New HSP genotypes and phenotypes

Research from China, Australia, Greece, the UK, Republic of Moldova, France, Cyprus, Italy, the USA, Japan, Sweden, Algeria, Portugal, Turkey, Belgium and India

What are genotypes and phenotypes?

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

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

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

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

New symptoms for SPG4 found, associated with new, sporadic SPAST mutation

Elevation of cerebrospinal fluid (CSF) protein in this case has never been described before in SPG4, and only having previously been reported in two SPG11 cases that presented like multiple sclerosis (MS). The sporadic SPAST mutation found in this case is new.


Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of inherited neurological disorders.1 We report a sporadic patient with HSP who carried a novel SPG4 mutation (c.1141T>G) in a highly conserved region of the gene. The patient presented with a typical pure form of HSP with progressive lower extremity weakness and spasticity, but he also developed lower limb amyotrophy, spinal cord atrophy, and progressive CSF protein elevation, which has not previously been described in SPG4 HSP.

The patient was a 58-year-old right-handed Chinese male who had experienced progressive lower limb weakness and stiffness since the age of 29 years. He was first seen at the age of 46 years, at which time he was still able to walk independently. An examination revealed symmetric diffuse muscle atrophy and weakness [Medical Research Council (MRC) grade 4] in the lower limbs, spasticity of both legs with hyperreflexia, positive bilateral Babinski sign, and a scissors gait. Cerebrospinal fluid (CSF) showed a mildly elevated protein level of 53 mg/dL (normal 15–45 mg/dL), but otherwise the CSF findings were normal.

At 57 years of age his lower limb muscle strength had decreased to MRC grade 3. His score on the Spastic Paraplegia Rating Scale was 30. A repeat CSF examination again showed protein elevation (77 mg/dL).

Genetic screening using next-generation sequencing identified a novel, heterozygous missense mutation in the SPAST gene in exon 8: c.1141T>G, p.(Phe381Val), NM_014946.3. Other studies have also found that a phenylalanine-to-valine substitution, or vice versa, can cause disease.2

None of his family members reported any neurological motor symptoms, and they had all passed the average age at which the onset of HSP occurs, suggesting that this was a sporadic case of HSP.

The finding of spinal cord atrophy on MRI is not uncommon in cases of complicated SPG4 due to axonal degeneration; however, the progressive increase in CSF protein over a 11-year disease period has not been reported previously. Elevation of CSF protein in HSP is rare, having only been reported in two SPG11 cases with clinical presentations mimicking multiple sclerosis.3,4 The present report further extends the spectrum of SPAST mutations and the genotype–phenotype correlation in SPG4 HSP, and highlights the finding of elevated CSF protein levels in some cases.

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SOURCE: J Clin Neurol. 2021 Jan;17(1):152-153. doi: 10.3988/jcn.2021.17.1.152. PMID: 33480217

Novel SPG4 Mutation in a Patient with Sporadic Hereditary Spastic Paraplegia and Elevated Cerebrospinal Fluid Protein

Hongda She #  1 Xin Zheng #  2 Yingxiu Xiao #  3 Frank Mastaglia  4 Anthony Akkari  4 Jingshan Wu  5

1 Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

2 Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing, China.

3 Department of Neurology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.

4 Perron Institute for Neurological and Translational Science, QE II Medical Centre, Nedlands, Australia.

5 Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia.

# Contributed equally.

New SPG11 associated mutation discovered

Atypical case of SPG11 and of HSP generally


Hereditary spastic paraplegias (HSP) are phenotypically and genotypically diverse. We describe a unique case of autosomal recessive HSP (ARHSP) diagnosed at age 44 in a patient previously described as having “spinal muscular ataxia” [sic]. Predominant lower motor neuron findings and lack of clinical spasticity reduced suspicion for HSP in early life. The identified SPG11 mutation was novel and the presentation was atypical for HSP in general and SPG11 disease specifically.

SOURCE: J Clin Neurosci. 2020 Nov;81:90-91. doi: 10.1016/j.jocn.2020.09.004. Epub 2020 Sep 29. PMID: 33222977 Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.

Homozygous frameshift mutation of SPG11 as a cause of progressive flaccid paralysis, ataxia and dysphagia

Kate Lilley  1 Sandeep Bhuta  2 Arman Sabet  2 Simon A Broadley  3

1 Gold Coast University Hospital, Southport, QLD 4215, Australia.

2 Gold Coast University Hospital, Southport, QLD 4215, Australia; Menzies Health Institute Queensland, Griffith University, QLD 4222, Australia.

3 Gold Coast University Hospital, Southport, QLD 4215, Australia; Menzies Health Institute Queensland, Griffith University, QLD 4222, Australia.

