Natural History Study of Patients with HPDL Mutations

A Patient Registry and Natural History Study of Patients with Biallelic HPDL Mutations

This study uses medical records that allow retrospective data extraction of clinical manifestation to assess the natural history of HPDL mutations

Study Overview

• Status: Recruiting
• Conditions: Genetic Disease; Mitochondrial Encephalomyopathies; Neonatal Encephalopathy; Mutation; Hereditary Spastic Paraplegia; White Matter Disease; Spastic Paraplegia
• Intervention / Treatment: Other: Patient Registry; Other: Dry blood spots sampling

Detailed Description

A novel mitochondrial disease arises from mutations in HPDL, which codes for 4-hydroxyphenylpyruvate dioxygenase-like protein. The main purpose of this study is to establish a patient registry to gather medical data from consenting HPDL mutation patients worldwide. From longitudinal data, we will be able to figure out the natural history of the disease, and genotype-phenotype correlation. Dry blood spots will be collected to develop biomarkers to understand the disease better.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Eun Hae Lee; Phone Number: 8582460547; Email: gleesonlab@health.ucsd.edu

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • Recruiting
      • Eun Hae Lee
      • Contact: Eun Hae Lee; Phone Number: 8582460547; Email: leeeh80@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The gene HPDL has been linked to an infantile neurodegenerative condition. The affected patients have various clinical manifestations from spastic paraplegia to NEDSWMA. Severely affected patients exhibit developmental delay, seizures, and spasticity, and can lead to death.

Description

Inclusion Criteria:

• Any individuals diagnosed with HPDL variants

• Clinical diagnosis can include:

  • HPDL-related hereditary spastic paraplegia (HSP)
  • HPDL-related neonatal mitochondrial encephalopathy
  • Spastic paraplegia -83 (SPG83)
  • Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA)

Exclusion Criteria:

• Any known genetic abnormality (other than HPDL mutation)
• Any condition that, in the opinion of the Site Investigator, could put the participant at undue risk and/or would ultimately prevent the completion of study procedures

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HPDL deficiency; Patients with HPDL mutations	Other: Patient Registry; Participants who have been diagnosed with HPDL mutations will be enrolled to patient registry.; Other: Dry blood spots sampling; Dry blood splots require 500nl of blood.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinician questionnaire	Clinician-reported clinical and genetic confirmation of HPDL mutations	12 months

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: New York University; Heinrich-Heine University, Duesseldorf; Universität Tübingen
• Investigators: Principal Investigator: Joseph Gleeson, UCSD

Publications and helpful links

General Publications

• Ghosh SG, Lee S, Fabunan R, Chai G, Zaki MS, Abdel-Salam G, Sultan T, Ben-Omran T, Alvi JR, McEvoy-Venneri J, Stanley V, Patel A, Ross D, Ding J, Jain M, Pan D, Lubbert P, Kammerer B, Wiedemann N, Verhoeven-Duif NM, Jans JJ, Murphy D, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Ibrahim K, Waters ER, Maroofian R, Gleeson JG. Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition. Genet Med. 2021 Mar;23(3):524-533. doi: 10.1038/s41436-020-01010-y. Epub 2020 Nov 14.
• Banh RS, Kim ES, Spillier Q, Biancur DE, Yamamoto K, Sohn ASW, Shi G, Jones DR, Kimmelman AC, Pacold ME. The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway. Nature. 2021 Sep;597(7876):420-425. doi: 10.1038/s41586-021-03865-w. Epub 2021 Sep 1.

Helpful Links

• website for patient registration

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: April 28, 2023
• First Submitted That Met QC Criteria: April 28, 2023
• First Posted (Actual): May 8, 2023

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: HPDL; HPDL related neonatal mitochondrial encephalopathy; HPDL related hereditary spastic paraplegia; Spastic paraplegia-83; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neuromuscular Diseases; Metabolic Diseases; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Nervous System Malformations; Polyneuropathies; Paralysis; Mitochondrial Diseases; Mitochondrial Myopathies; Hereditary Sensory and Motor Neuropathy; Muscle Spasticity; Genetic Diseases, Inborn; Brain Diseases; Leukoencephalopathies; Paraplegia; Spastic Paraplegia, Hereditary; Mitochondrial Encephalomyopathies
• Other Study ID Numbers: HPDL_NHS_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No