MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Hourani, Roula; El-Hajj, T.; Barada, Wissam; Hourani, Mukbil; Yamout, Bassem

doi:10.3174/ajnr.a1483

Cited by 46 publications

(36 citation statements)

References 33 publications

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“…Several recent studies using conventional MRI scans revealed an atrophic or dysplastic corpus callosum in different HSP subtypes such as SPG11 ‐asssociated complicated ARHSP or SPG4 ‐associated pure autosomal dominant HSP 39–42. In this context, our findings of a subtle reduction of white matter integrity in the corpus callosum of heterozygote SPG7 ‐ARHSP carriers may suggest that different HSP‐related genes share a common biological pathway leading to neurodegeneration of the corpus callosum 43…”

Section: Discussionsupporting

confidence: 54%

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

Warnecke¹,

Duning²,

Schirmacher³

et al. 2010

Movement Disorders

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Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult-onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss-of-function of the paraplegin-AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7-HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP.

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Section: Discussionsupporting

confidence: 54%

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

Warnecke¹,

Duning²,

Schirmacher³

et al. 2010

Movement Disorders

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“…White matter changes are present in FAHN and are also a core element of leukodystrophies. Presence of a thin corpus callosum seen in FAHN is also a hallmark feature in some of the HSPs [113]. …”

Section: Fa2h-associated Neurodegeneration (Fahn)/ Spg35mentioning

confidence: 99%

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Schneider¹,

Dušek²,

Hardy³

et al. 2013

Current Neuropharmacology

104

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Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic. Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

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“…[2][3][4] Autosomal recessive forms of HSP comprise mainly 'complicated' clinical types with extensive neurological and non-neurological manifestations. [5][6][7] The majority of HSP genes are associated with very rare or even unique clinical forms.…”

Section: Introductionmentioning

confidence: 99%

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

et al. 2014

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Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for B80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G4A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

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MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Cited by 46 publications

References 33 publications

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

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