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Open Access 01-12-2020 | Spastic Paraplegia | Original Communication

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Authors: Grace McMacken, Hanns Lochmüller, Boglarka Bansagi, Angela Pyle, Angela Lochmüller, Patrick F. Chinnery, Steve Laurie, Sergi Beltran, Leslie Matalonga, Rita Horvath

Published in: Journal of Neurology | Issue 12/2020

Abstract

Background

Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing.

Methods

Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother.

Results

Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30’s, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1.

Conclusions

The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.

Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G (2012) Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci 318:1–18CrossRef

Parodi L, Fenu S, Stevanin G, Durr A (2017) Hereditary spastic paraplegia: more than an upper motor neuron disease. Rev Neurol (Paris) 173:352–360CrossRef

Bhowmik AD, Patil SJ, Deshpande DV, Bhat V, Dalal A (2018) Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79. J Hum Genet 63:927CrossRef

Bilguvar K, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO, Baranoski JF, Erturk O et al (2013) Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc Natl Acad Sci U S A 110:3489–3494CrossRef

Rydning SL, Backe PH, Sousa MML, Iqbal Z, Øye A-M, Sheng Y, Yang M, Lin X, Slupphaug G, Nordenmark TH et al (2017) Novel UCHL1 mutations reveal new insights into ubiquitin processing. Hum Mol Genet 26:1031–1040CrossRef

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole genome association and population-based linkage analyses. Am J Hum Genet 81:559–575CrossRef

Kancheva D, Atkinson D, De Rijk P, Zimon M, Chamova T, Mitev V, Yaramis A, Maria Fabrizi G, Topaloglu H, Tournev I, Parman Y, Parma Y, Battaloglu E, Estrada-Cuzcano A, Jordanova A (2016) Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing. Genet Med 18(6):600–607CrossRef

Matalonga L, Laurie S, Papakonstantinou A, Piscia D, Mereu E, Bullich G, Thompson R, Horvath R, Pérez-Jurado L, Riess O et al (2020) Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity. J Mol Diagn. https://doi.org/10.1016/j.jmoldx.2020.06.008CrossRefPubMedPubMedCentral

Boudreaux DA, Maiti TK, Davies CW, Das C (2010) Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. Proc Natl Acad Sci U S A 107:9117–9122CrossRef

10.

Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson’s disease susceptibility. Cell 111:209–218CrossRef

11.

Ann ES, Mizoguchi A, Okajima S, Ide C (1994) Motor axon terminal regeneration as studied by protein gene product 9.5 immunohistochemistry in the rat. Arch Histol Cytol 57:317–330CrossRef

12.

Doran JF, Jackson P, Kynoch PA, Thompson RJ (1983) Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis. J Neurochem 40:1542–1547CrossRef

13.

Lin WM, Hsieh ST, Huang IT, Griffin JW, Chen WP (1997) Ultrastructural localization and regulation of protein gene product 9.5. NeuroReport 8:2999–3004CrossRef

14.

Chen F, Sugiura Y, Myers KG, Liu Y, Lin W (2010) Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction. Proc Natl Acad Sci U S A 107:1636–1641CrossRef

15.

Genç B, Jara JH, Schultz MC, Manuel M, Stanford MJ, Gautam M, Klessner JL, Sekerkova G, Heller DB, Cox GA et al (2016) Absence of UCHL 1 function leads to selective motor neuropathy. Ann Clin Transl Neurol 3:331–345CrossRef

16.

Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775–788CrossRef

17.

Behr C (1909) Die komplizierte, hereditär-familiäre optikusatrophie des kindesalters: ein bisher nicht beschriebener symptomkompleks. Klinische Monatsblätter für Augenheilkunde 47:138–160

18.

Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O (2001) Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 69:1218–1224CrossRef

19.

Marelli C, Amati-Bonneau P, Reynier P, Layet V, Layet A, Stevanin G, Brissaud E, Bonneau D, Durr A, Brice A (2011) Heterozygous OPA1 mutations in Behr syndrome. Brain 134:e169CrossRef

20.

Bonneau D, Colin E, Oca F, Ferré M, Chevrollier A, Guéguen N, Desquiret-Dumas V, N'Guyen S, Barth M, Zanlonghi X et al (2014) Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain 137:e301CrossRef

21.

Pyle A, Ramesh V, Bartsakoulia M, Boczonadi V, Gomez-Duran A, Herczegfalvi A, Blakely EL, Smertenko T, Duff J, Eglon G, Moore D, Yu-Wai-Man P, Douroudis K, Santibanez-Koref M, Griffin H, Lochmüller H, Karcagi V, Taylor RW, Chinnery PF, Horvath R (2014) Behr’s Syndrome is typically associated with disturbed mitochondrial translation and mutations in the C12orf65 gene. J Neuromuscul Dis 1(1):55–63CrossRef

22.

Kleffner I, Wessling C, Gess B, Korsukewitz C, Allkemper T, Schirmacher A, Young P, Senderek J, Husstedt IW (2015) Behr syndrome with homozygous C19ORF12 mutation. J Neurol Sci 357(1–2):115–118CrossRef

23.

Wilkinson KD, Deshpande S, Larsen CN (1992) Comparisons of neuronal (PGP 9.5) and non-neuronal ubiquitin C-terminal hydrolases. Biochem Soc Trans 20:631–637CrossRef

24.

Miyoshi Y, Nakayama S, Torikoshi Y, Tanaka S, Ishihara H, Taguchi T, Tamaki Y, Noguchi S (2006) High expression of ubiquitin carboxy-terminal hydrolase-L1 and -L3 mRNA predicts early recurrence in patients with invasive breast cancer. Cancer Sci 97:523–529CrossRef

25.

Takano T, Miyauchi A, Matsuzuka F, Yoshida H, Nakata Y, Kuma K, Amino N (2004) PGP9.5 mRNA could contribute to the molecular-based diagnosis of medullary thyroid carcinoma. Eur J Cancer Oxf Engl 40:614–618CrossRef

26.

Tezel E, Hibi K, Nagasaka T, Nakao A (2000) PGP9.5 as a prognostic factor in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res 6:4764–4767

27.

Yamazaki T, Hibi K, Takase T, Tezel E, Nakayama H, Kasai Y, Ito K, Akiyama S, Nagasaka T, Nakao A (2002) PGP9.5 as a marker for invasive colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 8:192–195

28.

Bi HL, Zhang XL, Zhang YL, Xie X, Xia YL, Du J, Li HH (2020) The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor. Sci Adv 6(16):eaax4826CrossRef

29.

Bishop P, Rocca D, Henley JM (2016) Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction. Biochem J 473(16):2453–2462CrossRef

30.

Bishop P, Rubin P, Thomson AR, Rocca D, Henley JM (2014) The ubiquitin C-terminal hydrolase L1 (UCH-L1) C-terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons. J Biol Chem 289(52):36140–36149CrossRef

Title: Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion
Authors: Grace McMacken
Hanns Lochmüller
Boglarka Bansagi
Angela Pyle
Angela Lochmüller
Patrick F. Chinnery
Steve Laurie
Sergi Beltran
Leslie Matalonga
Rita Horvath
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Spastic Paraplegia
Scoliosis
Cardiomyopathy
Published in: Journal of Neurology / Issue 12/2020
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-020-10059-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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