Trifunctional Protein Deficiency
Conditions
Keywords
trifunctional, protein, deficiency, TFP, weight, regulation
Brief summary
Several hormones involved in body weight regulation increase the subject's ability to burn fat for energy. The purpose of this study is to investigate how burning fat for energy may affect those hormones and body weight in children. The study will also determine if eating a diet higher in protein alters the amount of fat you burn and how these hormones control body weight.
Detailed description
A role for mitochondrial fatty acid oxidation in the peripheral signaling cascade of leptin, adiponectin and insulin has recently been proposed from animal studies but has not been investigated in humans. Children with trifunctional protein (TFP, including deficiency of long-chain hydroxyacyl-CoA dehydrogenase) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, inherited disorders of long-chain fatty acid ß-oxidation, lack an ability to oxidize fatty acids for energy. They have increased levels of body fat and circulating leptin and a high incidence of obesity. Current therapy for children with these disorders is based on frequent meals and consuming a low fat, very high carbohydrate diet. Despite treatment, exercise induced rhabdomyolysis is a common complication of TFP and VLCAD deficiency that frequently leads to exercise avoidance. The effects of these genetic defects on body composition and weight regulation have not been investigated. The contribution of fatty-acid oxidation during moderate intensity exercise in children has also not been reported. Two groups of subjects were recruited: one group of subjects had a long-chain fatty acid oxidation disorder (n=13). The other group is a group of controls (n=16). We studied peripheral signals of body weight regulation, glucose tolerance, body composition, and exercise metabolism in subjects with a long-chain fatty acid oxidation disorder compared to normal controls.
Interventions
None listed
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Oregon State University
Oregon Health and Science University
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
7 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* confirmed diagnosis of TFP, LCHAD, CPT2 or VLCAD deficiency * at least 7 years of age * willingness to complete overnight admission * generally healthy
Exclusion criteria
* inclusion in another research project that alters macronutrient intake * diabetes, thyroid disease or other endocrine dysfunction that alters body composition. * pregnancy * anemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| An Outcome of This Study is the Difference in Percent Body Fat (%BF) Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | Subjects will be compared to controls at one point in time. | Body composition by DEXA was measured in subjects with a long-chain fatty acid oxidation disorder (n=13). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed body composition measures. The difference in body composition between subjects and age matched controls was compared by t-test. |
| An Outcome of This Study is the Difference in Glucose Tolerance Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | Subjects will be compared to controls at one point in time. | Glucose tolerance was estimated by the Matsuda Index using glucose and insulin values from a standard oral glucose tolerance test. The Matsuda Index is calculated by the following formula: 10,000/ sq root of (fasting glucose mg/dl X fasting insulin in units/ml) X (mean glucose (mg/dl) X mean insulin (units/ml) and correlates with insulin sensitivity measured by the gold standard method of a hyperinsulinemic euglycemic clamp. Values of 2.5 or greater are considered insulin sensitive. Values of 2.4 or less are considered insulin resistance. The Matsuda Index of Insulin Sensitivity was measured in subjects with a long-chain fatty acid oxidation disorder (n=12). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed an oral glucose tolerance test. The difference in Mastuda Index between subjects and age matched controls was compared by t-test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Difference in Plasma Adiponectin Levels Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | Fasting total adiponectin (ug/ml) | Fasting total adiponectin levels in ug/ml were measured in both groups (subjects with a long-chain fatty acid oxidation disorder). The differences between groups were compared with a t-test |
| The Difference in Plasma Leptin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | Fasting leptin levels ng per kg of fat mass | Fasting leptin in ng/kg fat mass were measured in both groups (subjects with a long-chain fatty acid oxidation disorder; controls). The differences between groups were compared with a t-test |
| The Difference in Plasma Insulin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | Fasting insulin levels uUnits/ml | Fasting insulin levels in uU/ml were measured in both groups. The differences between groups were compared with a t-test |
Countries
United States
Participant flow
Recruitment details
Subjects with a long-chain fatty acid oxidation disorder were recruited through announcements on disease specific websites, and referrals from metabolic physicians. Controls were recruited through the OHSU website and word of mouth.
Pre-assignment details
After a subject had completed the protocol, potential control subjects were screened for age, gender and BMI that would allow for a 1 to 1 matching study design.
