Clinical, molecular, and genetic characteristics of the hereditary spastic paraplegia type 3

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Introduction. The autosomal dominant hereditary spastic paraplegia type 3 (SPG3), associated with the ATL1 gene, is a common form of the hereditary spastic paraplegia (HSP). The molecular genetic and clinical features of the SPG3 have not been sufficiently studied.

Study aim: to conduct the first clinical, molecular, and genetic study of HSP in Russia, using a high-throughput exome sequencing technology — massively parallel sequencing (MPS).

Materials and methods. Study subject: 14 identified families with SPG3. Clinical and molecular genetic methods used: Sanger sequencing, MPS panel for spastic paraplegia, multiplex ligation-dependent probe amplification.

Results. SPG3 made up 7.2% of the 195 examined families, 13.6% of 103 molecularly identified cases, and 16.9% of the dominant forms, coming in second place after SPG4 (>50%). We found 9 missense mutations in 14 families (7 in ‘hot exons’), with 4 new ones and the known p.Arg415Trp mutation identified in 4 families. One case was caused by a de novo mutation, the others were familial; incomplete penetrance was found in 5 families (subclinical cases). Gender distribution of the probands was equal, but there were more males among the affected relatives. Most of the 25 examined patients, as well as the relatives with clinical data, had early-onset (in the first decade of life, often at the age of 1 to 3 years), uncomplicated HSP with slow progression; many of those subjects were initially diagnosed with a cerebral palsy. Subclinical axonal polyneuropathy was found in 3 out of 6 cases using EMG. Atypical severe paraparesis was combined with skeletal pathology (likely independent of the major condition) in one female patient. Intellectual disability in males of another family was also considered to be an independent condition.

Conclusion. SPG3 has a significant prevalence among HSP in Russian patients. The clinical features in most cases are similar and relatively non-severe; clinical diagnosis may be challenging, especially in non-familial and non-apparent familial (incomplete penetrance) cases, as well as when combined with other conditions. An incorrect diagnosis of cerebral palsy is often made. A verified diagnosis is necessary for genetic counselling and is important for patient management. MPS methods are the most informative in the molecular genetic diagnosis of HSP.

About the authors

Galina E. Rudenskaya

Research Centre for Medical Genetics

Author for correspondence.
Russian Federation, Moscow

Varvara A. Kadnikova

Research Centre for Medical Genetics

Russian Federation, Moscow

Christian Beetz

Centogene AG

Germany, Rostock

Tatyana N. Proskokova

Far-Eastern State Medical University

Russian Federation, Khabarovsk

Irina G. Sermyagina

Research Centre for Medical Genetics

Russian Federation, Moscow

Anna A. Stepanova

Research Centre for Medical Genetics

Russian Federation, Moscow

Valery P. Fedotov

Voronezh Regional Clinical Hospital No. 1

Russian Federation, Voronezh

Elena L. Dadaly

Research Centre for Medical Genetics

ORCID iD: 0000-0001-5602-2805

D. Sci. (Med.), Prof., Head, Scientific advisory department

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.

Darya M. Guseva

Research Centre for Medical Genetics

Russian Federation, Moscow

Тatiana V. Markova

Research Centre for Medical Genetics

Russian Federation, Moscow

Oksana P. Ryzhkova

Research Centre for Medical Genetics

Russian Federation, Moscow


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Supplementary files

Supplementary Files

Copyright (c) 2020 Rudenskaya G.E., Kadnikova V.A., Beetz C..., Proskokova T.N., Sermyagina I.G., Stepanova A.A., Fedotov V.P., Dadaly E.L., Guseva D.M., Markova Т.V., Ryzhkova O.P.

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