New HSP genotypes and phenotypes

Research from the UK, China, Pakistan, Italy, Spain, France, Turkey, Austria, Canada, USA & Germany


Early-onset Parkinson’s & SPG35 HSP occurring together

Interaction between PARK2 & FA2H gene mutations



Mutations in the PARK2 gene have been implicated in the pathogenesis of early-onset Parkinson’s disease. We present a case of movement disorder in a 4-year-old child from consanguineous parents and with a family history of Dopamine responsive dystonia, who was diagnosed with early-onset Parkinson’s disease based on initial identification of a pathogenic PARK2 mutation.

However, the evolution of the child’s clinical picture was unusually rapid, with a preponderance of pyramidal rather than extrapyramidal symptoms, leading to re-investigation of the case with further imaging and genetic sequencing.

Interestingly, a second homozygous mutation in the FA2H gene, implicated in Hereditary Spastic Paraplegia, was revealed, appearing to have contributed to the novel phenotype observed, and highlighting a potential interaction between the two mutated genes.

SOURCE: Front Neurol. 2019 May 29;10:555. doi: 10.3389/fneur.2019.00555. eCollection 2019. PMID: 31191442

The interaction of Genetic Mutations in PARK2 and FA2H Causes a Novel Phenotype in a Case of Childhood-Onset Movement Disorder.

Benger M1, Mankad K2, Proukakis C3, Mazarakis ND4, Kinali M5.

1 Department of Neurosciences, King’s College Hospital, London, United Kingdom.

2 Department of Neuroradiology, Great Ormond Street Hospital, London, United Kingdom.

3 Institute of Neurology, University College London, London, United Kingdom.

4 Centre for Neuroinflammation & Neurodegeneration, Imperial College, London, United Kingdom.

5 Honorary Senior Lecturer in Paediatric Neurology, Imperial College, London, United Kingdom.



7 new mutations found in recessive HSP population

2 in SPG11; 2 in SPG48; 1 in SPG9; 1 in SPG46 and 1 in SPG78


BACKGROUND: Although many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.

METHODS: In this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants.

RESULTS: We identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction.

CONCLUSION: Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

SOURCE: Transl Neurodegener. 2019 Jun 26;8:19. doi: 10.1186/s40035-019-0157-9. eCollection 2019. PMID: 31289639

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia.

Wei Q#1, Dong HL#1, Pan LY#2, Chen CX1, Yan YT1, Wang RM1, Li HF1, Liu ZJ3, Tao QQ1, Wu ZY1,4.

1 Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009 China.

2 Longyan First Hospital, Fujian Medical University, Longyan, China.

3 Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

4 Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China.

# Contributed equally



New variant identified in SPG56 causing gene CYP2U1



Hereditary Spastic paraplegias (HSPs) are heterogeneous group of degenerative disorders characterized by progressive weakness and spasticity of the lower limbs, combined with additional neurological features. This study aimed to identify causative gene variants in two nonrelated consanguineous Pakistani families segregating HSP.

Whole exome sequencing (WES) was performed on a total of five individuals from two families including four affected and one phenotypically normal individual. The variants were validated by Sanger sequencing and segregation analysis. In family A, a novel homozygous variant c.604G > A (p.Glu202Lys) was identified in the CYP2U1 gene with clinical symptoms of SPG56 in 3 siblings. Whereas, a previously reported variant c.5769delT (p.Ser1923Argfs*28) in the SPG11 gene was identified in family B manifesting clinical features of SPG11 in 3 affected individuals.

Our combined findings add to the clinical and genetic variability associated with CYP2U1 and SPG11 variants highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.

SOURCE: J Clin Neurosci. 2019 Sep;67:19-23. doi: 10.1016/j.jocn.2019.06.039. Epub 2019 Jul 4. Copyright © 2019. Published by Elsevier Ltd. PMID: 31281085

Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families.

Zulfiqar S1, Tariq M1, Ali Z1, Fatima A1, Klar J2, Abdullah U1, Ali A1, Ramzan S1, He S3, Zhang J4, Khan A1, Shah S1, Khan S1, Makhdoom EH5, Schuster J2, Dahl N2, Baig SM6.

