New HSP genotypes and phenotypes

Research from France, Canada, Turkey, Germany, Norway, Spain, Italy, South Korea, India and the USA 


New mutation found in ERLIN2 gene

Associated with pure HSP for the first time


Mutations in the ERLIN2 gene, associated with recessive, complicated SPG18 HSP, have now been found to cause a dominantly inherited pure form of HSP. Therefore, this gene should be considered for testing in people with autosomal dominant HSP.



BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families.


METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools.


RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease.


CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.


SOURCE: Eur J Neurol. 2018 Mar 12. doi: 10.1111/ene.13625. [Epub ahead of print] PMID: 29528531 © 2018 EAN.

A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

Rydning SL1,2, Dudesek A3,4, Rimmele F3,4, Funke C5, Krüger S5, Biskup S5,6, Vigeland MD7, Hjorthaug HS7, Sejersted Y7, Tallaksen C1,2, Selmer KK1,7, Kamm C3.

1 Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

2 Department of Neurology, Oslo University Hospital, Oslo, Norway.

3 Department of Neurology, University of Rostock, Rostock, Germany.

4 German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany, Germany.

5 CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.

6 Hertie-Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.

7 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.




SPG58 HSP found with Spastic Ataxia

New mutation identified


Mutations in the KIF1C gene, associated with SPG58 HSP and Spastic Ataxia, have been found in two brothers who are exhibiting symptoms of both conditions – a severe, complicated form of HSP. The cerebellar signs associated with ataxia emerged before impairments of the legs, suggesting that HSP be considered a candidate in genetic testing / diagnosingpeople presenting with cerebellar symptoms.



Hereditary spastic paraplegias (HSPs) are a group of genetic disorders resulting in pyramidal tract impairment, predominantly in lower limbs.


KIF1C gene has recently been identified as one of the genetic causes of HSP and associated with pure or complicated HSP. We present three patients with complicated HSP from two unrelated families, who had early onset progressive cerebellar signs and developed pyramidal tract signs during follow-up.


Whole exome sequencing in these patients followed by segregation analysis identified novel truncating KIF1C mutations (c.463C> T; p.R155∗ and c.2478delA; p.Ala828Argfs∗13). Neuroimaging findings showed cerebral and upper cervical spinal atrophy, bilateral symmetrical pyramidal tract involvement, and focal cerebral white matter lesions.


Patients with KIF1C mutations may present with cerebellar signs and pyramidal findings may emerge later, therefore complicated HSP should be considered in the differential diagnosis of unidentified cases with cerebellar dysfunction.


SOURCE: Brain Dev. 2018 Jun;40(6):458-464. doi: 10.1016/j.braindev.2018.02.013. Epub 2018 Mar 12. PMID: 29544888

Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across life span.

Yücel-Yılmaz D1, Yücesan E2, Yalnızoğlu D3, Oğuz KK4, Sağıroğlu MŞ5, Özbek U2, Serdaroğlu E3, Bilgiç B6, Erdem S7, İşeri SAU2, Hanağası H6, Gürvit H6, Özgül RK1, Dursun A8.

1 Department of Pediatric Metabolism, Institute of Child Health, Hacettepe University, Turkey.

2 Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Turkey.

3 Department of Pediatric Neurology, Hacettepe University Faculty of Medicine, Turkey.

4 Department of Radiology, Hacettepe University Faculty of Medicine, Turkey.

5 Informatics and Information Security Research Center, National Research Institute of Electronics and Cryptology, TÜBİTAK, Turkey.

6 Behavioral Neurology and Movement Disorders Unit, Department of Neurology, İstanbul University Faculty of Medicine, Turkey.

7 Department of Neurology, Hacettepe University Faculty of Medicine, Turkey.

8 Department of Pediatric Metabolism, Hacettepe University Faculty of Medicine, Turkey. Electronic address: [email protected].




SPG50 HSP and iron accumulation

New mutation found in AP4M1 gene



OBJECTIVE: To describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation.


METHODS: The 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients.


RESULTS: In the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein.


CONCLUSIONS: Our results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.


SOURCE: Neurol Genet. 2018 Jan 24;4(1):e217. doi: 10.1212/NXG.0000000000000217. eCollection 2018 Feb. PMID: 29473051

AP4 deficiency: A novel form of neurodegeneration with brain iron accumulation?

