Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: LCHADD [IBIS]
lchad deficiency
Number of Symptoms 40
OrphanetNr: 5
OMIM Id: 609016
ICD-10: E71.3
G60
UMLs: C0342786
MeSH:
MedDRA:
Snomed: 237999008

Prevalence, inheritance and age of onset:

Prevalence: 0.4 of 100 000
Inheritance: Autosomal recessive
Monogenic
PMID:27078015 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: 3-hydroxyacyl-CoA dehydrogenase deficiency
 -Rare genetic disease
Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Metabolic disease with pigmentary retinitis
 -Rare eye disease
 -Rare genetic disease
Rare hereditary metabolic disease with peripheral neuropathy
 -Rare genetic disease
 -Rare neurologic disease
Syndrome with hypoparathyroidism
 -Rare endocrine disease
 -Rare genetic disease

Comment:

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive disorder (PMID:27078015) and the consequence of a mutation in HADHA, c.1528G>C, leading to a single amino acid substitution, p. Glu474Gln (PMID:22459206). This impairs primarily the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). HADHA is part of the trifunctional protein (TFP) heteroctomer (consisting of the two genes HADHA and HADHB conding for the two subunits alpha and beta of TFP) (PMID:22459206). LCHADD is an inborn error of fatty acid metabolism that affects the degradation of long chain fatty acids and causes insufficient energy production and accumulation of toxic intermediates. The treatment consists of a diet low in fat, with supplementation of medium-chain triglycerides that bypass the metabolic block. In addition, frequent feeds and extra carbohydrates are given during febrile illnesses to reduce lipolysis (PMID:23430524). LCHAD deficiency is clinically indistinguishable from severe TFPD (trifunctional protein deficiency) (ORPHANET, April 2016).

