TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability

Gali Heimer; Danit Oz-Levi; Eran Eyal; Shimon Edvardson; Andreea Nissenkorn; Elizabeth K Ruzzo; Amir Szeinberg; Channa Maayan; Meir Mai-Zahav; Ori Efrati; Elon Pras; Haike Reznik-Wolf; Doron Lancet; David B Goldstein; Yair Anikster; Stavit A Shalev; Orly Elpeleg; Bruria Ben Zeev

doi:10.1016/j.ejpn.2015.10.003

TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability

Eur J Paediatr Neurol. 2016 Jan;20(1):69-79. doi: 10.1016/j.ejpn.2015.10.003. Epub 2015 Oct 22.

Authors

Gali Heimer¹, Danit Oz-Levi², Eran Eyal³, Shimon Edvardson⁴, Andreea Nissenkorn⁵, Elizabeth K Ruzzo⁶, Amir Szeinberg⁷, Channa Maayan⁸, Meir Mai-Zahav⁹, Ori Efrati¹⁰, Elon Pras¹¹, Haike Reznik-Wolf¹², Doron Lancet², David B Goldstein¹³, Yair Anikster¹⁴, Stavit A Shalev¹⁵, Orly Elpeleg⁴, Bruria Ben Zeev¹⁶

Affiliations

¹ Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Med. Ctr., Israel; The Pinchas Borenstein Talpiot Medical Leadership Program, The Chaim Sheba Med. Ctr., Israel. Electronic address: galih.md@gmail.com.
² Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel.
³ Cancer Research Center, Pediatric Hemato/Oncology Unit, Edmond and Lily Safra Children's, Hospital, The Chaim Sheba Med. Ctr., Israel.
⁴ Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University, Med. Ctr., Jerusalem, Israel.
⁵ Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Med. Ctr., Israel; The Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel.
⁶ Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA.
⁷ Pediatric Sleep clinic, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Med. Ctr., Israel.
⁸ Familial Dysautonomia Centre, Pediatric Department, Hadassah Hospital, Hebrew University Hadassah, Medical School, Jerusalem, Israel.
⁹ Pulmonary Institute, Schneider Children's Med. Ctr., Sackler Faculty of Medicine, Tel Aviv University, Israel.
¹⁰ The Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel; Pediatric Pulmonary Unit, The Edmond and Lily Safra Children's Hospital, Sheba Med. Ctr., Israel.
¹¹ The Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel; Danek Gertner Institute of Human Genetics, Sheba Med. Ctr., Ramat Gan, Israel.
¹² Danek Gertner Institute of Human Genetics, Sheba Med. Ctr., Ramat Gan, Israel.
¹³ Institute for Genomic Medicine, Columbia University Medical School, Columbia University Med. Ctr., New York, NY 10032, USA.
¹⁴ The Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel; Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Med. Ctr., Israel.
¹⁵ Genetic Institute, Ha'Emek Med. Ctr., Afula 18101, Israel; Rappaport Faculty of Medicine, Technion, Israel.
¹⁶ Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Med. Ctr., Israel; The Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel. Electronic address: bruria.benzeev@sheba.health.gov.il.

PMID: 26542466
DOI: 10.1016/j.ejpn.2015.10.003

Abstract

Background: TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features. It was suggested to constitute a new subtype of complex hereditary spastic paraparesis (SPG49).

Results: We report here 3 additional patients from unrelated non-Bukharian families, harboring two novel mutations (c.1319delT, c.C566T) in this gene. Accumulating clinical data clarifies that in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events.

Conclusion: We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy. The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated and should therefore be considered in undiagnosed cases of intellectual disability with autonomic features and respiratory symptoms regardless of demographic origin.

Keywords: Autophagy; HSAN III; Hereditary spastic paraparesis; IKBKAP; Jewish Ashkenazi; TECPR2.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins / chemistry
Carrier Proteins / genetics*
Child, Preschool
Computational Biology
DNA / genetics
Dysautonomia, Familial / genetics*
Electrodiagnosis
Exome
Frameshift Mutation / genetics
Hereditary Sensory and Autonomic Neuropathies / genetics*
Hereditary Sensory and Autonomic Neuropathies / psychology
Humans
Infant
Infant, Newborn
Intellectual Disability / genetics*
Intellectual Disability / psychology
Jews
Male
Models, Molecular
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / genetics*
Neurologic Examination
Pedigree
Respiration Disorders / etiology
Respiration Disorders / genetics
Spastic Paraplegia, Hereditary / genetics*
Spastic Paraplegia, Hereditary / psychology

Substances

Carrier Proteins
Nerve Tissue Proteins
TECPR2 protein, human
DNA