Hereditary spastic paraplegias (HSP) are heterogeneous disorders, with more than 70 causative genes. Variants in SPAST are the most frequent genetic etiology and are responsible for spastic ...paraplegia type 4 (SPG4). Age at onset can vary, even between patients from the same family, and incomplete penetrance is described. Somatic mosaicism is extremely rare with only three patients reported in the literature. We report here SPAST mosaic variants in four unrelated patients. We confirm that mosaicism in SPAST is a very rare event with only four identified cases on more than 300 patients with a SPAST variant previously described by our clinical diagnostic laboratory.
Keywords: spastic paraplegia 48; hereditary spastic paraplegia; AP5Z1; epileptic seizures; rare disease; whole exome sequencing; SPG48 Article Note: M.B., J.H., V.C., G.K., H.H., and G.S. contributed ...equally to this work. Relevant conflicts of interest/financial disclosures: M.B. has received a research grant from the European Academy of Neurology (EAN) and travel grants from Merck, Teva, Genesis Pharma, Pfizer, and Novartis. G.K. has received research grants from Genesis Pharma and Teva and consultation fees, advisory boards, and honoraria from Genzyme, Genesis Pharma, Teva, and Novartis. J.T. has shares in a diagnostic laboratory (Tzartos Neurodiagnostics) in Athens. All other authors report no disclosures relevant to the manuscript. CAPTION(S): APPENDIX S1. Supplementary Information Byline: Marianthi Breza, Jennifer Hirst, Viorica Chelban, Guillaume Banneau, Laurene Tissier, Bophara Kol, Thomas Bourinaris, Samia A. Said, Yann Pereon, Anna Heinzmann, Rabab Debs, Raul Juntas-Morales, Victoria G. Martinez, Jean P. Camdessanche, Clarisse Scherer-Gagou, Jean-Medard Zola, Alkyoni Athanasiou-Fragkouli, Stephanie Efthymiou, George Vavougios, Georgios Velonakis, Maria Stamelou, John Tzartos, Constantin Potagas, Thomas Zambelis, Caterina Mariotti, Craig Blackstone, Jana Vandrovcova, Theodoros Mavridis, Chrisoula Kartanou, Leonidas Stefanis, Nicholas Wood, Georgia Karadima, Eric LeGuern, Georgios Koutsis, Henry Houlden, Giovanni Stevanin
Hereditary spastic paraplegia refers to rare genetic neurodevelopmental and/or neurodegenerative disorders in which spasticity due to length-dependent damage to the upper motor neuron is a core sign. ...Their high clinical and genetic heterogeneity makes their diagnosis challenging. Multigene panels allow a high-throughput targeted analysis of the increasing number of genes involved using next-generation sequencing. We report here the clinical and genetic results of 1550 index cases tested for variants in a panel of hereditary spastic paraplegia related genes analysed in routine diagnosis. A causative variant was found in 475 patients (30.7%) in 35/65 screened genes. SPAST and SPG7 were the most frequently mutated genes, representing 142 (9.2%) and 75 (4.8%) index cases of the whole series, respectively. KIF1A, ATL1, SPG11, KIF5A and REEP1 represented more than 1% (>17 cases) each. There were 661 causative variants (382 different ones) and 30 of them were structural variants. This large cohort allowed us to obtain an overview of the clinical and genetic spectrum of hereditary spastic paraplegia in clinical practice. Because of the wide phenotypic variability, there was no very specific sign that could predict the causative gene, but there were some constellations of symptoms that were found often related to specific subtypes. Finally, we confirmed the diagnostic effectiveness of a targeted sequencing panel as a first-line genetic test in hereditary spastic paraplegia. This is a pertinent strategy because of the relative frequency of several known genes (i.e. SPAST, KIF1A) and it allows identification of variants in the rarest involved genes and detection of structural rearrangements via coverage analysis, which is less efficient in exome datasets. It is crucial because these structural variants represent a significant proportion of the pathogenic hereditary spastic paraplegia variants (∼6% of patients), notably for SPAST and REEP1. In a subset of 42 index cases negative for the targeted multigene panel, subsequent whole-exome sequencing allowed a theoretical diagnosis yield of ∼50% to be reached. We then propose a two-step strategy combining the use of a panel of genes followed by whole-exome sequencing in negative cases.
Background: PRKN biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinson’s disease (PD). However, the variants responsible for suspected PRKN-PD ...individuals are not always identified with standard genetic testing. Objectives: Identify the genetic cause in two siblings with a PRKN-PD phenotype using long-read sequencing (LRS). Methods: The genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger sequencing, targeted sequencing, whole-exome sequencing and LRS. Results: MLPA and targeted sequencing identified one copy of exon four in PRKN but no other variants were identified. Subsequently, LRS unveiled a large deletion encompassing exon 3 to 4 on one allele and a duplication of exon 3 on the second allele; explaining the siblings’ phenotype. MLPA could not identify the balanced rearrangement of exon 3. Conclusions: This study highlights the potential utility of long-read sequencing in the context of unsolved typical PRKN-PD individuals.
ATL1
-related spastic paraplegia SPG3A is a pure form of hereditary spastic paraplegia. Rare complex phenotypes have been described, but few data concerning cognitive evaluation or molecular imaging ...of these patients are available. We relate a retrospective collection of patients with SPG3A from the Neurology Department of Nancy University Hospital, France. For each patient were carried out a
18
F-FDG PET (positron emission tomography), a electromyography (EMG), a sudoscan®, a cerebral and spinal cord MRI (magnetic resonance imaging) with measurement of cervical and thoracic surfaces, a neuropsychological assessment. The present report outlines standardised clinical and paraclinical data of five patients from two east-France families carrying the same missense pathogenic variation, NM_015915.4(ATL1): c.1483C > T p.(Arg495Trp) in
ATL1
. Mean age at onset was 14 ± 15.01 years. Semi-quantitatively and in comparison to healthy age-matched subjects, PET scans showed a significant cerebellar and upper or mild temporal hypometabolism in all four adult patients and hypometabolism of the prefrontal cortex or precuneus in three of them. Sudoscan® showed signs of small fibre neuropathy in three patients. Cervical and thoracic patients’ spinal cords were significantly thinner than matched-control, respectively 71 ± 6.59mm
2
(
p
= 0.01) and 35.64 ± 4.35mm
2
(
p
= 0.015). Two patients presented with a dysexecutive syndrome. While adding new clinical and paraclinical signs associated with
ATL1
pathogenic variations, we insist here on the variable penetrance and expressivity. We report small fibre neuropathy, cerebellar hypometabolism and dysexecutive syndromes associated with SPG3A. These cognitive impairments and PET findings may be related to a cortico-cerebellar bundle axonopathy described in the cerebellar cognitive affective syndrome (CCAS).
PDF