Symptom Information: Sort by abundance 

1
 (HPO:0011675) Arrhythmia 12637776 IBIS 226 / 7739
2
 (HPO:0000532) Chorioretinal abnormality 27078015 IBIS 5 / 7739
3
 (HPO:0000533) Chorioretinal atrophy Frequent [IBIS] 27078015 IBIS 24 / 7739
4
 (HPO:0000580) Pigmentary retinopathy Frequent [IBIS] 27078015 IBIS 49 / 7739
5
 (HPO:0000488) Retinopathy 24997711 IBIS 75 / 7739
6
 (HPO:0004360) Abnormality of acid-base homeostasis 26676313 IBIS 5 / 7739
7
 (HPO:0001942) Metabolic acidosis 26676313 IBIS 81 / 7739
8
 (HPO:0001508) Failure to thrive 26676313 IBIS 454 / 7739
9
 (HPO:0001943) Hypoglycemia Frequent [IBIS] 27078015 IBIS 131 / 7739
10
 (HPO:0001985) Hypoketotic hypoglycemia Frequent [IBIS] 25141826 IBIS 11 / 7739
11
 (HPO:0008160) 3-hydroxydicarboxylic aciduria 1537353 IBIS 1 / 7739
12
 (HPO:0001711) Abnormality of the left ventricle 26676313 IBIS 22 / 7739
13
 (HPO:0001638) Cardiomyopathy Frequent [IBIS] 27078015 IBIS 192 / 7739
14
 (HPO:0001639) Hypertrophic cardiomyopathy Frequent [IBIS] 26676313 IBIS 137 / 7739
15
 (HPO:0001644) Dilated cardiomyopathy Occasional [IBIS] 26676313 IBIS 141 / 7739
16
 (HPO:0002913) Myoglobinuria 22459206 IBIS 22 / 7739
17
 (HPO:0001635) Congestive heart failure 1537353 IBIS 232 / 7739
18
 (HPO:0100950) Long chain 3 hydroxyacyl coA dehydrogenase deficiency Very frequent [IBIS] 24997711 IBIS 1 / 7739
19
 (HPO:0003236) Elevated serum creatine phosphokinase 27117294 IBIS 214 / 7739
20
 (HPO:0001397) Hepatic steatosis Frequent [IBIS] 27078015 IBIS 75 / 7739
21
 (HPO:0003201) Rhabdomyolysis Frequent [IBIS] 27078015 IBIS 27 / 7739
22
 (HPO:0001252) Muscular hypotonia Frequent [IBIS] 23430524 IBIS 990 / 7739
23
 (HPO:0002480) Hepatic encephalopathy 1537353 IBIS 6 / 7739
24
 (HPO:0011096) Peripheral demyelination 1537353 IBIS 28 / 7739
25
 (HPO:0003477) Peripheral axonal neuropathy 1537353 IBIS 62 / 7739
26
 (HPO:0007141) Sensorimotor neuropathy 1537353 IBIS 27 / 7739
27
 (HPO:0001271) Polyneuropathy 24997711 IBIS 56 / 7739
28
 (HPO:0001259) Coma 24997711 IBIS 65 / 7739
29
 (HPO:0007185) Loss of consciousness 24997711 IBIS 9 / 7739
30
 (HPO:0001511) Intrauterine growth retardation Frequent [IBIS] 23430524 IBIS 358 / 7739
31
 (HPO:0100602) Preeclampsia Frequent [IBIS] 23430524 IBIS 9 / 7739
32
 (HPO:0004386) Gastrointestinal inflammation 26676313 IBIS 5 / 7739
33
 (HPO:0001394) Cirrhosis Occasional [IBIS] 22459206 IBIS 102 / 7739
34
 (HPO:0002240) Hepatomegaly Frequent [IBIS] 23430524 IBIS 467 / 7739
35
 (HPO:0006582) Reye syndrome-like episodes 1537353 IBIS 5 / 7739
36
 (MedDRA:10049058) HELLP syndrome Frequent [IBIS] 23430524 IBIS 2 / 7739
37
 (HPO:0045045) Elevated plasma acylcarnitine levels 2044590 IBIS 3 / 7739
38
 (MedDRA:10000746) Acute fatty liver of pregnancy Frequent [IBIS] 23430524 IBIS 1 / 7739
39
 (MedDRA:10038749) Resuscitation 26676313 IBIS 1 / 7739
40
 (OMIM) Dilated left ventricle 26676313 IBIS 5 / 7739

Associated genes:

HADHA;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
HADHA rs137852769 pathogenic RCV000174836.1
HADHA rs147103714 pathogenic RCV000177003.1
HADHA rs200017313 pathogenic RCV000173656.1
HADHA rs749848370 likely pathogenic RCV000169495.1
HADHA rs769580842 likely pathogenic RCV000169337.1
HADHA rs779113356 likely pathogenic RCV000169001.1
HADHA rs781222705 pathogenic RCV000177004.1
HADHA rs786204607 likely pathogenic RCV000169366.1
HADHA rs794727198 pathogenic RCV000175266.1
HADHA rs794727219 pathogenic RCV000175394.1
HADHA rs794727700 likely pathogenic RCV000178729.1

Additional Information:

Description: (OMIM) Isolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD) is an autosomal recessive disorder characterized by early-onset cardiomyopathy, hypoglycemia, neuropathy, and pigmentary retinopathy, and sudden death (IJlst et al., 1996).
Clinical Description OMIM Wanders et al. (1989) described sudden infant death syndrome (SIDS) in a 3-day-old infant caused by deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. Duran et al. (1991) reported that the younger sister of this patient began at the age of ...
Molecular genetics OMIM To identify the molecular basis of the deficiency in 26 Dutch patients with a deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase, IJlst et al. (1994) sequenced the cDNAs encoding the alpha and beta subunits of the trifunctional enzyme and identified ...
Population genetics OMIM Ibdah et al. (1999) found 17 different mutations among the 24 children in their study. In the 19 children with isolated deficiency of LCHAD, 71% of alleles had the E510Q mutation, and none of the 10 alleles (all ...