Roubertie A1, Hieu N1, Roux CJ1, Leboucq N1, Manes G1, Charif M1, Echenne B1, Goizet C1, Guissart C1, Meyer P1, Marelli C1, Rivier F1, Burglen L1, Horvath R1, Hamel CP1, Lenaers G1.

1 Département de Neuropédiatrie (A.R., B.E., P.M., F.R.), CHU Gui de Chauliac, Montpellier; Institut des Neurosciences de Montpellier (A.R., N.H., G.M., C.P.H.), INSERM U1051, Université de Montpellier; Service de Neuroradiologie (C.-J.R., N.L.), CHU Gui de Chauliac, Montpellier; Equipe MitoLab (M.C., G.L.), UMR CNRS 6015-INSERM 1083, Institut MitoVasc, University of Angers, France; Department of Medical Genetics (C. Goizet), Hopital Pellegrin, Bordeaux University Hospital; MRGM Laboratory (C. Goizet), INSERM U1211, University of Bordeaux; Laboratoire de Génétique Moléculaire (C. Guissart), CHU de Montpellier; U1046 INSERM (P.M., F.R.), UMR9214 CNRS, Université de Montpellier; Department of Neurology (C.M.), University Hospital Gui de Chauliac, Montpellier; Centre de Référence des Malformations et Maladies Congénitales du Cervelet (L.B.), Service de Génétique, Hôpital Armand Trousseau, AP-HP, Paris, France; Wellcome Trust Centre for Mitochondrial Research (R.H.), Institute of Genetic Medicine, Newcastle University, United Kingdom; and Centre of Reference for Genetic Sensory Diseases (C.P.H.), Montpellier, France.



SPG50 HSP overlaps another condition

New mutation and phenotype found


A new mutation in the AP4M1 gene (SPG50 HSP) was identified in two brothers with severe, complicated HSP – one of whom showed symptoms not previously reported in HSP. The AP4M1 gene is also associated with ‘AP–4 deficiency syndrome’.



Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID).


The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms “AP-4 deficiency syndrome” for this clinically recognizable phenotype. Using whole-exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP-4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition.


In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development.


SOURCE: Am J Med Genet A. 2018 Apr;176(4):985-991. doi: 10.1002/ajmg.a.38628. Epub 2018 Feb 12. PMID: 29430868

A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocularanomalies.

Accogli A1,2, Hamdan FF3, Poulin C1,4, Nassif C3, Rouleau GA5, Michaud JL3,6, Srour M1,4.

1 Department of Pediatrics, McGill University, Montreal, Canada.

2 Istituto Giannina Gaslini, Genova, Italy.

3 CHU Sainte-Justine Research Center, Montréal, Canada.

4 Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

5 Montreal Neurological Institute, McGill University, Montreal, Canada.

6 Departments of Pediatrics and Neurosciences, Université de Montréal, Montreal, Canada.



New SPAST mutation discovered in Spanish family

SPAST mutations, associated with SPG4 HSP, now number more than 250


Dear Editor,

The hereditary spastic paraplegia autosomal dominant (HSP-AD) is a group of neurodegenerative diseases of genetic origin that cause progressive spasticity and weakness in the lower extremities due to the degeneration of corticospinal tract1. Currently described are about 79 loci and over 70 chromosomal pathogenic variants causing HSP2. 40% of all families with HSP-AD have pathogenic variants of the SPAST gene , at the 2p22.3 loci . This gene, also known as SPG4, is made up of 17 exons and codes for the protein spastin. This protein is an ATPase associated with diverse cellular activities such as proteolysis, cell cycle, vesicular transport, peroxisome biogenesis and mitochondrial functions3.

More than 250 pathogenic variants have been described in the SPAST gene of different types (deletions, insertions and base substitution), and in most of the families described there are specifically unique mutations. Some of these variants seem to condition certain particularities such as greater precocity and severity in men, earlier onset, cognitive and vesical involvement or late onset.

The clinical phenotype is indistinguishable, among the different mutational mechanisms (nonsense, deletion, rearrangement, among others), with haploinsufficiency being the molecular basis of this variability 4.

