Natural History Study of Pyruvate Dehydrogenase Deficiency

Pyruvate dehydrogenase (PDH) deficiency is one of the most common mitochondrial disorders. Patients with this genetic condition have difficulty utilising carbohydrates to produce energy and develop a combination of problems including seizures, poor balance, developmental delay, disability and have a reduced life expectancy. As for most mitochondrial disorders there is a lack of effective treatments. It is essential to understand the mechanisms underlying the disease in order to identify new treatments, and to understand the natural history of disease in order to prepare for clinical trials. To date, a natural history study of PDH deficiency has not been undertaken in the UK.

The researchers aim to undertake the first natural history study of PDH deficiency in the UK, to describe the spectrum of symptoms, genetics, management and outcomes in both children and adult patients.

Study Overview

• Status: Recruiting
• Conditions: Pyruvate Dehydrogenase Complex Deficiency; Pyruvate Dehydrogenase E1 Alpha Deficiency; Pyruvate Dehydrogenase E1-Beta Deficiency; Pyruvate Dehydrogenase E2 Deficiency; Pyruvate Dehydrogenase Phosphatase Deficiency

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

Contacts and Locations

• Study Contact: Name: Nandaki Keshavan, MA, MB BChir; Phone Number: 020 7905 2608; Email: n.keshavan@ucl.ac.uk
• Study Contact Backup: Name: Vanshree Patel, PhD; Phone Number: 0207 905 42271; Email: vanshree.patel@gosh.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Great Ormond Street Hospital
    • Contact: Shamima Rahman, PhD; Email: shamima.rahman@gosh.nhs.uk
    • Principal Investigator: Shamima Rahman, PhD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Children and Adults with a diagnosis of (primary) Pyruvate Dehydrogenase Deficiency who are recruited from the community via tertiary healthcare services

Description

Inclusion Criteria:

1. Compatible clinical history AND

2a Enzymatic confirmation demonstrating reduced PDH activity in patient cells or muscle tissue OR

2b Confirmed pathogenic mutation in a gene associated with primary PDH deficiency (PDHA1, PDHB, PDHX, PDP1, DLAT) OR

2c First degree relative with a confirmed pathogenic mutation causing primary PDH deficiency

Exclusion Criteria:

Patients with 'secondary PDH deficiency' that is patients who meet criteria 1 and 2a but who have received a genetic diagnosis which confirms pathogenic variants in a gene not associated with primary PDH deficiency.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patient cohort; Non interventional study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Newcastle Mitochondrial Disease Scale	Newcastle Paediatric and Adult Mitochondrial Disease Scale This is a validated scoring system for mitochondrial disease patients and measures severity of disease using multiple different clinical outcome measures and questionnaires. A higher score indicates greater disease severity.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial Disease Phenotype	PDH deficiency Phenotype	Baseline
Genetic Diagnosis	Molecular diagnosis	Baseline
Medical History	Family history, past medical history	Baseline
Disease timecourse	Onset, symptom debut, final outcome, follow-up.	Baseline
Neuroimaging	MRI/MRS Head	Baseline
Assessment of Neurophysiological outcome measures from source data	This is an observational retrospective from source data and may include the following neurophysiological measures: EMG, EEG, Nerve conduction Studies	Baseline
Assessment of Cognitive and Developmental outcomes from source data	Retrospective assessments documented within source data for cognitive assessments that have occurred in the past in all patients.	Baseline
Assessment of Cognitive and Developmental outcomes at baseline	For prospective component, cognitive assessments will be performed at baseline in adult patients only: Wechsler Test of Adult Reading (WTAR) test Symbol Search Speed of comprehension test	Baseline
Assessment of biochemical outcome measures from source data	This is an observational retrospective from source data and may include the following biological outcome measures: EMG, EEG, Nerve conduction Studies: Blood and CSF lactate, pyruvate, amino acids, urine organic acids, PDH enzymology, OXPHOS studies, skeletal muscle histology	Baseline
Management	Drug and non-drug treatments	Baseline

Collaborators and Investigators

• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Collaborators: National Institute for Health Research, United Kingdom; The Freya Foundation
• Investigators: Study Director: Shamima Rahman, PhD, Great Ormond Street Hospital NHS Foundation Trust

Publications and helpful links

General Publications

• Phoenix C, Schaefer AM, Elson JL, Morava E, Bugiani M, Uziel G, Smeitink JA, Turnbull DM, McFarland R. A scale to monitor progression and treatment of mitochondrial disease in children. Neuromuscul Disord. 2006 Dec;16(12):814-20. doi: 10.1016/j.nmd.2006.08.006. Epub 2006 Nov 22.
• Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012 Jul;106(3):385-94. doi: 10.1016/j.ymgme.2012.03.017.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: February 2, 2022
• First Submitted That Met QC Criteria: February 16, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Prognosis; Quality of life; Natural History; Outcome measures; Outcomes; PDH deficiency; Genotype-phenotype correlation
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Mitochondrial Diseases; Brain Diseases, Metabolic, Inborn; Pyruvate Metabolism, Inborn Errors; Pyruvate Dehydrogenase Complex Deficiency Disease
• Other Study ID Numbers: 19GR12; 278183 (Other Identifier: Health Research Authority, United Kingdom); 283427 (Other Identifier: Health Research Authority, United Kingdom)

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