1 Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan.

2 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

3 Radiology Department, Allied Hospital, Faisalabad, Pakistan; BGI-Shenzhen, Shenzhen 518083, China.

4 BGI-Shenzhen, Shenzhen 518083, China.

5 Department of Physiology, Government College University, Faisalabad, Pakistan.

6 Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan. Electronic address: [email protected].



New mutation found in SPG76 associated CAPN1 gene

Pure/uncomplicated form of HSP presented



CAPN1 encodes calpain-1, a large subunit of μ-calpain, a calcium-activated cysteine protease widely present in the central nervous system. Mutations in CAPN1 have recently been identified in a complicated form of HSP with a combination of cerebellar ataxia and corticomotor tract disorder (SPG76). Therefore, CAPN1 is now considered one of those genes that clinically manifest with a spectrum of disorders ranging from spasticity to cerebellar ataxia and represent a link between Spinocerebellar Ataxia and HSP, two groups of diseases previously considered separate but sharing pathophysiological pathways.

We here describe clinical and molecular findings of two Italian adult siblings affected with a pure form of HSP and harboring the novel homozygote c.959delA variant (p.Tyr320Leufs*73) in the CAPN1 gene. Although the reason why mutations in CAPN1 may cause heterogeneous clinical pictures remains speculative, our findings confirm that the spectrum of the CAPN1-linked phenotypes includes pure HSP with onset during the third decade of life. Further studies are warrantied in order to clarify the mechanism underlying the differences in CAPN1 mutation clinical expression.

SOURCE: Front Neurol. 2019 Jun 5;10:580. doi: 10.3389/fneur.2019.00580. eCollection 2019. PMID: 31231303

A Novel CAPN1 Mutation Causes a Pure Hereditary Spastic Paraplegia in an Italian Family.

Cotti Piccinelli S1, Bassi MT2, Citterio A2, Manganelli F3, Tozza S3, Santorelli FM4, Gallo Cassarino S1, Caria F1, Baldelli E1, Galvagni A1, Santoro L3, Padovani A1, Filosto M1.

1 Unit of Neurology, Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia, Brescia, Italy.

2 Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Lecco, Italy.

3 Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy.

4 Unit of Molecular Medicine, IRCCS Foundation Stella Maris, Pisa, Italy.



9 new mutations found in DDHD2 gene associated with SPG54

Despite this genetic variation, the clinical and neuroradiological phenotype is quite uniform



Recessive mutations in DDHD2 cause SPG54, a complex hereditary spastic paraplegia (HSP) with less than forty patients reported worldwide.

In this retrospective, multicenter study we describe eight additional SPG54 cases harboring homozygous or compound heterozygous DDHD2 variants. Finally, we reviewed literature data on SPG54, with the aim to better define the phenotype and the brain magnetic resonance imaging (MRI) pattern as well as genotype-phenotype correlations.

SPG54 is typically characterized by early-onset (i.e., congenital or, more frequently, infantile) delay in motor and cognitive milestones, coupled or followed by appearance of spasticity. Cognitive impairment is absent in adult-onset cases. Spasticity progresses over time. Abnormal eye movement, found in about 50% of cases, is the feature most frequently associated with spasticity and developmental delay. Cerebellar ataxia is a prominent sign in several patients, including one adult of this study, suggesting to include SPG54 in the differential diagnosis of spastic-ataxia syndromes. Brain MRI shows thin corpus callosum and non-specific periventricular white matter lesions in about 90% and 70% of cases, respectively. Brain MR spectroscopy reveals abnormal lipid peak in 90% of investigated patients.

Twenty-one pathogenic changes have been reported so far, many of which are nonsense or small deletion/duplication. Most mutations appear to be private, with only two mutations recurring in three (i.e., R287*) or more families (i.e., D660H). The identification of nine novel variants expands the molecular spectrum of DDHD2-related HSP and corroborates the notion of a quite homogeneous clinical and neuroradiological phenotype in spite of different genotypes.

SOURCE: J Neurol. 2019 Jul 13. doi: 10.1007/s00415-019-09466-y. [Epub ahead of print] PMID: 31302745

Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants.

