Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

Johanna Palmio; Panu Kiviranta; Päivi H. Hartikainen; Pirjo Isohanni; Mari Auranen; Karoliina Videman; Sini Penttilä; Sara Lehtinen; Jarkko Kirjavainen; Susanna Hintikka; Katriina Paloviita; Janna Saarela; Bjarne Udd

doi:10.1212/NXG.0000000000200155

Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

Johanna Palmio^*
, Panu Kiviranta
, Päivi H. Hartikainen
, Pirjo Isohanni
, Mari Auranen
, Karoliina Videman
, Sini Penttilä
, Sara Lehtinen
, Jarkko Kirjavainen
, Susanna Hintikka
, Katriina Paloviita
, Janna Saarela
, Bjarne Udd

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

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Abstract

Background and Objectives Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS).MethodsNine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

Original language	English
Article number	e200155
Number of pages	7
Journal	Neurology: Genetics
Volume	10
Issue number	3
DOIs	https://doi.org/10.1212/NXG.0000000000200155
Publication status	Published - 7 May 2024
Publication type	A1 Journal article-refereed

Funding

The authors J. Palmio, P. Isohanni, M. Auranen, and B. Udd are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). J. Palmio was financially supported by Tampere University Hospital Support Foundation, Tampere University Hospital (Project number MK339). P. Kiviranta, P. Hartikainen, P. Isohanni, M. Auranen, K. Videman, S. Penttil\u00E4, and S. Lehtinen report no disclosures relevant to the manuscript. J. Kirjavainen has attended advisory boards of Biogen and Roche (treatment of SMA). S. Hintikka, K. Paloviita, J. Saarela, and B. Udd report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.

Funders	Funder number
Tampere University Hospital Support Foundation
ERN EpiCARE -jäsenkeskus
European Reference Network for Rare Neuromuscular Diseases
MK339

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Publication forum level 1

ASJC Scopus subject areas

Clinical Neurology
Genetics(clinical)

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https://urn.fi/URN:NBN:fi:tuni-202411069914Licence: CC BY-NC-ND

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Palmio, J., Kiviranta, P., Hartikainen, P. H., Isohanni, P., Auranen, M., Videman, K., Penttilä, S., Lehtinen, S., Kirjavainen, J., Hintikka, S., Paloviita, K., Saarela, J., & Udd, B. (2024). Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity. Neurology: Genetics, 10(3), Article e200155. https://doi.org/10.1212/NXG.0000000000200155

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abstract = "Background and Objectives Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS).MethodsNine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.",

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Palmio, J, Kiviranta, P, Hartikainen, PH, Isohanni, P, Auranen, M, Videman, K, Penttilä, S, Lehtinen, S, Kirjavainen, J, Hintikka, S, Paloviita, K, Saarela, J & Udd, B 2024, 'Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity', Neurology: Genetics, vol. 10, no. 3, e200155. https://doi.org/10.1212/NXG.0000000000200155

TY - JOUR

T1 - Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

AU - Palmio, Johanna

AU - Kiviranta, Panu

AU - Hartikainen, Päivi H.

AU - Isohanni, Pirjo

AU - Auranen, Mari

AU - Videman, Karoliina

AU - Penttilä, Sini

AU - Lehtinen, Sara

AU - Kirjavainen, Jarkko

AU - Hintikka, Susanna

AU - Paloviita, Katriina

AU - Saarela, Janna

AU - Udd, Bjarne

PY - 2024/5/7

Y1 - 2024/5/7

N2 - Background and Objectives Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS).MethodsNine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

AB - Background and Objectives Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS).MethodsNine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

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DO - 10.1212/NXG.0000000000200155

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AN - SCOPUS:85206835656

SN - 2376-7839

VL - 10

JO - Neurology: Genetics

JF - Neurology: Genetics

IS - 3

M1 - e200155

ER -

Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

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