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1.
Acta Neurol Scand ; 138(3): 245-250, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29732542

ABSTRACT

OBJECTIVES: A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. METHOD: The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. RESULTS: A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. CONCLUSIONS: A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.


Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Brain Diseases, Metabolic, Inborn/genetics , Dipeptidases/deficiency , Proteins/genetics , Adult , Amino Acid Metabolism, Inborn Errors/pathology , Amino Acid Metabolism, Inborn Errors/physiopathology , Brain Diseases, Metabolic, Inborn/pathology , Brain Diseases, Metabolic, Inborn/physiopathology , Dipeptidases/genetics , Female , Follow-Up Studies , Humans , Male , Mutation , Pedigree , Phenotype
2.
Eur J Neurol ; 25(7): 943-e71, 2018 07.
Article in English | MEDLINE | ID: mdl-29528531

ABSTRACT

BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.


Subject(s)
Heterozygote , Membrane Proteins/genetics , Mutation , Spastic Paraplegia, Hereditary/genetics , Adult , Female , Humans , Male , Middle Aged , Pedigree
3.
Eur J Neurol ; 23(4): 763-71, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26756429

ABSTRACT

BACKGROUND AND PURPOSE: SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway. METHODS: Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described. RESULTS: The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant. CONCLUSION: SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway.


Subject(s)
Metalloendopeptidases/genetics , Paraplegia/genetics , Spastic Paraplegia, Hereditary/genetics , ATPases Associated with Diverse Cellular Activities , Adolescent , Adult , Child , Humans , Mutation , Norway , Paraplegia/pathology , Paraplegia/physiopathology , Pedigree , Phenotype , Polymorphism, Single Nucleotide , Spastic Paraplegia, Hereditary/pathology , Spastic Paraplegia, Hereditary/physiopathology , Young Adult
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