Februari 2012
25
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LCHADD/MTPD – Latest Evidence
This part of the document will be changed in the first revision, in which the level of evidence will
be displayed throughout this care pathway.
LCHADD/MTPD
Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD, MIM 609016) and
Mitochondrial Trifunctional Protein (MTP) Deficiency (MIM 609015) are autosomal recessive
disorders of the fatty acid oxidation.
1
The mitochondrial trifunctional protein is an enzyme complex composed of three enzymes that
catalyze the mitochondrial beta-oxidation of fatty acid: Long Chain 3-Hydroxyacyl-CoA
Dehydrogenase (LCHAD), Long Chain Enoyl-CoA Hydratase (LCEH) and Long Chain Ketoacyl-CoA
Thiolase (LCKAT).
2
The HADHA gene encodes LCHAD and LCEH, whereas the HADHB gene encodes LCKAT. Both
enzymes are located at chromosome 2 (2p23).
Mutations in either subunit of the MTP can result in MTP-deficiency with reduced activity of all
three MTP enzymes. The 1528 G>C mutation causing the missense mutation E510Q in the MTP α-
subunit is frequent in patient with LCHADD.
3
No clear phenotype-genotype associating exists.
2,4
MTP-deficiency (MTPD) is characterized by decreased activity of all 3 enzymes, whereas LCHADD is
caused by an in isolated LCHAD-enzyme deficiency.
3,5
The estimated prevalence varies from 1:250.000 (LCHADD) / 1:750.000 (MTP-deficiency) in the USA
and Australia to 1:50.000 (LCHADD) in Sweden and 1:300.000 in the Netherlands.
6-8
As a result of the LCHADD or MTPD the long chain fatty acids cannot be oxidized.
This leads to symptoms associated with energy deficiency in fatty acid oxidation-dependent tissue
(
heart, liver, muscle) and the toxic properties of accumulating intermediated. The symptoms can
be triggered by prolonged fasting, exercise, infection, exposure to cold or fat-enriched diet.
4
Even
in the fed state mitochondrial β-oxidation is an important source of energy for high energy
consuming tissues, but it becomes essential when carbohydrate stores are depleted.
2
Three clinical phenotypes of LCHADD and MTPD have been described:
2,4,9,10
All these symptoms are reversible with sufficient supply of energy. However the severe form is still
highly associated with neonatal death, since fulminant acute symptoms may be therapy-resistant
and the patient may be deceased even before diagnosis.
2,4
Peripheral neuropathy (causing progressive muscle weakness, muscular atrophy and sensory
disorders) and retinopathy (with increasing visual field defects, deterioration of color vision and
dark adaptation) are irreversible long term complications in LCHADD and MTPD.
2,4
These are
possibly due to the toxic effect of the accumulation of hydroxyl acylcarnitines
4
.
Another
hypotheses is that docosahexanoic acid (DHA) deficiency plays a role in pigmentary retinopathy
11
.
Peripheral neuropathy is most common in MTPD (80%), whereas retinopathy is more common in
LCHADD patients (30-50%).
4
Furthermore pregnant mothers carrying a fetus with LCHADD or MTPD are at risk for HELLP
(
Hemolysis, Elevated Liver enzymes, Low Platelets) and AFLP (Acute Fatty Liver of Pregnancy).
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Treatment
Diet
The main purpose of the therapeutic interventions, is to secure sufficient caloric intake during
periods of metabolic stress and fasting and to prevent the accumulation of β-oxidation
intermediates. Therefore fasting should be avoided and adequate energy intake should be
provided during infections and other fast-inducing conditions. In addition a restriction of LCT (Long
Chain Triglyceride) intake, supplementation with MCT (Medium Chain Triglyceride) and a high
carbohydrate diet is recommended.
3,11,12
The use of uncooked cornstarch at bedtime might be
considered as a slowly released form of glucose.
1