When symptoms occur in childhood, other diagnoses must be considered, such as structural injuries, infections and metabolic diseases. The pathogenic variants that produce pediatric HSP are in the ATL1 gene (SPG3A) followed by the SPAST5 gene .

We present a new pathogenic variant in the SPAST gene, in 3 members of a Spanish family affected by HSP-AD.


SOURCE: Neurologia. 2018 Mar 8. pii: S0213-4853(18)30036-7. doi: 10.1016/j.nrl.2018.01.014. [Epub ahead of print] PMID: 29526314

A novel pathogenic variant of the SPAST gene in a Spanish family with hereditary spastic paraplegia.

Bertran Recasens B1, Figueras Aguirre G1, Aznar-Lain G2, Rubio MA3.

1 Servicio de Neurología, Hospital del Mar, Barcelona, España.

2 Unidad de Neurología Pediátrica, Servicio de Pediatría, Hospital del Mar, Barcelona, España.

3 Unidad de Neuromuscular, Servicio de Neurología, Hospital del Mar, Barcelona, España; Instituto Hospital del Mar de Investigaciones Médicas (IMIM), Barcelona, España. Electronic address: [email protected].



First case of SPG31 HSP in Korea

The mutation identified in the REEP1 gene had previously been reported in association with complicated HSP.


Dear Editor,

Hereditary spastic paraplegia (HSP) encompasses a heterogeneous group of genetic disorders characterized by progressive lower-limb spastic paralysis due to degeneration of the corticospinal tract. HSP has been classified into pure and complicated forms according to the existence of mental retardation, epilepsy, cerebellar ataxia, optic atrophy, and peripheral neuropathy. To date 66 causative genes for HSP have been reported, of which 20 are associated with autosomal-dominant inheritance ( Three genes account for up to 50% of the pathogenic variants in families with autosomal-dominant HSP: the causative gene is SPAST in 40%, ATL1 in 10%, and REEP1 in 4.5% to 6%.1 However, pathogenic variants in REEP1 have not been reported in Korea.2 Here we report a pathogenic variant of REEP1 in a Korean family with autosomal-dominant HSP.

The proband in the HSP family (an 8-year-old boy) presented to our clinic with gait disturbance. He first noticed an unstable gait at an age of 5 years, since when his gait disturbance had progressed slowly. When we examined him at the age of 8 years, he was still able to ambulate independently. A neurological examination demonstrated muscle weakness and brisk reflexes of the lower extremities. His ankle joints were affected by contracture. However, the motor function of the upper extremities was normal, and he did not exhibit cognitive decline, sensory deficits, or bladder dysfunction. Magnetic resonance images of the brain and spinal cord were normal, as were the findings of electrophysiological studies.

To identify pathogenic variants, whole-exome sequencing was performed on the proband (III-8). Our screening of HSP-related genes revealed a heterozygous pathogenic variant (c.337C>T) (p.Arg113*) in REEP1. This variant was previously reported as the pathogenic variant in complicated HSP. DNA sequencing by capillary electrophoresis of samples from extended family members identified the REEP1variant in four affected family members and one asymptomatic family member. Read the full letter.


SOURCE: J Clin Neurol. 2018 Apr;14(2):248-250. doi: 10.3988/jcn.2018.14.2.248. PMID: 29629531

Pathogenic Variant of REEP1 in a Korean Family with Autosomal-Dominant Hereditary Spastic Paraplegia.

Park HJ#1, Lee MJ#2, Lee JE3, Park KD3, Choi YC4.

1 Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.

2 Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea.

3 Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea.

4 Department of Neurology, Yonsei University College of Medicine, Seoul, Korea. [email protected].

# Contributed equally




Rare variant of SPG53 HSP gene mutation identified

Found in two sisters with idiopathic transverse myelitis (ITM) for which there was family history



OBJECTIVE: To identify genetic differences among siblings with a family history of idiopathic transverse myelitis (ITM).


METHODS: We compared whole-exome sequencing (WES) on germline samples from the 2 affected sisters with ITM with 3 of their healthy siblings.


