Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Park, Joohyun; Cipriani, Valentina; Demidov, German; Rocca, Clarissa; Senderek, Jan; Butryn, Michaela; Velić, Ana; Lam, Tanya; Galanaki, Evangelia; Calì, Elisa; Vestito, Letizia; Maroofian, Reza; Deininger, Natalie; Rautenberg, Maren; Admard, Jakob; Hahn, Gesa-Astrid; Bartels, Claudius; Os, Nienke J H van; Horváth, Rita; Chinnery, Patrick F.; Tiet, May Yung; Hewamadduma, Channa; Hadjivassiliou, Marios; Tofaris, George K.; Wood, Nicholas; Hayer, Stefanie N.; Bender, Friedemann; Menden, Benita; Cordts, Isabell; Klein, Katrin; Nguyen, Huu Phuc; Krauss, Joachim K.; Blahak, Christian; Strom, Tim M.; Sturm, Marc; Warrenburg, Bart van de; Lerche, Holger; Maček, Boris; Synofzik, Matthis; Ossowski, Stephan; Timmann, Dagmar; Wolf, Marc E.; Rieß, Olaf; Schöls, Ludger; Houlden, Henry; Haack, Tobias B.; Hengel, Holger; Ambrose, J. C.; Arumugam, Prabhu; Baple, Emma L.; Bleda, Marta; Boardman-Pretty, F.; Boissière, Julien; Boustred, C. R.; Brittain, Helen; Caulfield, Mark; Chan, G. C.; Craig, Clare; Daugherty, Louise C.; Burca, Anna de; Devereau, A.; Elgar, Greg; Foulger, Rebecca E.; Fowler, Tom; Furió-Tarí, P.; Hackett, J.M.; Halai, Dina; Hamblin, Angela; Henderson, Shirley; Holman, John E.; Hubbard, Tim; Ibáñez, Kristina; Jackson, R.; Jones, Louise; Kasperavičiūtė, Dalia; Kayikci, Melis; Lahnstein, L.; Lawson, Katy L.; Leigh, Sarah; Leong, Ivone; Lopez, Fabrice; Maleady‐Crowe, F.; Mason, Jeremy; McDonagh, Ellen M.; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C.; Odhams, C. A.; Patch, Christine; Perez-Gil, D.; Polychronopoulos, Dimitris; Pullinger, J.; Rahim, T.; Rendon, Augusto; Riesgo-Ferreiro, P.; Rogers, T.; Ryten, Mina; Savage, K.; Sawant, K.; Scott, Richard; Siddiq, Afshan; Sieghart, A.; Smedley, Damian; Smith, Katherine R.; Sosinsky, Alona; Spooner, W.; Stevens, Hallam; Stuckey, A.; Sultana, Răzvan; Thomas, E. R. A.; Thompson, S. R.; Tregidgo, Carolyn; Tucci, Arianna; Walsh, E.; Watters, Scott; Welland, M. J.; Williams, Eleanor; Witkowska, K.; Wood, S. M.; Zarowiecki, Magdalena

doi:10.1016/j.gim.2022.07.006

Cited by 10 publications

(12 citation statements)

References 41 publications

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“…The proband in our case also had a history of type 2 diabetes mellitus which could explain the small vessel disease evident on neuroimaging. Although a sensorimotor neuropathy has been described in previous UCHL1 cases, the predominant preganglionic sensory loss, as confirmed with abnormal SSEPs in our case is rare and has not been extensively described before 3 . As well as being abundantly present in the brain, 2 animal embryonic models have demonstrated that UCHL1 is present at high levels in the developing dorsal root ganglia as well as in paired spinal nerves along the length of the developing spinal cord 5 .…”

Section: Discussionsupporting

confidence: 68%

“…Hereditary spastic paraplegias and hereditary ataxias are rare neurodegenerative diseases 3 . This case report is unique in that we have demonstrated the even rarer co‐occurrence of a phenotype consisting of PNH associated with EDS and a late‐onset spastic sensory ataxia from a FLNA variant and UCHL1 deletion respectively.…”

Section: Discussionmentioning

confidence: 68%

“…Hereditary spastic paraplegias and hereditary ataxias are rare neurodegenerative diseases. 3 This case report is unique in that we have demonstrated the even rarer co-occurrence of a phenotype consisting of PNH associated with EDS and a late-onset spastic sensory ataxia from a FLNA variant and UCHL1 deletion respectively. The X-linked FLNA heterozygous frameshift variant is deemed pathogenic as this null variant impedes the protein's function where LoF is a known mechanism for disease involving PNH 1 and it is also absent from control databases (gnomAD v2.1.1).…”

Section: Discussionmentioning

confidence: 70%

“…Although a sensorimotor neuropathy has been described in previous UCHL1 cases, the predominant preganglionic sensory loss, as confirmed with abnormal SSEPs in our case is rare and has not been extensively described before. 3 As well as being abundantly present in the brain, 2 animal embryonic models have demonstrated that UCHL1 is present at high levels in the developing dorsal root ganglia as well as in paired spinal nerves along the length of the developing spinal cord. 5 The second complicating factor in the current case is the pathogenic variant in FLNA, resulting in a complex phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…3 Recently, heterozygous loss of function (LoF) variants have been described in autosomal dominant families with significantly decreased UCHL1 levels by approximately 50%. 3 While the same neurological systems are affected in the haploinsufficient cases, compared to biallelic variants, the disease has a milder course with a later disease onset. 3 This study describes a rare case of a female patient presenting with a late-onset sensory ataxia, upper motor neuron signs, severe sensory loss, joint pains and periventricular heterotopia brought about by a combination of a pathogenic deletion in the UCHL1 gene and a frameshift variant in the FLNA gene.…”

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confidence: 99%

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Digenic FLNA and UCHL1 variants resulting in a complex phenotype

Pernice,

O'Donnell,

Rossor

et al. 2024

J Peripheral Nervous Sys

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AimX‐linked variants in FLNA are associated with the Ehlers‐Danlos‐Syndrome (EDS)‐variant form of periventricular heterotopia, and autosomal dominant variants in UCHL1 are associated with a late‐onset spastic ataxia, peripheral neuropathy, and optic atrophy. Here we present a rare case involving both a novel heterozygous whole gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype.MethodsA 67‐year‐old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4‐year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities, and severe sensory loss.ResultsNeurophysiology including SSEPs confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene.ConclusionsTo the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 70%