Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar
involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations

ANTENORA, ANTONELLA

BILO, LEONILDA

CRISCUOLO, CHIARA

de Leva M.F.

DE MICHELE, GIUSEPPE

FILLA, ALESSANDRO

Longo D.

Pappatà S.

PELUSO, SILVIO

QUARANTELLI, MARIO

Santorelli F.M.

Tessa A.

English

Pappatà S.

Archivio della ricerca - Università degli studi di Napoli Federico II

ORIGINAL COMMUNICATIONComplex phenotype in an Italian family with a novel mutationin SPG3AMaria Fulvia de Leva Æ Alessandro Filla Æ Chiara Criscuolo Æ Alessandra Tessa ÆSabina Pappatà Æ Mario Quarantelli Æ Leonilda Bilo Æ Silvio Peluso ÆAntonella Antenora Æ Dario Longo Æ Filippo M. Santorelli Æ Giuseppe De MicheleReceived: 3 June 2009 / Revised: 11 August 2009 / Accepted: 25 August 2009 / Published online: 19 September 2009! Springer-Verlag 2009Abstract Mutations in the SPG3A gene represent a sig-nificant cause of autosomal dominant hereditary spasticparaplegia with early onset and pure phenotype. Wedescribe an Italian family manifesting a complex pheno-type, characterized by cerebellar involvement in the pro-band and amyotrophic lateral sclerosis-like syndrome inher father, in association with a new mutation in SPG3A.Our findings further widen the notion of clinical hetero-geneity in SPG3A mutations.Keywords Hereditary spastic paraplegias ! SPG3A !Amyotrophic lateral sclerosisIntroductionHereditary spastic paraplegias (HSP) are a group of neu-rodegenerative diseases characterized by progressivespasticity in the lower limbs, presenting either in isolation(‘‘pure’’) or associated with a wide array of additionalfeatures (‘‘complicated’’ forms), and great genetic hetero-geneity sustained by the identification of 39 loci, 19 ofwhich are described in autosomal dominant (AD) kindreds(HUGO database, www.genenames.org).The SPG3A form of ADHSP typically presents with apure phenotype, early onset and benign prognosis. TheSPG3A gene is mutated in approximately 10% of ADHSPfamilies, and it is considered the most common cause ofearly-onset ADHSP [1].We report peculiar phenotypic features of two patientsfrom an Italian family carrying a novel SPG3A mutation.Written informed consent was obtained for both patients.Patients and methodsCase 1A 39-year-old woman had experienced progressive walk-ing disturbance since 5 years of age. Her neurologicalexamination showed spastic gait, lower limb spasticity andproximal weakness, four-limb hyperreflexia, positive jawjerk reflex, bilateral Troemner, ankle clonus and Babinskisigns. Slight bilateral dysmetric finger-to-nose testing anddysdiadochokinesia were also present. There were nosphincter or cognitive disturbances. The neurophysiologicstudy showed normal motor and sensitive nerve conductionvelocities (M- and S-NCV), normal brainstem auditory andvisual evoked potentials; absent somatosensory and motorevoked potentials (SSEP and MEP) from the lower limbs.Brain MRI revealed mild vermis atrophy and wide frontalsubarachnoid spaces (Fig. 1a). Cerebral [18F]-fluorodeox-iglucose PET showed hypometabolism in the cerebellumand the dorsolateral frontal cortex (Fig. 1b).M. F. de Leva (&) ! A. Filla ! C. Criscuolo ! L. Bilo !S. Peluso ! A. Antenora ! G. De MicheleDepartment of Neurological Sciences, Federico II University,Via S. Pansini 5, 80131 Naples, Italye-mail: marulvia@hotmail.comS. Pappatà ! M. QuarantelliNational Research Council/Department of Biomorphologicaland Functional Sciences, Biostructure and Bioimaging Institute,Federico II University, Naples, ItalyA. Tessa ! F. M. SantorelliMolecular Medicine, IRCCS Bambino Gesù Hospital,Rome, ItalyD. LongoDepartment of IFM Chemistry and Molecular Imaging,University of Turin, Turin, Italy123J Neurol (2010) 257:328–331DOI 10.1007/s00415-009-5311-3Case 2The 70-year-old father of the patient described in Case 1had 3-year progressive weakness of the right leg, leading tothe need of a cane. His neurological examination, at the ageof 68 years, revealed weakness, wasting, and sporadicfasciculations in the lower limbs, particularly on the rightside where he had foot drop. Tendon reflexes were briskwith left side prevalence and left ankle clonus, while rightankle reflex was absent; the plantar responses were flexor.Mental status, cranial nerves, sensory system, coordination,muscle tonus, and upper limb strength were normal. Theneurophysiologic evaluation showed a severe decrease ofright external popliteal sciatic nerve muscle action poten-tial amplitude on MNCV; chronic denervation on EMG ofdifferent muscles (right biceps