Mitochondrial trifunctional protein deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: MTP [IBIS]
TFPD [IBIS]
Trifunctional protein deficiency with myopathy and neuropathy, included
Number of Symptoms 40
OrphanetNr: 746
OMIM Id: 609015
ICD-10: G71.3
UMLs: C0342786
MeSH: D024741
MedDRA:
Snomed: 237999008

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000
Inheritance:
Age of onset: All ages
PMID:12838198 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Disorder of mitochondrial fatty acid oxidation
 -Rare genetic disease
Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial myopathy
 -Rare genetic disease
 -Rare neurologic disease
Rare hereditary metabolic disease with peripheral neuropathy
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid β-oxidation that may be due to mutations in 2 different nuclear genes, HADHA and HADHB (PMID:23868323). The mitochondrial trifunctional protein (TP) is an enzyme complex with three activities: enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and 3-ketoacyl-CoA thiolase. Studies on defects in this enzyme in patients with MTP deficiency suggest that there are two types of defect. Patients in group 1 have normal amount of cross-reacting material by immunoblot and lack only long-chain 3-hydroxyacyl-CoA dehydrogenase activity. Patients in group 2 have a trace amount of cross-reacting material, with all three activities being low (PMID:8651282). MTP deficiency can be divided into two major clinical phenotypes: an early-onset form (neonatal, 48%, n=21), generally presenting with hypoketotic hypoglycemia and cardiomyopathy, and a less frequent myopathic form, presenting in teenagers and adults. Mortality is high (76%, n=21), mostly attributable to cardiac involvement (PMID:12838198). LCHAD deficiency is clinically indistinguishable from severe TFPD (ORPHANET, April 2016).

Symptom Information: Sort by abundance 

1
 (HPO:0003652) Recurrent myoglobinuria 14694500 IBIS 2 / 7739
2
 (HPO:0002913) Myoglobinuria 12838198 IBIS 22 / 7739
3
 (HPO:0000580) Pigmentary retinopathy Occasional 11% (n=9) 12838198 IBIS 49 / 7739
4
 (HPO:0001270) Motor delay 12838198 IBIS 322 / 7739
5
 (HPO:0001284) Areflexia Frequent [IBIS] 78% (n=9) 12838198 IBIS 198 / 7739
6
 (HPO:0001254) Lethargy Frequent [IBIS] 57% (n=7) 12838198 IBIS 104 / 7739
7
 (HPO:0009830) Peripheral neuropathy Frequent [IBIS] 70% (n=10) 12838198 IBIS 206 / 7739
8
 (HPO:0002686) Prenatal maternal abnormality 12838198 IBIS 3 / 7739
9
 (HPO:0001560) Abnormality of the amniotic fluid 27014569 IBIS 7 / 7739
10
 (HPO:0001789) Hydrops fetalis 12838198 IBIS 63 / 7739
11
 (HPO:0001396) Cholestasis Occasional [IBIS] 13% (n=8) 12838198 IBIS 136 / 7739
12
 (HPO:0002910) Elevated hepatic transaminases 12838198 IBIS 158 / 7739
13
 (HPO:0001392) Abnormality of the liver Frequent [IBIS] 60% (n=10) 12838198 IBIS 28 / 7739
14
 (HPO:0008872) Feeding difficulties in infancy Frequent [IBIS] 90% (n=10) 12838198 IBIS 153 / 7739
15
 (HPO:0001518) Small for gestational age Frequent [IBIS] 40% (n=20) 12838198 IBIS 107 / 7739
16
 (HPO:0001508) Failure to thrive Frequent [IBIS] 70% (n=10) 12838198 IBIS 454 / 7739
17
 (HPO:0001635) Congestive heart failure 12838198 IBIS 232 / 7739
18
 (HPO:0001638) Cardiomyopathy Frequent [IBIS] 73% (n=21) 12838198 IBIS 192 / 7739
19
 (HPO:0001644) Dilated cardiomyopathy 10400133 IBIS 141 / 7739
20
 (HPO:0011675) Arrhythmia Occasional [IBIS] 10% (n=10) 12838198 IBIS 226 / 7739
21
 (HPO:0003236) Elevated serum creatine phosphokinase 27117294 IBIS 214 / 7739
22
 (HPO:0001943) Hypoglycemia 27117294 IBIS 131 / 7739
23
 (HPO:0003128) Lactic acidosis 27014569 IBIS 116 / 7739
24
 (HPO:0001987) Hyperammonemia 8651282 IBIS 50 / 7739
25
 (HPO:0001985) Hypoketotic hypoglycemia Frequent [IBIS] 67% (n=21) 12838198 IBIS 11 / 7739
26
 (HPO:0002104) Apnea 10400133 IBIS 106 / 7739
27
 (HPO:0002093) Respiratory insufficiency 14694500 IBIS 410 / 7739
28
 (HPO:0003394) Muscle cramps Frequent [IBIS] 83% (n=6) 12838198 IBIS 106 / 7739
29
 (HPO:0003326) Myalgia 12838198 IBIS 143 / 7739
30
 (HPO:0008947) Infantile muscular hypotonia 12838198 IBIS 482 / 7739
31
 (HPO:0003546) Exercise intolerance 24305961 IBIS 62 / 7739
32
 (HPO:0001252) Muscular hypotonia Frequent [IBIS] 57% (n=21) 12838198 IBIS 990 / 7739
33
 (HPO:0003201) Rhabdomyolysis 23868323 IBIS 27 / 7739
34
 (HPO:0001324) Muscle weakness 24305961 IBIS 859 / 7739
35
 (OMIM) Rhabdomyolysis, episodic 23868323 IBIS 1 / 7739
36
 (OMIM) Hepatic dysfunction 8651282 IBIS 1 / 7739
37
 (OMIM) Increased serum acylcarnitines 10400133 IBIS 1 / 7739
38
 (MedDRA:10049438) General physical health deterioration Frequent [IBIS] 43% (n=21) 12838198 IBIS 1 / 7739
39
 (OMIM) Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase 8651282 IBIS 1 / 7739
40
 (MedDRA:10047920) Wheelchair user 24305961 IBIS 3 / 7739

