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X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis.

ABSTRACT: We present a family in which an initial clinical diagnosis of autosomal dominant pure hereditary spastic paraparesis (HSP) was made on the basis of a three generation pedigree in which both males and females presented with a spastic paraparesis. Subsequent biochemical and genetic analysis revealed that the family was in fact affected by the adrenomyeloneuropathy subtype of X-linked adrenoleukodystrophy. In the family described, both males and females were affected by a spastic paraparesis, and there was no male to male transmission, consistent with both autosomal dominant and X-linked inheritance. This report illustrates the importance of assaying very long chain fatty acids (VLCFAs) in any HSP family where there is no male to male transmission.

SUBMITTER: Shaw-Smith CJ

PROVIDER: S-EPMC1763580 | biostudies-other | 2004 May

REPOSITORIES: biostudies-other

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X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis.

Shaw-Smith C J CJ Lewis S J G SJ Reid E E

Journal of neurology, neurosurgery, and psychiatry 20040501 5

We present a family in which an initial clinical diagnosis of autosomal dominant pure hereditary spastic paraparesis (HSP) was made on the basis of a three generation pedigree in which both males and females presented with a spastic paraparesis. Subsequent biochemical and genetic analysis revealed that the family was in fact affected by the adrenomyeloneuropathy subtype of X-linked adrenoleukodystrophy. In the family described, both males and females were affected by a spastic paraparesis, and t ...[more]

PMID: 15090559

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Project description:ImportanceThe family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.ObjectiveTo identify the genetic cause for a novel form of pure autosomal dominant HSP.Design, setting, and participantsWe examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened.Main outcome and measureMutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene.ResultsWe identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.Conclusions and relevanceThis study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.

Dataset Information

X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis.

Publications

X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis.

Similar Datasets

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