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Expanded phenotype in a patient with spastic paraplegia 7.

ABSTRACT: Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.

SUBMITTER: Gass J

PROVIDER: S-EPMC5628248 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Expanded phenotype in a patient with spastic paraplegia 7.

Gass Jennifer J Blackburn Patrick R PR Jackson Jessica J Macklin Sarah S van Gerpen Jay J Atwal Paldeep S PS

Clinical case reports 20170824 10

Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in <i>SPG7</i>. ...[more]

PMID: 29026558

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Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7).

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A patient-derived neural stem cell model for hereditary spastic paraplegia

Project description:Hereditary Spastic Paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPG4 are a major cause of autosomal-dominant HSP. Spastin, the protein encoded by SPG4, is a microtubule-severing protein and is enriched in the distal axon of corticospinal motor neurons which degenerate in HSP patients. How SPG4 mutations cause axon degeneration in patients is not understood. Multipotent neural stem cells, accessible from patient olfactory mucosa biopsies, provided a new patient-derived cell models for HSP. Olfactory neurosphere-derived cells were obtained from cohorts of HSP patients with, and without, mutations in SPG4 and from healthy controls. Patient cells had extensive changes in expression of cell cycle-related genes and in genes associated with microtubule formation. Despite this, cell proliferation and metabolic functions of the patient cells were similar to controls. Cells with mutated SPG4 had significantly less spastin and acetylated tubulin but significantly more stathmin, a tubulin-depolymerising protein. These cells also significant deficits in the intracellular distribution of peroxisomes and mitochondria, compared to control cells. This model reveals that SPG4-HSP patient-derived neural stem/progenitors compensate for the cell cycle-related effects of reduced spastin levels in the nucleus, in part by large changes in gene expression, but failed to correct deficits in organelle trafficking. The results raise the question of whether these deficits arise directly from the loss of spastin or indirectly from the compensation. Patient-derived olfactory stem cells provide a new model for examining the neural consequences of human genetic mutations in their natural setting: at normal gene dosages against normal genetic backgrounds.

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Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.

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Reply: Spastic paraplegia in ‘dominant optic atrophy plus’ phenotype due to OPA1 mutation.

Project description: Not available

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Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype.

Project description:BackgroundHereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.MethodsWhole-exome sequencing was done in a Canada-wide HSP cohort.ResultsThree additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.ConclusionOur study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.

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GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

| PRJNA313999 | ENA

Spastic paraplegia as the predominant phenotype in a cohort of Chinese patients with adrenoleukodystrophy.

Project description:BackgroundX-linked adrenoleukodystrophy (ALD) is one of the most common peroxisomal disorders characterized by abnormal accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues and caused by mutations within ABCD1. Clinically, ALD present with various phenotypes, ranging from asymptomatic type to rapidly progressive childhood cerebral form. However, no remarkable abnormality in cerebral white matter usually makes it difficult to distinguish adult ALD from hereditary spastic paraplegia (HSP).MethodsWe analyzed the features of seven Chinese ALD patients who had a primary phenotype of spastic paraplegia. Sequencing was performed in the probands and their familial members. Detailed clinical, VLCFAs test, hormone test, magnetic resonance imaging, and electromyogram are presented.ResultsWe reported seven ALD patients from a Chinese cohort of 142 HSP patients. Genetic investigations revealed five known ABCD1 mutations (c.346G>C, c.521A>G, c.829G>T, c.1415_1416delAG, and c.1849C>T) and two novel mutations (c.454C>G, c.1452_1482del). Further auxiliary testing revealed that they had higher VLCFA and/or adrenal insufficiency.ConclusionsOur findings expand the mutation spectrum of ABCD1 and indicate that ALD represent a significant portion (4.9%, 7/142) of the spastic paraplegia entities. ALD should be considered in male patients with spastic paraplegia, even if there was no positive family history.

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