Associated genes:

HADHA; HADHB;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
HADHA rs137852769 pathogenic RCV000009266.4
HADHA rs137852770 pathogenic RCV000009268.4
HADHA rs137852771 pathogenic RCV000009271.4
HADHA rs137852772 pathogenic RCV000009273.3
HADHA rs137852773 pathogenic RCV000009274.3
HADHA rs137852774 pathogenic RCV000009275.4
HADHA rs137852775 pathogenic RCV000009276.5
HADHA rs147103714 pathogenic RCV000177002.1
HADHA rs200017313 pathogenic RCV000173655.1
HADHA rs781205883 pathogenic RCV000178060.1
HADHA rs781222705 pathogenic RCV000009270.4
HADHA rs786205088 pathogenic RCV000009269.4
HADHA rs794727198 pathogenic RCV000175265.1
HADHA rs794727219 pathogenic RCV000175393.1
HADHB rs121913131 pathogenic RCV000015969.22
HADHB rs121913132 pathogenic RCV000015970.26
HADHB rs121913133 pathogenic RCV000015971.26
HADHB rs121913134 pathogenic RCV000015972.22
HADHB rs267606859 pathogenic RCV000015974.26
HADHB rs764623179 pathogenic RCV000170518.2

Additional Information:

Description: (OMIM) The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by ...
Clinical Description OMIM Wanders et al. (1992) reported an infant, born of first-cousin parents, who presented with hypoglycemia and major hypotonia at 2 days of age. The infant developed respiratory failure and showed poor spontaneous motility and absence of suckling and ...
Genotype-Phenotype Correlations OMIM In 2 unrelated patients with slowly progressive neuropathy and recurrent myoglobinuria, Ibdah et al. (1998) confirmed MTP deficiency and identified biallelic mutations in exon 9 of the HADHA gene (600890.0008-600890.0010). One of the patients had been reported by ...
Molecular genetics OMIM In a patient with MTP deficiency, Brackett et al. (1995) identified compound heterozygosity for 2 mutations in the HADHA gene (600890.0003 and 600890.0004). The patient presented in the neonatal period with hypoglycemia and cardiomyopathy and later died unexpectedly ...