Participants by arm
| Arm | Count |
|---|---|
| Subjects Subjects are patients with a long-chain fatty acid oxidation disorder including CPT2, VLCAD, TFP or LCHAD deficiency. | 14 |
| Controls Subjects do not have a fatty acid oxidation disorder. | 12 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Subjects | Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 10 Participants | 21 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Age Continuous | 14 years STANDARD_DEVIATION 8 | 15 years STANDARD_DEVIATION 7 | 14.3 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment Canada | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Europe | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
An Outcome of This Study is the Difference in Glucose Tolerance Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls.
Glucose tolerance was estimated by the Matsuda Index using glucose and insulin values from a standard oral glucose tolerance test. The Matsuda Index is calculated by the following formula: 10,000/ sq root of (fasting glucose mg/dl X fasting insulin in units/ml) X (mean glucose (mg/dl) X mean insulin (units/ml) and correlates with insulin sensitivity measured by the gold standard method of a hyperinsulinemic euglycemic clamp. Values of 2.5 or greater are considered insulin sensitive. Values of 2.4 or less are considered insulin resistance. The Matsuda Index of Insulin Sensitivity was measured in subjects with a long-chain fatty acid oxidation disorder (n=12). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed an oral glucose tolerance test. The difference in Mastuda Index between subjects and age matched controls was compared by t-test.
Time frame: Subjects will be compared to controls at one point in time.
Population: Study design was based on 1 to 1 matching of subjects and controls. Thirteen subjects but only 12 controls completed the protocol. We report results of 12 subjects compared to 12 matched controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects | An Outcome of This Study is the Difference in Glucose Tolerance Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | 2.8 units on a scale | Standard Deviation 1.8 |
| Controls | An Outcome of This Study is the Difference in Glucose Tolerance Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | 3.13 units on a scale | Standard Deviation 1.57 |
Primary
An Outcome of This Study is the Difference in Percent Body Fat (%BF) Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls.
Body composition by DEXA was measured in subjects with a long-chain fatty acid oxidation disorder (n=13). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed body composition measures. The difference in body composition between subjects and age matched controls was compared by t-test.
Time frame: Subjects will be compared to controls at one point in time.
Population: Study design was based on 1 to 1 matching of subjects and controls. Thirteen subjects but only 12 controls completed the protocol. We report results of 12 subjects compared to 12 matched controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects | An Outcome of This Study is the Difference in Percent Body Fat (%BF) Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | 31.8 percentage of body fat | Standard Deviation 6.8 |
| Controls | An Outcome of This Study is the Difference in Percent Body Fat (%BF) Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. | 27.2 percentage of body fat | Standard Deviation 9.1 |
Secondary
The Difference in Plasma Adiponectin Levels Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test
Fasting total adiponectin levels in ug/ml were measured in both groups (subjects with a long-chain fatty acid oxidation disorder). The differences between groups were compared with a t-test
Time frame: Fasting total adiponectin (ug/ml)
Population: Study was designed as a one to one matching design. Thirteen subjects but only 12 controls completed the protocol. We report results of 12 subjects and 12 matched controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects | The Difference in Plasma Adiponectin Levels Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 17.3 ug/ml | Standard Deviation 7.2 |
| Controls | The Difference in Plasma Adiponectin Levels Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 24.4 ug/ml | Standard Deviation 13.5 |
Secondary
The Difference in Plasma Insulin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test
Fasting insulin levels in uU/ml were measured in both groups. The differences between groups were compared with a t-test
Time frame: Fasting insulin levels uUnits/ml
Population: Study was designed as a one to one matching design. Thirteen subjects but only 12 controls completed the protocol. Samples were missing on one subject so 11 subjects were compared to 11 controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects | The Difference in Plasma Insulin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 17 uU/ml | Standard Deviation 8 |
| Controls | The Difference in Plasma Insulin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 13 uU/ml | Standard Deviation 5 |
Secondary
The Difference in Plasma Leptin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test
Fasting leptin in ng/kg fat mass were measured in both groups (subjects with a long-chain fatty acid oxidation disorder; controls). The differences between groups were compared with a t-test
Time frame: Fasting leptin levels ng per kg of fat mass
Population: Study was designed as a one to one matching design. Thirteen subjects but only 12 controls completed the protocol. We report results of 12 subjects and 12 matched controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects | The Difference in Plasma Leptin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 0.99 ng/kg | Standard Deviation 0.8 |
| Controls | The Difference in Plasma Leptin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test | 0.91 ng/kg | Standard Deviation 0.57 |