-), a right subclonic patella tendon reflex, and mildly impaired left hook transition. Nerve conduction studies revealed subclinical polyneuropathy. Ophthalmologic investigations, and MRI of the brain and spinal cord were non-informative. Genetic work-up revealed the novel variant c.683-2A > C in the SPAST gene. The family history was positive for HSP in her mother and sister. Pure HSP4 was diagnosed.


CONCLUSIONS: Pure HSP4 may manifest at onset with year-long pollakisuria exclusively. HSP4 may take a mild course over years, allowing the patient to do sports and to practice a demanding job.


SOURCE: J Clin Neurosci. 2019 Jun;64:4-5. doi: 10.1016/j.jocn.2019.03.067. Epub 2019 Apr 5. PMID: 30962061 Copyright © 2019 Elsevier Ltd. All rights reserved.

Familial, long-term pollakisuria as initial manifestation of HSP4 due to the SPAST variant c.683-2A>C.

Finsterer J1, Wakil SM2, Laccone F3.

1 Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria. Electronic address: [email protected].

2 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

3 Institute of Medical Genetics, Head of the Section “Clinical Genetics”, Medical School of Vienna, Vienna, Austria.



New mutation in CAPN1 (SPG76 HSP) discovered in China



Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological disorders characterized by lower limb spasticity and weakness, with or without additional neurological symptoms or other system involvement, which are defined as complicated and pure phenotypes, respectively.1

CAPN1(MIM: 114220) has recently been identified as the causative gene for spastic paraplegia 76 (SPG76), an autosomal recessive HSP associated with either a pure or complicated phenotype, accompanied by ataxia, mild cognitive decline, or axonal peripheral involvement.2,3 Here we report the first Chinese HSP patient with biallelic CAPN1 pathogenic variants.

Our 38-year-old female patient (Fig. 1A), born into a consanguineous Chinese family, first noticed symptoms of slowly progressive lower limb stiffness and unsteadiness at the age of 35 years. No bladder dysfunction was reported. A neurological examination showed symmetrical hyperreflexia in both the upper and lower extremities. The muscle tension was increased in all four extremities, she was positive for bilateral patellar clonus, and bilateral pes cavus was observed. The patient did not present signs of cerebellar ataxia. The muscle force was normal in all limbs. Hematological and biochemical tests, a nerve electrophysiological study, and brain MRI all produced unremarkable findings. Her healthy parents and younger sister were also comprehensively checked by two experienced neurologists.

The homozygosity mapping revealed 19 extended (>2.0 Mb) runs of homozygosity harboring 7 candidate genes responsible for autosomal recessive HSPs. Direct sequencing of these candidate genes identified a novel homozygous nonsense variant (c.1015C>T) in CAPN1 (NM_001198868), resulting in a premature stop codon (p.R339*) (Fig. 1B). Cosegregation analysis revealed that the pathogenic variant was cosegregated with the disease in the family. The healthy parents of the patient and her younger sister were all heterozygotes for the c.1015C>T variant (Fig. 1B).

CAPN1 has both pure and complicated phenotypes, and our patient presented with a pure phenotype. Ataxia is the most prominent feature in patients with a complicated phenotype. CAPN1 encodes the protein calpain-1, with a high expression level in the cerebellum during the prenatal and early postnatal periods, indicating a potential role for calpain-1 in cerebellar development.4 It is particularly interesting that a missense CAPN1 variant was found to be associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed.5 Calpain-1 homozygous knockout mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including altered synaptic transmission, enhanced neuronal apoptosis, and decreased number of cerebellar granule cells.3

In conclusion, we report a Chinese patient with a pure HSP phenotype caused by a novel nonsense homozygous variant (c.1015C>T, p.R339*) in CAPN1. This is the first report of a CAPN1 pathogenic variant in a patient of Chinese descent. Additional studies are needed to evaluate the frequency and phenotype-genotype correlation of CAPN1 in the Chinese population.


SOURCE: J Clin Neurol. 2019 Apr; 15(2): 271–272. Published online 2019 Mar 26. doi: 10.3988/jcn.2019.15.2.271 PMID: 30938113

A Novel Homozygous CAPN1 Pathogenic Variant in a Chinese Patient with Pure Hereditary Spastic Paraplegia

You Chen,a Zhidong Cen,a Xiaosheng Zheng,a,b Fei Xie,a,c Si Chen,a,d and Wei Luo,a

a Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

b Intensive Care Unit, Zhejiang Hospital, Hangzhou, China.

c Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

d Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China, National Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.



Two different new mutations in CAPN1 (SPG76 HSP) also discovered in China



BACKGROUND: Hereditary spastic paraplegias (HSP) are of great clinical and genetic heterogeneity. According to the clinical features, HSP can be divided into pure or complicated subtypes which combined with other neurological symptoms including cerebellar ataxia. Up to date, 78 loci or genes have been implicated in HSP. CAPN1 was a novel gene detected recently for spastic paraplegia 76 (SPG76).


METHODS: Patients referred to our clinic with spastic or spastic-ataxic gait were collected. Genetic testing of the probands were performed by target sequencing of a panel containing over 4000 known virulence genes. And the candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. The clinical materials of these patients were demonstrated retrospectively.


RESULTS: Two Chinese patients, both from consanguineous families, each carried a novel homozygous mutation of CAPN1, p.R48X and p.R339X. The male proband presented pure HSP subtype while the female proband presented complicated HSP symptoms with cerebellar ataxia. We then reviewed all the literatures of HSP patients carrying CAPN1 mutations and summarized the molecular spectrum and clinical characteristics of CAPN1-related SPG76.


CONCLUSION: These two SPG76 patients carrying CAPN1 mutations were the first reported in China. By reviewing the clinical manifestations of SPG76 patients, we validated the “spastic-ataxia” phenotype and emphasized the association between spasticity and ataxia, indicating the importance of CAPN1 screening in HSP patients.


SOURCE: Orphanet J Rare Dis. 2019 Apr 25;14(1):83. doi: 10.1186/s13023-019-1053-1. PMID: 31023339

Two hovel homozygous mutations of CAPN1 in Chinese patients with hereditary spastic paraplegia and literatures review.

Peng F1, Sun YM1, Quan C1, Wang J1, Wu JJ2,3.

1 Department & Institute of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.

2 Department & Institute of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China. [email protected].

3 Department of Neurology, Jing’an District Center Hospital of Shanghai, 259 Xikang Road, Shanghai, 200040, China.



New mutation in FARS2 (SPG77) gene identified

Difficulty in speaking a new symptom for this HSP type



Herein we present two siblings with hereditary spastic paraplegia caused by novel compound heterozygous variant and deletion in FARS2 and expansion of the disease spectrum to include dysphonia.


SOURCE: J Child Neurol. 2019 May 19:883073819846805. doi: 10.1177/0883073819846805. [Epub ahead of print] PMID: 31106652

FARS2 Causing Complex Hereditary Spastic Paraplegia With Dysphonia: Expanding the Disease Spectrum.

Forman EB1,2, Gorman KM1,2, Ennis S2, King MD1,2.

1 Department of Neurology and Neurophysiology, Children’s University Hospital, Dublin, Ireland.

2 Academic Centre on Rare Disease (ACoRD), University College Dublin, Ireland.

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