Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency Clinical Presentation

Updated: Jan 11, 2019
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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LCHAD deficiency can initially present with sudden unexpected postnatal collapse (SUPS) in the immediate newborn period. [15]

A study of four patients with LCHAD deficiency reported clinical onset in the form of acute encephalopathy between ages 9 months and 3 years. [16]

Acute metabolic crises usually manifest as hypoketotic hypoglycemia that may be accompanied by cardiomyopathy, hypotonia, and hepatomegaly. These metabolic crises occur more frequently in infancy and early childhood.

Careful analysis of patients who presented with hypoglycemia revealed that most of them had a constellation of easily missed, nonspecific symptoms before the hypoglycemic episode.

Many patients may present with myopathy characterized by profound weakness, often accompanied by cardiomyopathy. [17] Three-fourths of patients studied with trifunctional protein deficiency, including LCHAD deficiency, had long-term myopathic symptoms. [18]

Some patients may present in infancy or childhood with myoglobinuria or as adults with exercise-induced muscle pains and rhabdomyolysis.

Some patients present with peripheral sensorimotor polyneuropathy. In one case, the patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy. [19, 20] A case of acute dilated cardiomyopathy was reported in a 3-year-old patient with LCHAD deficiency. [21]

Progressive visual loss has been documented in over 70% of patients with LCHAD activity deficiency.

Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy.

LCHAD deficiency should also be considered in patients who present clinically with hemophagocytic lymphohistiocytosis (HLH), especially those with a family history of consanguineous marriage and laboratory results of hypoglycemia, metabolic acidosis, and high creatinine kinase levels. [22]



LCHAD deficiency often manifests as a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic changes. [23]

Neuropsychological examination   

Patients with LCHAD deficiency have a specific cognitive pattern, including intellectual disability and specific autistic deficiencies. [24] They may have a normal intelligence quotient (IQ) with weaknesses in auditive verbal memory and adaptive and executive functions.

Neurological examination

The acute episode of hypoketotic hypoglycemic encephalopathy may begin with a seizure.

Most patients are hypotonic, at least in infancy.

Examination may reveal profound weakness, decreased movements, and a frog-leg position.

Deep tendon reflexes may be absent in infancy.

The patient may toe-walk and display an equinus deformity.

Extensor plantar responses have been reported.


Examination of the heart may reveal cardiomegaly, poor heart sounds, and gallop rhythm.

Skeletal muscle

In 8 cases, light microscopy of muscle specimens showed fatty infiltration and fiber degeneration. [25]


Most patients have hepatomegaly.

Jaundice may develop in infancy along with elevation of the transaminases.

Ophthalmological examination

In the youngest patients, the fundus may be pale. Thereafter, aggregation of pigment has been detected in the posterior pole and macular region.

Progressive atrophy of the retinal pigment epithelium, choroid, neural retina, and retinal vessels follow initial pigment abnormalities. This may lead to a completely bare sclera in the central fundus.

Posterior staphylomas and delicate lens opacities also may be observed. Cataracts have also been reported.



A molecular defect that affects the mitochondrial trifunctional protein (MTP) causes LCHAD activity deficiency.

Molecular defects are responsible for the two types of defect of MTP (ie, LCHAD activity deficiencies, MTP deficiencies).

The molecular defect affects the function of the MTP, which contains the activity of LCHAD activity, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.

In most patients, the deficiency is isolated to LCHAD activity; yet, in some patients, defective activity of all 3 enzymes of the protein is observed.

In isolated LCHAD activity deficiency, most of the patients are homozygous for a guanine-to-cytosine transversion at position 1528, involving the alpha subunit of the MTP in the active site domain of the LCHAD activity encoding region. The nicotinamide adenine dinucleotide (NAD) cofactor-binding sequence resides in this region.

Other mutations have been described, usually in compound with G1528C.

MTP deficiency is caused by numerous mutations in either alpha or beta subunit DNA encoding regions with resulting decreased functioning of all 3 enzyme activities of LCHAD. [26]




Psychomotor retardation and seizures derived from episodes of hypoketotic hypoglycemic encephalopathy

Hypotonia and delayed motor development that may be permanent or transient after symptomatic periods

Hepatic dysfunction that may be as severe as massive total hepatic necrosis in infancy

Dilated cardiomyopathy that may present as a rapidly fatal cardiomyopathy in infancy [27]

Peripheral neuropathy

Pigmentary retinopathy

Pregnancy: Pregnancy complications reported in LCHAD deficiency carriers (with a LCHAD-deficient fetus), include HELLP syndrome and acute fatty liver of pregnancy.