brachii, right and left firstdorsal interosseous, left vastus medialis, right and leftanterior tibialis, right internal gastrocnemius), signs ofactive denervation at the lower limbs, normal genioglossusEMG; prolonged central conduction time on SSEP andnormal MEP. Brain MRI was unremarkable; spine MRIshowed several disc protrusions, more evident at L4-S1levels. At that time he received the diagnosis of clinicallyprobable-laboratory supported amyotrophic lateral sclero-sis (ALS).Recently he developed progressive dyspnea with theneed for a respiratory assistive device and severe impair-ment of fine hand movements. A recent EMG confirmedsigns of active denervation even in the upper limbs (rightand left first dorsal interosseous, left deltoid).Molecular analysesSequencing the SPG3A gene coding exons and flankingintronic regions disclosed a novel heterozygous missensemutation in exon 12 at nucleotide c.1247 G[A(p.Arg416His) (Fig. 2a). Arginine 416 is highly conservedamong species (Fig. 2b) and Polyphen modelling analysis(http://genetics.bwh.harvard.edu/pph/) predicts the aminoacid substitution to be possibly damaging, with a position-specific independent counts (PSIC) score difference of1.756.The mutation was found also in case 2 but not in 25ADHSP patients, in 50 sporadic cases nor in 250 Italianhealthy controls. Multiplex ligation-dependent probeamplification [probe mixtures P165-HSP-B1 and P211-B2HSP [MRC-Holland, The Netherlands)] [2], denaturinghigh performance liquid chromatography and directsequencing of SPG4 [3] in case 1 did not detect anypathogenic changes. Also, mutations in NIPA1/SPG6,KIF5A/SPG10, REEP1/SPG31, and BSCL2/SPG17 hadbeen ruled out [4]. We have also excluded Krabbe diseasein the proband by b-galactocerebrosidase activity estima-tion (5.4 nmol/h/mgP; normal value 2.0–6.0). The twosiblings of the proband refused both clinical and molecularassessment.Fig. 1 Axial and sagittal slices of MRI T1 weighted images (a) and[18F] FDG PET scans (b) in case 1. Images were normalised in theMontreal Neurological Institute space using SPM2 (WellcomeDepartment of Imaging Neuroscience, London, UK). MRI showsenlargement of the IV ventricle and mild cerebellar vermis atrophy.The [18F] FDG cerebral distribution appears reduced in the cerebel-lum, mainly in the vermis. Slight hypometabolism is evident in theprefrontal cortex. L left side; R right sideJ Neurol (2010) 257:328–331 329123A homology model of region encompassing residues67–436 in atlastin-1 was also built up using the MOE(molecular operating environment 2006, www.chemcomp.com) software package (Fig. 2c).DiscussionWe detected a novel mutation (c.1247 G[A) in exon 12 ofthe SPG3A gene in an Italian patient with HSP. Thismutation was also found in her father who presented with apeculiar ALS-like phenotype. SPG3A encodes atlastin-1, adynamin/guanylate-binding protein with transmembranedomains, likely involved in membrane trafficking andaxonal development [5]. Of the SPG3A mutations descri-bed so far, about 35% are located in exon 12 [1]. Themutation here detected causes an arginine to histidinesubstitution in a conserved motif for protein kinase Cphosphorylation according to the Prosite search [6], in themiddle of an alpha helix near the C-terminus, just beforethe transmembrane domain (Fig. 2c). It lies far from thecatalytic GTPase domain, suggesting a possible role inmembrane association or oligomerization.To date there is convincing evidence that the ‘‘appar-ently’’ pure phenotype of patients harboring mutations inSPG4 might also be complicated by additional neurologicalfeatures, including cerebellar involvement and thin corpuscallosum [7] and dysarthria and ataxia with reducedregional cerebellar blood flow at PET scan [8]. Case 1showed clinical and neuroimaging features that suggest acerebellar involvement also in SPG3A, possibly related tothis novel mutation.There are some reports of an ALS-like phenotype inpatients with mutations in SPG4. These include a case ofrapidly progressive spinal and bulbar upper motor neuronsyndrome [9] and that of a patient with early onset ALSand long term survival [10]. Also, in a large screen of HSPpatients, neurophysiologic evidence of lower motor dys-function was recorded in a subgroup of individuals har-boring mutations in SPG4, one of whom showedprogressive bulbar dysfunction and respiratory insuffi-ciency [11]. Even more recently, a new SPG4 mutation hasbeen associated with the clinical features of the Silversyndrome (MIM #270685) which includes distal amyo-trophies [12]. There are only