Nicita F1, Stregapede F2, Tessa A3, Bassi MT4, Jezela-Stanek A5, Primiano G6, Pizzuti A7, Barghigiani M3, Nardella M2, Zanni G2, Servidei S6, Astrea G3, Panzeri E4, Maghini C8, Losito L9, Ploski R10, Gasperowicz P10, Santorelli FM3, Bertini E2, Travaglini L2.

1 Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy. [email protected].

2 Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy.

3 Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

4 Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy.

5 Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.

6 UOC Neurofisiopatologia Fondazione Policlinico Universitario A. Gemelli IRCCS, Istituto Di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy.

7 Department of Experimental Medicine, Sapienza University, Umberto I Polyclinic Hospital, Rome, Italy.

8 Neuromuscular Disorders Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy.

9 Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Scientific Institute IRCCS E. Medea, Brindisi, Italy.

10 Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.



2 new disease-causing mutations in P5CS gene identified

These SPG9B cases more severe than SPG9A in several respects



In 2015-2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia. In vitro production of the ALDH18A1 product, Δ1 -pyrroline-5-carboxylate synthetase (P5CS), appeared necessary for cracking SPG9 disease-causing mechanisms.

We now describe a baculovirus-insect cell system that yields mgs of pure human P5CS and that has proven highly valuable with two novel P5CS mutations reported here in new SPG9B patients. We conclude that both mutations are disease-causing, that SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits.

SOURCE: Ann Clin Transl Neurol. 2019 Aug;6(8):1533-1540. doi: 10.1002/acn3.50821. Epub 2019 Jul 19. © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. PMID: 31402623

P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9.

Magini P1, Marco-Marin C2,3, Escamilla-Honrubia JM2,3, Martinelli D4, Dionisi-Vici C4, Faravelli F5, Forzano F6, Seri M1,7, Rubio V2,3, Panza E1,7.

1 Medical Genetics Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.

2 Instituto de Biomedicina de Valencia of the CSIC, Valencia, Spain.

3 Centro para Investigación Biomédica en Red sobre Enfermedades Raras CIBERER-ISCIII, Valencia, Spain.

4 Division of Metabolism, Bambino Gesù Children’s Research Hospital, Rome, Italy.

5 Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, United Kingdom.

6 Clinical Genetics Department, SE Thames Regional Genetics Service, Guy’s & St Thomas’ NHS Foundation Trust, London, United Kingdom.

7 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.



2 new mutations found in MAG gene

Associated with SPG75 (Spastic Ataxia)



Homozygous mutations in MAG, encoding the myelin-associated glycoprotein, a transmembrane component of the myelin sheath, have been associated with SPG75 recessive spastic paraplegia. Here, we report the first patient with two compound heterozygous novel MAG mutations (p.A151V and p.S373R) and early developmental delay with a progressive complex phenotype characterized by spastic paraplegia, peripheral sensorimotor neuropathy, intellectual disability, and sensorial dysfunctions with severe optic atrophy and hearing involvement. Brain imaging showed progressive global cerebellar atrophy.

We propose that complex hereditary spastic paraplegia, with axonal and demyelinating polyneuropathy, sensorial impairment and intellectual disability might suggest MAG mutations.

SOURCE: Ann Clin Transl Neurol. 2019 Aug;6(8):1572-1577. doi: 10.1002/acn3.50860. Epub 2019 Jul 27. © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. PMID: 31402626

Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!

Roubertie A1,2,3, Charif M4, Meyer P1,5, Manes G2, Meunier I2,3, Taieb G6, Junta Morales R6, Guichet A7, Delettre C2, Sarzi E2, Leboucq N8, Rivier F1,5, Lenaers G4.

