A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23

Dick, Katherine; Al-Mjeni, Rayhanah; Baskir, W; Koul, Roshan; Simpson, Michael A.; Patton, Michael A.; Raeburn, Sandy; Crosby, Andrew H.

doi:10.1212/01.wnl.0000319610.29522.8a

Cited by 50 publications

(29 citation statements)

References 18 publications

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“…6,8 In contrast, patients homozygous for amino-acid substitutions (eg, p.R235C and p.D35Y) generally had milder phenotypes comprising only spastic paraplegia and mild cognitive decline. [4][5][6] Our patient, with a combination of a null deletion and a missense substitution, displayed an intermediate phenotype.…”

Section: Discussionmentioning

confidence: 72%

“…14 Of note, another family with a homozygous mutation affecting the adjacent amino acid (p.R235C) had enzyme activity that was decreased by 20-40%. 4,6 Both F236 and R235 are highly conserved across genera including mice, the frog X. laevis, the plant A. thaliana, and the yeast S. cerevisiae (Figure 1), and thus are likely to be important for FA2H function.…”

Section: Discussionmentioning

confidence: 99%

“…2, 3 Similar findings are seen in affected humans with FA2H deficiency, manifesting with several demyelinating phenotypes including spastic paraplegia type 35 (SPG35; MIM#612319), 'leukodystrophy, dysmyelinating, and spastic paraparesis with or without dystonia' (MIM#612443), or neurodegeneration with brain iron accumulation. [4][5][6][7][8] These are collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN).…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6][7][8] Several consanguineous families have been described with different combinations of these features, with the inconsistent features possibly reflecting the effects of homozygous mutations in other genes modifying the phenotypes. [4][5][6][7][8] Alternatively, the amount of residual enzyme activity may be having a role, with individuals possessing a complete loss of FA2H activity having more severe neurodegeneration than individuals with residual FA2H activity. We describe an outbred individual with FAHN who possesses several typical clinical features of the disorder; however, he also has an axonal sensory neuropathy not previously associated with FAHN.…”

Section: Introductionmentioning

confidence: 99%

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Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

et al. 2011

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Fatty acid hydroxylase-associated neurodegeneration due to fatty acid 2-hydroxylase deficiency presents with a wide range of phenotypes including spastic paraplegia, leukodystrophy, and/or brain iron deposition. All previously described families with this disorder were consanguineous, with homozygous mutations in the probands. We describe a 10-year-old male, from a non-consanguineous family, with progressive spastic paraplegia, dystonia, ataxia, and cognitive decline associated with a sural axonal neuropathy. The use of high-throughput sequencing techniques combined with SNP array analyses revealed a novel paternally derived missense mutation and an overlapping novel maternally derived B28-kb genomic deletion in FA2H. This patient provides further insight into the consistent features of this disorder and expands our understanding of its phenotypic presentation. The presence of a sural nerve axonal neuropathy had not been previously associated with this disorder and so may extend the phenotype.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

et al. 2011

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“…To date, 15 genes and more than 20 additional loci have been identified for autosomal dominant (AD), autosomal recessive and X-linked forms of HSP [5,7]. The spastin gene (SPG4) mutation is the most frequent cause of AD HSP (around 40% of families) and is also frequent in sporadic HSP (13%), but not in PLS [3].…”

Section: Sirsmentioning

confidence: 99%

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

et al. 2009

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Molecular Genetics of Hereditary Spastic Paraplegias

Novelli

Contino

2009

Encyclopedia of Life Sciences

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Hereditary spastic paraplegias (HSPs) are a group of single‐gene disorders in which the axons of the corticospinal tract either fail to develop normally or undergo progressive degeneration. The main clinical feature of all HSPs is a bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities, which occurs in relative isolation in pure or uncomplicated HSPs (PHSPs) or in combination with other features in complicated HSPs (CHSPs). So far, about 40 different chromosomal HSP loci have been identified by genetic linkage analysis and an increasing number of gene mutations are being identified, representing one of the most significant examples of genetic heterogeneity. Autosomal and X‐linked patterns of inheritance, both dominant and recessive, have been described. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis. Key Concepts: Hereditary spastic paraplegias (HSP) are a group of single‐gene disorders characterized by bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities (pure or uncomplicated HSPs). The phenotype can be complicated by additional features (complicated HSPs). HSPs affect 1/10 000 individuals. Pathogenesis depends on abnormalities in intracellular trafficking, trasnsport and endocytosis, neural cell recognition and signalling, myelination and mitochondrial proteins. About 40 different chromosomal loci and 20 genes have been identified indicating the extraordinarly strong genetic heterogeneity. Patterns of inheritance include autosomal and X‐linked, both recessive and dominant. Mutations in Spastin (SPG4) account for approximately 40% of autosomal dominant HSPs, and more then any other HSP defect. Autosomal recessive HSP account for approximately 15–20% of all types of HSPs. Genotype–phenotype correlation and penetrance can be extremely variable even among the same family and/or gene defect. Genetic counselling is particularly challenging because of genetic heterogeneity and should take in consideration pattern of inheritance, geographical epidemiology and clinical evaluation with a multidisciplinary approach. To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.

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A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23

Abstract: We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.

Cited by 50 publications

References 18 publications

Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

Molecular Genetics of Hereditary Spastic Paraplegias

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