Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype

Haberlová, Jana; Claeys, Kristl G.; Zámečnı́k, Josef; Jonghe, Peter De; Seeman, Pavel

doi:10.1007/s00415-008-0598-z

Cited by 13 publications

(6 citation statements)

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“…However, previous reports have shown the existence of some severe symptoms in HSPs-SPG3A patient. For example, Haberlova et al reported a HSPs-SPG3A patient with a severe and early complicated phenotype, which was caused by the M408T mutation in ATL1 gene [25]. Furthermore, a de novo G409D mutation in the ATL1 gene exhibited an extremely severe spastic paraplegia combined with general hypertonia and hypokinesia since the neonatal period in one patient [47].…”

Section: Discussionmentioning

confidence: 99%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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“…For example, SPG4 HSP, initially considered to be prototypical of uncomplicated HSP, has been associated with mental retardation and dementia [46, 197, 232, 243], ataxia [169] , thin corpus callosum [174], and muscle wasting [157, 175]. Similarly, SPG3A, which usually manifests as childhood onset, uncomplicated autosomal dominant HSP, has been associated with motor-sensory axonal neuropathy, distal wasting, and thin corpus callosum [56, 90, 116, 176]. Conversely, although autosomal recessive SPG7 (paraplegin mutation) and SPG11 (spatacsin mutation) usually manifest as “complicated HSP syndromes” (with ataxia being frequent in SPG7 HSP and mental retardation being frequent in SPG11 HSP), both of these types of HSP may also manifest as “uncomplicated” spastic paraplegia syndromes.…”

Section: Clinical Classificationmentioning

confidence: 99%

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms

2013

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Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000 [39, 70, 77, 154, 185]. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Post mortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); mitochondrial function (e.g. SPG13/chaperonin 60/heat shock protein 60, SPG7/paraplegin; and mitochondrial ATP6; 4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); 5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin) [113-115], “mutilating sensory neuropathy with spastic paraplegia” due to CcT5 mutation and presumably SPG18/ERLIN2); 6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); 7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and 8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders. For recent review of HSP including historical descriptions, differential diagnosis, and additional references see [78].

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“…More than 20 mutations in ATL1 have been reported in patients and families exhibiting a pure spastic paraplegia phenotype (SPG3A) with usually early disease onset but variable penetrance. SPG3A is caused by a length‐dependant axonopathy of the corticospinal motor neurons [12,20]. However, occasional involvement of the peripheral nerves has also been described [12,14,21–25] with some of the patients having axonal motor and sensory neuropathies [12,14,22,26].…”

Section: Discussionmentioning

confidence: 99%

“…It may be caused by mutations in the serine palmitoyltransferase long chain subunit 1 and 2 genes ( SPTLC1 [6,7], SPTLC2 [8]) and in the Ras‐related GTPase RAB7 gene [9,10]. Very recently, we have shown that mutations in the atlastin‐1 ( ATL‐1) gene, which is known to be frequently mutated in early‐onset pure hereditary spastic paraplegia ((SPG3A) (OMIM 182600) [11–16], can also result in an HSN I phenotype [17].…”

Section: Introductionmentioning

confidence: 99%

The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features

Leonardis

Auer‐Grumbach

Papić

et al. 2012

Euro J of Neurology

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Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype

Cited by 13 publications

References 10 publications

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms

The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features

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