Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia Publisher Pubmed

Husain RA¹ ; Grimmel M² ; Wagner M^{3, 4, 5} ; Hennings JC⁶ ; Marx C⁷ ; Feichtinger RG⁸ ; Saadi A⁹ ; Rostasy K¹⁰ ; Radelfahr F^{11, 12} ; Bevot A¹³ ; Doblerneumann M¹³ ; Hartmann H¹⁴ ; Colleaux L¹⁵ ; Cordts I¹⁶ Show All Authors

Husain RA¹
Grimmel M²
Wagner M^{3, 4, 5}
Hennings JC⁶
Marx C⁷
Feichtinger RG⁸
Saadi A⁹
Rostasy K¹⁰
Radelfahr F^{11, 12}
Bevot A¹³
Doblerneumann M¹³
Hartmann H¹⁴
Colleaux L¹⁵
Cordts I¹⁶
Kobeleva X¹⁷
Darvish H¹⁸
Bakhtiari S¹⁹
Kruer MC¹⁹
Besse A²⁰
Ng ACH²¹
Chiang D²¹
Bolduc F²¹
Tafakhori A²²
Mane S²³
Ghasemi Firouzabadi S²⁴
Huebner AK⁶
Buchert R²
Beckwoedl S²
Muller AJ²
Laugwitz L^{2, 13}
Nagele T²⁵
Wang ZQ^{7, 26}
Strom TM^{3, 4}
Sturm M²
Meitinger T^{3, 4, 27}
Klockgether T^{17, 28}
Riess O^{2, 29}
Klopstock T^{11, 12, 27}
Brandl U¹
Hubner CA⁶
Deschauer M¹⁶
Mayr JA⁸
Bonnen PE²⁰
Kragelohmann I¹³
Wortmann SB^{3, 4, 8, 30}
Haack TB^{2, 29}

Show Affiliations

1. Department of Neuropediatrics, Jena University Hospital, Jena, 07747, Germany
2. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tubingen, 72076, Germany
3. Institute of Human Genetics, Technical University of Munich (TUM), School of Medicine, Munich, 81675, Germany
4. Institute of Human Genetics, Helmholtz Zentrum Munchen, Neuherberg, 85764, Germany
5. Institute of Neurogenomics, Helmholtz Zentrum Munchen, Neuherberg, 85764, Germany
6. Institute of Human Genetics, Jena University Hospital, Jena, 07747, Germany
7. Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, 07745, Germany
8. University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, 5020, Austria
9. Department of Neurology, Ben Aknoun Hospital, Benyoucef Benkhedda University, Algiers, 16028, Algeria
10. Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, 45711, Germany
11. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, 80336, Germany
12. German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Germany
13. Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tubingen, 72072, Germany
14. Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, Hannover, 30625, Germany
15. INSERM UMR1163, Developmental Brain Disorders Laboratory, Imagine Institute, Paris-Descartes University, Paris, France
16. Department of Neurology, Technische Universitat Munchen, School of Medicine, Munich, 81675, Germany
17. Department of Neurology, University of Bonn, Bonn, 53127, Germany
18. Cancer Research Center and Department of Medical Genetics, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
19. Barrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, 85004, AZ, United States
20. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, United States
21. Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada
22. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
23. Yale Center for Genome Analysis, Yale University School of Medicine, West Haven, 06516, CT, United States
24. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
25. Department of Neuroradiology, University Hospital Tuebingen, Tubingen, 72072, Germany
26. Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany
27. Munich Cluster for Systems Neurology (SyNergy), Munich, 81377, Germany
28. German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany
29. Centre for Rare Diseases, University of Tuebingen, Tubingen, 72076, Germany
30. Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, 6525 GA, Nijmegen, Netherlands

Source: American Journal of Human Genetics Published:2020

Abstract

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder. © 2020 American Society of Human Genetics

Experts (# of related papers)

Hamid Reza Mirzaei (1)

Style	Citing Format
MLA	Husain RA, et al.. "Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia." American Journal of Human Genetics, vol. 107, no. 2, 2020, pp. 364-373.
APA	Husain RA, Grimmel M, Wagner M, Hennings JC, Marx C, Feichtinger RG, Saadi A, Rostasy K, Radelfahr F, Bevot A, Doblerneumann M, Hartmann H, Colleaux L, Cordts I, Kobeleva X, Darvish H, Bakhtiari S, Kruer MC, Besse A, ... Haack TB (2020). Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. American Journal of Human Genetics, 107(2), 364-373.
Chicago	Husain RA, Grimmel M, Wagner M, Hennings JC, Marx C, Feichtinger RG, Saadi A, et al.. "Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia." American Journal of Human Genetics 107, no. 2 (2020): 364-373.
Harvard	Husain RA et al. (2020) 'Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia', American Journal of Human Genetics, 107(2), pp. 364-373.
Vancouver	Husain RA, Grimmel M, Wagner M, Hennings JC, Marx C, Feichtinger RG, et al.. Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. American Journal of Human Genetics. 2020;107(2):364-373.
BibTex	@article{ author = {Husain RA and Grimmel M and Wagner M and Hennings JC and Marx C and Feichtinger RG and Saadi A and Rostasy K and Radelfahr F and Bevot A and Doblerneumann M and Hartmann H and Colleaux L and Cordts I and Kobeleva X and Darvish H and Bakhtiari S and Kruer MC and Besse A and Ng ACH and Chiang D and Bolduc F and Tafakhori A and Mane S and Ghasemi Firouzabadi S and Huebner AK and Buchert R and Beckwoedl S and Muller AJ and Laugwitz L and Nagele T and Wang ZQ and Strom TM and Sturm M and Meitinger T and Klockgether T and Riess O and Klopstock T and Brandl U and Hubner CA and Deschauer M and Mayr JA and Bonnen PE and Kragelohmann I and Wortmann SB and Haack TB}, title = {Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia}, journal = {American Journal of Human Genetics}, volume = {107}, number = {2}, pages = {364-373}, year = {2020} }
RIS	TY - JOUR AU - Husain RA AU - Grimmel M AU - Wagner M AU - Hennings JC AU - Marx C AU - Feichtinger RG AU - Saadi A AU - Rostasy K AU - Radelfahr F AU - Bevot A AU - Doblerneumann M AU - Hartmann H AU - Colleaux L AU - Cordts I AU - Kobeleva X AU - Darvish H AU - Bakhtiari S AU - Kruer MC AU - Besse A AU - Ng ACH AU - Chiang D AU - Bolduc F AU - Tafakhori A AU - Mane S AU - Ghasemi Firouzabadi S AU - Huebner AK AU - Buchert R AU - Beckwoedl S AU - Muller AJ AU - Laugwitz L AU - Nagele T AU - Wang ZQ AU - Strom TM AU - Sturm M AU - Meitinger T AU - Klockgether T AU - Riess O AU - Klopstock T AU - Brandl U AU - Hubner CA AU - Deschauer M AU - Mayr JA AU - Bonnen PE AU - Kragelohmann I AU - Wortmann SB AU - Haack TB TI - Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia JO - American Journal of Human Genetics VL - 107 IS - 2 SP - 364 EP - 373 PY - 2020 ER -

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