1 Département de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France.

2 Institut des Neurosciences de Montpellier, INSERM U1051, Université de Montpellier, France.

3 Centre of Reference for Genetic Sensory Diseases, CHU Gui de Chauliac, Montpellier, France.

4 MitoLab, UMR CNRS 6015, INSERM 1083, Université d’Angers, 49933, Angers, France.

5 PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France.

6 Département de Neurologie, CHU Gui de Chauliac, Montpellier, France.

7 Department of Biochemistry and Genetics, Angers University Hospital, Angers, France.

8 Département de Neuroradiologie, CHU Gui de Chauliac, 34 295, Montpellier, France.



New pathogenic variant in ZFYVE26/Spastizin gene discovered

Associated with SPG15



Hereditary spastic paraplegia (HSP) is a group of rare neurodegenerative disorder with genetic and clinical heterogeneity. It has autosomal dominant (AD), autosomal recessive (AR) and X-linked forms. HSPs are clinically classified into ‘pure’ and ‘complicated’ (complex) forms. SPG11 (KIAA1840) and SPG15 (ZFYVE26) are the most common ARHSPs with thin corpus callosum (TCC). They typically present with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life.

Here, we present a patient girl, born to a couple who were first cousins, was admitted to the pediatric neurology outpatient clinic at 14 years of age because of walking with help, dysarthria and forgetfulness. Her examination revealed a motor mental retardation, bilateral leg spasticity, increased deep tendon reflexes in lower limbs, bilateral pigmentary retinopathy; TCC and white matter hyperintensities on brain MRI, sensorimotor axonal polyneuropathy findings in lower limbs on electromyography.

Based on the clinical features and the imaging studies, the diagnosis of HSP was suspected. Targeted next generation sequencing (NGS) was performed using Inherited NGS Panel that consists of 579 gene associated with Mendelian disorders. Analysis of the patient revealed a c.6398_6401delGGGA(p.Arg2133Asnfs*15)(Exon35) homozygous novel change in ZFYVE26 gene.

Genotype-phenotype correlation of HSP is complicated due to heterogeneity. The clinical similarity of HSP types increases the importance of genetic diagnosis. There are few reports about pathogenic variants in ZFYVE26 gene in the literature. This case report is one of the few studies that revealed a novel pathogenic variant in ZFYVE26 gene using NGS.

SOURCE: Int J Neurosci. 2019 Aug 19:1-5. doi: 10.1080/00207454.2019.1653293. [Epub ahead of print] PMID: 31385551

A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene.

Özdemir TR1, Gençpınar P2, Arıcan P3, Öztekin Ö4, Dündar NO2, Özyılmaz B1.

1 Genetic Diagnostic Center, Health Sciences University, Izmir Tepecik Training and Research Hospital , Izmir , Turkey.

2 Department of Pediatric Neurology, Izmir Katip Celebi University , Izmir , Turkey.

3 Department of Pediatric Neurology, Health Sciences University, Izmir Tepecik Training and Research Hospital , Izmir , Turkey.

4 Department of Radiology, Health Sciences University, Izmir Tepecik Training and Research Hospital , Izmir , Turkey.



2 new mutations in HACE1 gene found

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is the HSP type associated with this gene


OBJECTIVE: We aim to characterize the causality and molecular and functional underpinnings of HACE1 deficiency in a mouse model of a recessive neurodevelopmental syndrome called spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). 

METHODS: By exome sequencing, we identified 2 novel homozygous truncating mutations in HACE1 in 3 patients from 2 families, p.Q209* and p.R332*. Furthermore, we performed detailed molecular and phenotypic analyses of Hace1 knock-out (KO) mice and SPPRS patient fibroblasts.

RESULTS: We show that HACE1 KO mice display many clinical features of SPPRS including enlarged ventricles, hypoplastic corpus callosum, as well as locomotion and learning deficiencies. Mechanistically, loss of HACE1 results in altered levels and activity of the small guanosine triphosphate (GTP)ase, RAC1. In addition, HACE1 deficiency results in reduction in synaptic puncta number and long-term potentiation in the hippocampus. Similarly, in SPPRS patient-derived fibroblasts, carrying a disruptive HACE1 mutation resembling loss of HACE1 in KO mice, we observed marked upregulation of the total and active, GTP-bound, form of RAC1, along with an induction of RAC1-regulated downstream pathways.

CONCLUSIONS: Our results provide a first animal model to dissect this complex human disease syndrome, establishing the first causal proof that a HACE1 deficiency results in decreased synapse number and structural and behavioral neuropathologic features that resemble SPPRS patients.