two reports of axonal sensory-motor neuropathy in SPG3A families [13, 14]. Case 2showed clinical and neurophysiologic evidence of upperand lower motor syndrome, fulfilling the El Escorialdiagnostic criteria for clinically probable-laboratory sup-ported ALS (www.wfnals.org). The relationship betweenthe novel SPG3A mutation and ALS-like phenotype in thispatient remains unclear. It seems possible to hypothesizeeither a double-trouble phenotype in a carrier of a mutationin SPG3A or that an ALS-like phenotype is an additional,A C B Fig. 2 a Electropherogram of the sequences flanking residue R416 inthe patient (upper panel) and a normal control (bottom panel). Anarrow indicates the p.Arg416His mutation. The sequence reported isin the inverse direction. b Species alignments of 60 human atlastinamino acids showing the conservation of residue R416 (boxed)(GeneBank accession num.: NP 056999.2, XP 533252.2, NP848743.1, NP 056999.2, XP 863862.1, NP 001072222). c Mutatedhomology model of the V67-N436 sequence of human atlastinisoform ‘‘a’’ was built up using the MOE package starting from thecrystal structures of human guanylate-binding protein 1 (hGBP1 PDB1DG3 [15]). His416 is located in the helical domain330 J Neurol (2010) 257:328–331123though rare, clinical manifestation of the novelp.Arg416His variant. Less likely, SPG3A mutations mightincrease susceptibility for ALS.Although further studies are required to clarify theseissues, it seems useful to alert neurologists to this possiblecomorbid association and, more importantly, to call for acomplete neuroimaging assessment even in ‘‘pure’’ADHSP patients.Acknowledgments The authors are grateful to the patients and toDr. P. Formichi (Operative Unit of Neurology and NeurometabolicDiseases, University of Siena, Italy) for the galactocerebrosidase assay.References1. Namekawa M, Ribai P, Nelson I et al (2006) SPG3A is the mostfrequent cause of hereditary spastic paraplegia with onset beforeage 10 years. Neurology 66:112–1142. Beetz C, Nygren AO, Schickel J et al (2006) High frequency ofpartial SPAST deletions in autosomal dominant hereditary spasticparaplegia. Neurology 67:1926–19303. Patrono C, Scarano V, Cricchi F et al (2005) Autosomal dominanthereditary spastic paraplegia: DHPLC-based mutation analysis ofSPG4 reveals eleven novel mutations. Hum Mutat 25:5064. Tessa A, Silvestri G, de Leva MF et al (2008) A novel KIF5A/SPG10 mutation in spastic paraplegia associated with axonalneuropathy. J Neurol 255:1090–10925. Stevanin G, Ruberg M, Brice A (2008) Recent advances inthe genetics of spastic paraplegias. Curr Neurol Neurosci Rep8:198–2106. Zhao X, Alvarado D, Rainier S et al (2001) Mutations in a newlyidentified GTPase gene cause autosomal dominant hereditaryspastic paraplegia. Nat Genet 29:326–3317. Orlacchio A, Kawarai T, Totaro A et al (2004) Hereditary spasticparaplegia: clinical genetic study of 15 families. Arch Neurol61:849–8558. Nielsen JE, Johnsen B, Koefoed P et al (2004) Hereditary spasticparaplegia with cerebellar ataxia: a complex phenotype associ-ated with a new SPG4 gene mutation. Eur J Neurol 11:817–8249. Brugman F, Wokke JH, Scheffer H et al (2005) Spastin mutationsin sporadic adult-onset upper motor neuron syndromes. AnnNeurol 58:865–86910. Meyer T, Schwan A, Dullinger JS et al (2005) Early-onset ALSwith long-term survival associated with spastin gene mutation.Neurology 65:141–14311. McDermott CJ, Burness CE, Kirby J et al (2006) Clinical featuresof hereditary spastic paraplegia due to spastin mutation. Neu-rology 67:45–5112. Orlacchio A, Patrono C, Gaudiello F et al (2008) Silver syndromevariant of hereditary spastic paraplegia: a locus to 4p and allelismwith SPG4. Neurology 70:1959–196613. Scarano V, Mancini P, Criscuolo C et al (2005) The R495Wmutation in SPG3A causes spastic paraplegia associated withaxonal neuropathy. J Neurol 252:901–90314. Ivanova N, Claeys KG, Deconinck T et al (2007) Hereditaryspastic paraplegia 3A associated with axonal neuropathy. ArchNeurol 64:706–71315. Prakash B, Praefcke GJ, Renault L, Wittinghofer A, Herrmann C(2000) Structure of human guanylate-binding protein 1 repre-senting a unique class of GTP-binding proteins. Nature 403:567–571J Neurol (2010) 257:328–331 331123

Complex phenotype in an Italian family with a novel mutation in SPG3A.

https://www.iris.unina.it/bitstream/11588/359547/1/SPG3A.pdf

Complex phenotype in an Italian family with a novel mutation in SPG3A.

Abstract

Similar works

Full text

Available Versions

Archivio della ricerca - Università degli studi di Napoli Federico II