Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share By
Bi-Allelic Hpdl Variants Cause a Neurodegenerative Disease Ranging From Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia Publisher Pubmed



Husain RA1 ; Grimmel M2 ; Wagner M3, 4, 5 ; Hennings JC6 ; Marx C7 ; Feichtinger RG8 ; Saadi A9 ; Rostasy K10 ; Radelfahr F11, 12 ; Bevot A13 ; Doblerneumann M13 ; Hartmann H14 ; Colleaux L15 ; Cordts I16 Show All Authors
Authors
  1. Husain RA1
  2. Grimmel M2
  3. Wagner M3, 4, 5
  4. Hennings JC6
  5. Marx C7
  6. Feichtinger RG8
  7. Saadi A9
  8. Rostasy K10
  9. Radelfahr F11, 12
  10. Bevot A13
  11. Doblerneumann M13
  12. Hartmann H14
  13. Colleaux L15
  14. Cordts I16
  15. Kobeleva X17
  16. Darvish H18
  17. Bakhtiari S19
  18. Kruer MC19
  19. Besse A20
  20. Ng ACH21
  21. Chiang D21
  22. Bolduc F21
  23. Tafakhori A22
  24. Mane S23
  25. Ghasemi Firouzabadi S24
  26. Huebner AK6
  27. Buchert R2
  28. Beckwoedl S2
  29. Muller AJ2
  30. Laugwitz L2, 13
  31. Nagele T25
  32. Wang ZQ7, 26
  33. Strom TM3, 4
  34. Sturm M2
  35. Meitinger T3, 4, 27
  36. Klockgether T17, 28
  37. Riess O2, 29
  38. Klopstock T11, 12, 27
  39. Brandl U1
  40. Hubner CA6
  41. Deschauer M16
  42. Mayr JA8
  43. Bonnen PE20
  44. Kragelohmann I13
  45. Wortmann SB3, 4, 8, 30
  46. Haack TB2, 29

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
Related Docs
View other Related Docs
1. Rtn2 Deficiency Results in an Autosomal Recessive Distal Motor Neuropathy With Lower Limb Spasticity, Brain (2024)
2. Childhood-Onset Choreo-Dystonia Due to a Recurrent Novel Homozygous Nonsense Hpca Variant: Case Series and Literature Review, Movement Disorders Clinical Practice (2023)
3. Description of Clinical Features and Genetic Analysis of One Ultra-Rare (Spg64) and Two Common Forms (Spg5a and Spg15) of Hereditary Spastic Paraplegia Families, Journal of Neurogenetics (2021)
Experts (# of related papers)
View all Related Experts
Ali Reza Tavasoli (4)
Mahmoudreza Ashrafi (3)
Other Related Docs
4. A Comprehensive Study of Mutation and Phenotypic Heterogeneity of Childhood Mitochondrial Leukodystrophies, Brain and Development (2024)
5. Whole Genome Sequencing Identifies a Novel Homozygous Exon Deletion in the Nt5c2 Gene in a Family With Intellectual Disability and Spastic Paraplegia, npj Genomic Medicine (2017)
6. Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review, Molecular Syndromology (2023)
7. Phenotypic Continuum of Nfu1-Related Disorders, Annals of Clinical and Translational Neurology (2022)
8. Crystallographic Modeling of the Pnpt1:C.1453A>G Variant As a Cause of Mitochondrial Dysfunction and Autosomal Recessive Deafness; Expanding the Neuroimaging and Clinical Features, Mitochondrion (2021)
9. Biallelic Variants in Ogdh Encoding Oxoglutarate Dehydrogenase Lead to a Neurodevelopmental Disorder Characterized by Global Developmental Delay, Movement Disorder, and Metabolic Abnormalities, Genetics in Medicine (2023)
10. Molecular Diagnosis of Hereditary Neuropathies by Whole Exome Sequencing and Expanding the Phenotype Spectrum, Archives of Iranian Medicine (2020)
11. Three Iranian Patients With Rare Subtypes of Hereditary Spastic Paraplegia (Hsp): Spg76, Spg56, and Spg69, Neurogenetics (2025)
12. Genetic Homogeneity of a Tdp1 Variant, C.1478A>G, As the Main Disease-Causing Variant of Spinocerebellar Ataxia With Axonal Neuropathy 1 (Scan1) in the Middle East: A Systematic Review, Pediatric Neurology (2025)
13. The First Reports of Fa2h-Associated Neurodegeneration From Two Unrelated Iranian Families, Neurological Sciences (2023)
14. Expanding the Clinical and Neuroimaging Features of Nkx6-2-Related Hereditary Spastic Ataxia Type 8, European Journal of Medical Genetics (2020)
15. Broadening the Phenotype and Genotype Spectrum of Novel Mutations in Pontocerebellar Hypoplasia With a Comprehensive Molecular Literature Review, BMC Medical Genomics (2024)
16. Biallelic Loss-Of-Function Variants in the Splicing Regulator Nsrp1 Cause a Severe Neurodevelopmental Disorder With Spastic Cerebral Palsy and Epilepsy, Genetics in Medicine (2021)
17. Pathogenic Significance of Scn1a Splicing Variants Causing Dravet Syndrome: Improving Diagnosis With Targeted Sequencing for Variants by in Silico Analysis, Clinical Neurology and Neurosurgery (2018)
18. Identification of a Novel Missense C.386G > a Variant in a Boy With the Pomgnt1-Related Muscular Dystrophy-Dystroglycanopathy, Acta Neurologica Belgica (2021)
19. Mitochondrial Copy Number and D-Loop Variants in Pompe Patients, Cell Journal (2016)
20. Gdap1-Related Charcot–Marie–Tooth Disease: Axonal or Demyelinating Subtype? Autosomal Recessive or Autosomal Dominant Inheritance?, Journal of the Peripheral Nervous System (2025)