New GBA2 mutation causing SPG46 found

First cases of SPG46 recorded in India


Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogenous group of neurodegenerative disorders. So far, there are 40 spastic paraplegias (SPG) with genetic abnormalities identified in more than 80 genes [1]. SPG type-46 (SPG46) is one of the rare complicated autosomal recessive forms of HSP.

This occurs secondary to biallelic mutations in the GBA2 gene, which disrupt the function of its gene product glucosylceramidase beta-2 (GBA2). To date, around 35 cases of SPG46 due to 17 different genetic variants in GBA2 gene have been reported worldwide. To the best of our knowledge there are no reports of SPG46 from India.

This report describes two cases of genetically proven SPG46 from India with truncating mutations in GBA2, of which one was a novel mutation.

SOURCE: Parkinsonism Relat Disord. 2021 Jan;82:13-15. doi: 10.1016/j.parkreldis.2020.11.007. Epub 2020 Nov 17. PMID: 33227682

SPG46 due to truncating mutations in GBA2: Two cases from India

Vikram V Holla  1 Bharath Kumar Surisetti  1 Shweta Prasad  2 Naveen Thota  1 Albert Stezin  2 Pramod Kumar Pal  1 Ravi Yadav  3

1 Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore, 560029, Karnataka, India.

2 Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore, 560029, Karnataka, India; Department of Clinical Neurosciences, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore, 560029, Karnataka, India.

3 Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore, 560029, Karnataka, India.

ACO2 gene variant causes complex HSP

First case in Japan

Episodic visual loss during bouts of fever accompanying complex HSP due to ACO2 gene variants characterise this first ever case found in a 20-year-old Japanese woman.


Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra.

Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.

SOURCE: Hum Genome Var. 2021 Jan 26;8(1):4. doi: 10.1038/s41439-021-00136-y. PMID: 33500398

Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants

Takenori Tozawa  1   2 Akira Nishimura  3 Tamaki Ueno  4   5 Akane Shikata  6 Yoshihiro Taura  7 Takeshi Yoshida  8 Naoko Nakagawa  9 Takahito Wada  9 Shinji Kosugi  9 Tomoko Uehara  10 Toshiki Takenouchi  11 Kenjiro Kosaki  10 Tomohiro Chiyonobu  7

1 Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. [email protected].

2 Department of Pediatrics, Ayabe City Hospital, Ayabe, Japan. [email protected].

3 Department of Neonatology, Japanese Red Cross Society Kyoto Daiichi Hospital, Kyoto, Japan.

4 Department of Pediatrics, Ayabe City Hospital, Ayabe, Japan.

5 Department of Pediatrics, Tokai Central Hospital, Kakamigahara, Japan.

6 Kyoto Prefectural Maizuru Rehabilitation Center for Children, Maizuru, Japan.

7 Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

8 Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9 Department of Medical Ethics/Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.

10 Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

11 Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Rare, pure SPG72 found in Nepalese family

Early onset, mild symptoms, slow progression


Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs due to pyramidal tract dysfunction.

REEP2 mutations have been identified as a cause of “pure” HSP, SPG72, with both autosomal dominant and autosomal recessive inheritance. We describe a rare Nepalese family with early-onset pure-type HSP harboring a heterozygous REEP2 missense mutation (c.119T>G, p.Met40Arg). This is only the second SPG72 family with autosomal dominant inheritance.

The proband presented slow and spastic gait at age 2 years and the symptoms progressed slowly. The proband’s father and uncle presented even milder symptoms of pure spastic paraplegia. Our study may provide an opportunity to further study the genotype-phenotype correlation of SPG72.

SOURCE: J Hum Genet. 2021 Feb 1. doi: 10.1038/s10038-020-00882-x. Online ahead of print. PMID: 33526816

A Nepalese family with an REEP2 mutation: clinical and genetic study

Haitian Nan  1 Ryusuke Takaki  1   2 Takanori Hata  1 Kishin Koh  1 Yoshihisa Takiyama  3

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

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

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

Three new mutations found in the SPG7 gene

Causes of related ataxia studied


Hereditary spastic paraplegia (SPG) can be due to many different mutations in at least 9 different genes, one of which is SPG7 (Hewamadduma et al. 2018). Patients with homozygous SPG7 mutations are usually male (Erfanian Omidvar et al. 2019) and present in the 4th decade with ataxia and are then found to have pyramidal signs in the lower limbs.

We tested vestibular function with video head impulses (vHIT) (Halmágyi and Curthoys, 2018) in 3 patients from 3 families with 3 different novel autosomal recessive SPG7 mutations to find out if vestibular impairment (Starkov et al. 2020) might be contributing to their ataxia.