SOURCE: Neurol Genet. 2019 Apr 29;5(3):e330. doi: 10.1212/NXG.0000000000000330. eCollection 2019 Jun. PMID: 31321300

HACE1 deficiency leads to structural and functional neurodevelopmental defects.

Nagy V1, Hollstein R1, Pai TP1, Herde MK1, Buphamalai P1, Moeseneder P1, Lenartowicz E1, Kavirayani A1, Korenke GC1, Kozieradzki I1, Nitsch R1, Cicvaric A1, Monje Quiroga FJ1, Deardorff MA1, Bedoukian EC1, Li Y1, Yigit G1, Menche J1, Perçin EF1, Wollnik B1, Henneberger C1, Kaiser FJ1, Penninger JM1.

1   IMBA (V.N., T.-P.P., P.M., A.K., I.K., R.N., J.M.P.), Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter Campus, Austria; Department of Medical Genetics (J.M.P.), Life Science Institute, University of British Columbia, Vancouver, Canada; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (V.N., E.L.), Vienna, Austria; Section for Functional Genetics at the Institute of Human Genetics (R.H., F.J.K.), University of Lübeck; German Center for Cardiovascular Research (DZHK e.V.) (F.J.K.), Partner Site Hamburg/Kiel/Lübeck, Lübeck; Institute of Cellular Neurosciences (M.K.H., C.H.), University of Bonn Medical School, Germany; Centre for Neuroendocrinology (M.K.H.), Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Department of Neurophysiology and Neuropharmacology (A.C., F.J.M.Q.), Center for Physiology and Pharmacology, Medical University of Vienna, Austria; Drug Safety and Metabolism (R.N.), IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Division of Genetics and the Roberts Individualized Medical Genetics Center (M.A.D., E.C.B.), Children’s Hospital of Philadelphia, PA; Departments of Pediatrics (M.A.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Institute of Human Genetics (Y.L., G.Y., B.W.), University Medical Center Göttingen, Germany; Institute of Neurology (C.H.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) (C.H.), Bonn, Germany; Zentrum für Kinder- und Jugendmedizin (G.C.K.), Neuropädiatrie, Klinikum Oldenburg, Germany; Department of Medical Genetics (E.F.P.), Faculty of Medicine, Gazi University, Ankara, Turkey; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (P.B., J.M.), Vienna, Austria.



New mutation found in SPG20 gene SPART

Detailed examination of the cellular impairments caused



Loss-of-function mutations in the SPART gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. SPART encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance.

Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the SPART gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca2+ homeostasis that was restored after transient expression of wild-type Spartin.

Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in SPART leads to a profound bioenergetic imbalance.

SOURCE: FASEB J. 2019 Aug 7:fj201802722Rdoi: 10.1096/fj.201802722R. [Epub ahead of print] PMID: 31314595

A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.

Diquigiovanni C1, Bergamini C2, Diaz R3, Liparulo I2, Bianco F1, Masin L2, Baldassarro VA4, Rizzardi N2, Tranchina A1, Buscherini F1, Wischmeijer A5, Pippucci T1, Scarano E6, Cordelli DM7, Fato R2, Seri M1, Paracchini S3, Bonora E1.

1 Department of Medical and Surgical Sciences (DIMEC), St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

2 Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.

3 School of Medicine, University of St. Andrews, St. Andrews, United Kingdom.

4 IRET Foundation, Ozzano Emilia, Bologna, Italy.

5 Department of Pediatrics, Clinical Genetics Service, Regional Hospital of South Tyrol, Bolzano, Italy.

6 Rare Disease Unit, Department of Pediatrics, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

7 Child Neurology and Psychiatry Unit, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.



New mutation identified in SPG3A ATL1 gene

Associated with hearing loss



Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72).

Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations.


A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord.

The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation.


We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

SOURCE: World J Clin Cases. 2019 Jun 6;7(11):1358-1366. doi: 10.12998/wjcc.v7.i11.1358. PMID: 31236401

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature.

Xiao XW1, Du J1, Jiao B1, Liao XX2, Zhou L1, Liu XX1, Yuan ZH1, Guo LN1, Wang X1, Shen L1, Lin ZY3.

1 Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.

2 Department of Geriatrics Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.

3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China. [email protected].


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