RESULTS: The 2 sisters with ITM both had acute onset of sensory loss in the legs, weakness, and bowel/bladder dysfunction. The first developed ITM at age 15 years with a clinical nadir of complete paralysis, which slowly recovered over a few years. MRI demonstrated a persistent T2 lesion in the lower thoracic cord. The second developed ITM at age 50 years with a nadir of sensory loss from T6 down and paraparesis in the legs, associated with an MRI lesion at T6. She also made a partial recovery with treatment.


Both sisters are homozygous for a missense variant in VPS37A (c.700C>A, p.Leu234Ile) identified by WES. We performed targeted sequencing of VPS37A in an additional 86 samples from patients with ITM and 175 with other diseases to investigate the p.Leu234Ile variant. We identified another patient with ITM homozygous for the same rare variant. No patients with multiple sclerosis, neuromyelitis optica, other neurologic conditions, or any healthy controls in public databases were homozygous for this variant.


CONCLUSIONS: A rare missense variant in VPS37A may predispose to development of ITM. Further studies are necessary to determine the frequency of this variant in the patient population and the mechanism through which it contributes to the risk of disease.


SOURCE: Neurol Genet. 2018 Jan 30;4(1):e213. doi: 10.1212/NXG.0000000000000213. eCollection 2018 Feb. PMID: 29473047

Familial monophasic acute transverse myelitis due to the pathogenic variant in VPS37A.

Mealy MA1, Nam TS1, Pardo SJ1, Pardo CA1, Sobreira NL1, Avramopoulos D1, Valle D1, Burns KH1, Levy M1.

1 Department of Neurology (M.A.M., S.J.P., C.A.P., M.L.), Institute of Genetic Medicine (N.L.S., D.A., D.V., K.H.B.), and Department of Pathology (K.H.B.), Johns Hopkins University, Baltimore, MD; and Department of Neurology (T.-S.N.), Chonnam National University Medical School, Gwangju, South Korea.




New mutation found in GBA2 gene

Responsible for SPG46 HSP



Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e. complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders.

We report on a 56 year-old man affected by sporadic complicated HSP consisting of pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP.


SOURCE: Clin Neurol Neurosurg. 2018 May;168:60-63. doi: 10.1016/j.clineuro.2018.02.042. Epub 2018 Mar 3. PMID: 29524657

Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia.

Coarelli G1, Romano S2, Travaglini L3, Ferraldeschi M2, Nicita F3, Spadaro M4, Fornasiero A2, Frontali M4, Salvetti M2, Bertini E3, Ristori G5.

1 Assistance Publique-Hôpitaux de Paris (AP-HP) & Paris 13 University, Avicenne Hospital, Neurology Department, 93009, Bobigny, France.

2 Center for Experimental Neurological Therapies, Sant’Andrea Hospital, Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.

3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesu’ Children’s Research Hospital, Rome, Italy.

4 National Research Council, Institute of Translational Pharmacology, Rome, Italy.

5 Center for Experimental Neurological Therapies, Sant’Andrea Hospital, Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy. Electronic address: [email protected].



New SPG79 HSP gene mutation discovered


Spastic Paraplegia-79 (SPG79) is an autosomal recessive type of childhood onset complicated by hereditary spastic paraplegia. SPG79 is characterized by spasticity, paraplegia, optic atrophy, cerebellar signs, and other variable clinical features. Recessive, disease causing variants in Ubiquitin C-terminal hydrolase-L1 (UCHL1) gene have been implicated as a cause for SPG79 in two families till now.


In this study, we report on a third family of SPG79 with two similarly affected siblings, harboring a novel homozygous splice-site variant in the UCHL1 gene (NM_004181.4: c.459+2T>C). The variant was identified by whole-exome sequencing and validated by Sanger sequencing in the family.


SOURCE: J Hum Genet. 2018 May 7. doi: 10.1038/s10038-018-0463-6. [Epub ahead of print] PMID: 29735986

Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79.

Das Bhowmik A1, Patil SJ2, Deshpande DV1, Bhat V3, Dalal A4.

1 Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.

2 Department of Medical Genetics, Mazumdar Shaw Medical Center, Narayana Health City, Bangalore, India.

3 Department of Radiology, Mazumdar-Shaw Medical Center, Narayana Health City, Bangalore, India.

4 Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India. [email protected].


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