SOURCE: Clin Neurophysiol. 2021 Jan;132(1):77-79. doi: 10.1016/j.clinph.2020.10.012. Epub 2020 Nov 4. PMID: 33248435

Vestibulo-ocular reflex impairment in SPG7 hereditary spastic paraplegia

Gülden Akdal  1 Koray Koçoğlu  2 Cemile Koçoğlu  3 Elçin Bora  4 Ayşe Nazlı Başak  5 Gábor Michael Halmágyi  6

1 Dokuz Eylül University, Faculty of Medicine, Department of Neurology, İzmir, Turkey; Dokuz Eylül University, Institute of Health Sciences, Department of Neuroscience, İzmir, Turkey.

2 Dokuz Eylül University, Institute of Health Sciences, Department of Neuroscience, İzmir, Turkey.

3 University of Antwerp, Faculty of Phamaceutical, Biomedical and Veterinary Sciences, Antwerp, Belgium.

4 Dokuz Eylül University, Faculty of Medicine, Department of Medical Genetics, İzmir, Turkey.

5 Koç University, School of Medicine, Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Research Center for Translational Medicine, Istanbul, Turkey.

6 University of Sydney, Royal Prince Alfred Hospital, Neurology Department, Sydney, Australia.

Multicenter study of SPG48

Endolysosome accumulation found in SPG48 skin cells


Bi-allelic mutations in AP5Z1 are known to cause a rare, autosomal-recessive, complex form of hereditary spastic paraplegia (HSP) referred to as SPG48 (MIM#613647). To date, only 11 SPG48 patients have been reported. The clinical spectrum of SPG48 is complex and heterogeneous, presenting with neuropathy, ataxia, dystonia, and parkinsonism in addition to spastic paraplegia (SP).

AP5Z1 codes for the subunit of the AP-5 complex, implicated in vesicular-mediated intracellular sorting and trafficking of cargo proteins. Functional studies demonstrate the accumulation of multi-lamellar structures (endolysosomes) in SPG48 skin fibroblasts.

SOURCE: Mov Disord. 2021 Feb 5. doi: 10.1002/mds.28487. Online ahead of print. PMID: 33543803

Expanding the Spectrum of AP5Z1-Related Hereditary Spastic Paraplegia (HSP-SPG48): A Multicenter Study on a Rare Disease

Marianthi Breza #  1 Jennifer Hirst #  2 Viorica Chelban #  3   4 Guillaume Banneau  5   6 Laurène Tissier  5 Bophara Kol  5 Thomas Bourinaris  3 Samia A Said  5 Yann Péréon  7 Anna Heinzmann  5 Rabab Debs  8 Raul Juntas-Morales  9 Victoria G Martinez  9 Jean P Camdessanche  9 Clarisse Scherer-Gagou  9 Jean-Médard Zola  9 Alkyoni Athanasiou-Fragkouli  3 Stephanie Efthymiou  3 George Vavougios  10 Georgios Velonakis  11 Maria Stamelou  1   12   13 John Tzartos  1 Constantin Potagas  1 Thomas Zambelis  1 Caterina Mariotti  14 Craig Blackstone  15 Jana Vandrovcova  3 Theodoros Mavridis  1 Chrisoula Kartanou  1 Leonidas Stefanis  1 Nicholas Wood  3   16 Georgia Karadima  1 Eric LeGuern  5   17 Georgios Koutsis #  1 Henry Houlden #  3   16 Giovanni Stevanin #  5   17   18

1 1st Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

2 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.

3 Department of Neuromuscular Disease, Institute of Neurology, University College London, London, United Kingdom.

4 Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Chisinau, Republic of Moldova.

5 Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique – Hôpitaux de Paris, Sorbonne Université, Paris, France.

6 Département de Génétique Médicale, Institut Fédératif de Biologie, Toulouse, France.

7 Department of Clinical Neurophysiology, Reference centre for NMD, CHU Nantes, Place Alexis-Ricordeau, Nantes, France.

8 Department of Clinical Neurophysiology, APHP, Pitié-Salpêtrière Hospital, Paris, France.

9 Département de Neurologie, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

10 Department of Neurology, Athens Naval Hospital, Athens, Greece.

11 2nd Department of Radiology, National and Kapodistrian University of Athens, Medical School, Attikon Hospital, Athens, Greece.

12 Parkinson’s Disease and Movement Disorders Department, Hygeia Hospital, Athens, Greece.

13 School of Medicine, European University of Cyprus, Nicosia, Cyprus.

14 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Instituto Neurologico Carlo Besta, Milan, Italy.

15 Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

16 Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom.

17 Sorbonne Université, Institut du Cerveau, INSERM, CNRS, CHU Pitié-Salpêtrière, Paris, France.

18 PSL Research University, EPHE, Neurogenetics Team, Paris, France.

# Contributed equally.

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