Mitochondrial impairment the cause
Autosomal recessive SPG57 complex HSP was found in two separate families, confirming earlier findings in a single small family. Mutations in the TFG gene were discovered and a study of cultured neurons showed mitochondrial fragmentation, the extent of which correlated with clinical severity. Other mutations in the TFG gene are responsible for dominantly inherited Charcot Marie Tooth type 2 and Hereditary Motor Sensory Neuropathy, Proximal.
Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy.
Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity.
Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions.
SOURCE: Hum Mutat. 2016 Nov;37(11):1157-1161. doi: 10.1002/humu.23060. Epub 2016 Aug 30. © 2016 WILEY PERIODICALS, INC. PMID: 27492651 DOI: 10.1002/humu.23060
Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.
Harlalka GV1, McEntagart ME2, Gupta N3, Skrzypiec AE4, Mucha MW4, Chioza BA1, Simpson MA5, Sreekantan-Nair A1, Pereira A6, Günther S7, Jahic A7, Modarres H6, Moore-Barton H2, Trembath RC5, Kabra M3, Baple EL1, Thakur S8, Patton MA2, Beetz C9, Pawlak R4, Crosby AH1.
1 University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
2 Medical Genetics Unit, Floor 0, Jenner Wing, St. George’s University of London, Cranmer Terrace, London, UK.
3 Division of Genetics, Department of Pediatrics, Old O.T. Block, All India Institute of Medical Sciences, New Delhi, India.
4 Laboratory of Neuronal Plasticity and Behaviour, University of Exeter Medical School, University of Exeter, Exeter, UK.
5 Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Hospital, London, UK.
6 Department of Neurology, Atkinson Morley Wing, St. George’s Hospital, Tooting, London, UK.
7 Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
8 Department of Genetics and Fetal Medicine, Fortis La femme, S-549, New Delhi, India.
9 Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany. [email protected]