New HSP mutations discovered

Posted - September 2015 in Research Highlights

Research from US, China, Middle East and Greece

 

Below are the abstracts of four separate research studies over the past quarter in three of which new HSP mutations have been discovered and identified, and in the fourth study a mistaken diagnosis of HSP based on biochemical findings was finally resolved as adrenomyeloneuropathy by genetic testing.

 

SPG56 – autosomal dominant, complicated HSP

AIM:

Hereditary spastic paraplegias (HSP) are a genetically and clinically heterogeneous group of disorders. At present, nineteen autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy.

 

METHODS:

A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis.

 

RESULTS:

All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum LOD score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease producing mutations were detected.

 

CONCLUSION:

We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motorpolyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.

 

SOURCE: Int J Neurosci. 2015 May 22. [Epub ahead of print] PMID: 26000935 [PubMed – as supplied by publisher]

 

Autosomal Dominant Hereditary Spastic Paraplegia with AxonalSensory Motor Polyneuropathy maps to Chromosome 21q22.3.

 

Peddareddygari LR1, Hanna PAIgo RP JrLu YAWon SHirano MGrewal RP.

 

1a The Neuro-genetics Institute, 501 Elmwood Ave, Sharon Hill, Pennsylvania , USA.

 

 

SPG 11 – autosomal recessive, complicated HSP

We used a combined approach of whole-exome sequencing and candidate mutation validation to identify the disease-causing gene in a hereditary spastic paraplegia (HSP) patient with lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum.

 

HSP is a clinically and genetically heterogeneous neurodegenerative disorder characterized by degeneration of the corticospinal tract motor neurons and resulting in progressive lower limb spasticity, often with a complicated phenotype. We identified novel compound heterozygous mutations in the SPG11 gene in this patient as follows: a mutation in exon 32, c.6194C > G transition (p.S2056X) and a novel c.5121+1C > T splicing mutation.

 

Our finding suggests that these novel compound heterozygous mutations in SPG11 are associated with HSP and lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. This study also demonstrates that exome sequencing is an efficient and rapid diagnostic tool for identifying the causes of some complex and genetically heterogeneous neurodegenerative diseases.

 

SOURCE: J Clin Neurosci. 2015 Jul;22(7):1150-4. doi: 10.1016/j.jocn.2015.01.014. Epub 2015 May 21. Copyright © 2015 Elsevier Ltd. All rights reserved. PMID: 26003865 [PubMed – in process]

 

Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes.

 

Li YS1, Mao CY1, Shi CH2, Song B2, Wu J2, Qin J2, Ji Y1, Niu HX1, Luo HY1, Shang DD1, Sun SL1, Xu YM3.

 

  • 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou 450000, Henan, China.
  • 2Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou 450000, Henan, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
  • 3Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou 450000, Henan, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].

 

 

SPG 54 – autosomal recessive, complicated HSP

BACKGROUND:

Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum.

 

RESULTS:

A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.

 

CONCLUSION:

This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

 

SOURCE: BMC Res Notes. 2015 Jun 27;8:271. doi: 10.1186/s13104-015-1227-4. PMID: 26113134 [PubMed – in process] PMCID: PMC4482296

 

Truncating mutation in intracellular phospholipase A gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54).

 

Alrayes N1,2, Mohamoud HS3,4, Jelani M5,6, Ahmad S7, Vadgama N8, Bakur K9, Simpson M10, Al-Aama JY11,12, Nasir J13.

  • 1Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. [email protected]
  • 2Division of Biomedical Sciences (BMS), Human Genetics Research Center, St. George’s University of London (SGUL), London, SW17 0RE, UK. [email protected]
  • 3Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. [email protected]
  • 4Division of Biomedical Sciences (BMS), Human Genetics Research Center, St. George’s University of London (SGUL), London, SW17 0RE, UK. [email protected]
  • 5Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. [email protected]
  • 6Medical Genetics and Molecular Biology Unit, Biochemistry Department, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25000, Pakistan. [email protected]
  • 7Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. [email protected]
  • 8Division of Biomedical Sciences (BMS), Human Genetics Research Center, St. George’s University of London (SGUL), London, SW17 0RE, UK. [email protected]
  • 9Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. [email protected]
  • 10Genetics and Molecular Medicine, King’s College London, Guy’s Hospital, London, SE1 9RT, UK. [email protected]
  • 11Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. [email protected]
  • 12Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. [email protected]
  • 13Division of Biomedical Sciences (BMS), Human Genetics Research Center, St. George’s University of London (SGUL), London, SW17 0RE, UK. [email protected]

 

 

Mistaken diagnosis of HSP: Gene testing established adrenomyeloneuropathy

OBJECTIVES:

To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool.

 

METHODS:

Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband.

 

RESULTS:

NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174_1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented.

 

CONCLUSIONS:

This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis.

 

SOURCE: J Neurol Sci. 2015 Aug 15;355(1-2):199-201. doi: 10.1016/j.jns.2015.05.031. Epub 2015 May 29. Copyright © 2015 Elsevier B.V. All rights reserved.

 

A novel ABCD1 mutation detected by next generation sequencing in presumed hereditary spastic paraplegia: A 30-year diagnostic delay caused by misleading biochemical findings.

 

Koutsis G1, Lynch DS2, Tucci A3, Houlden H2, Karadima G4, Panas M4.

  • 1Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece. Electronic address: [email protected]
  • 2Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
  • 3Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.
  • 4Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece.

 

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