MCAD deficiency, MELAS and Kearns–Sayre syndrome: board review

MCAD deficiency and fatty-acid oxidation defects

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common fatty-acid oxidation disorder, inherited as autosomal recessive. During fasting the body cannot burn fat for energy or make ketones, so glucose runs out and ketones stay low.

A child who is well between episodes becomes vomiting, lethargic and hypoglycemic during a fasting illness. Untreated episodes can cause seizures, coma and sudden death.

• Pattern: fasting or illness → hypoglycemia with low ketones.
• Marker: high C8 (octanoylcarnitine) on the acylcarnitine profile.
• During an episode, send a plasma acylcarnitine profile and urine organic acids before or as glucose is given.
• Contrast: hypoglycemia with ketones plus urine reducing substances that are not glucose suggests galactosemia or hereditary fructose intolerance.

Abnormal MCAD newborn screen

A positive MCAD screen is urgent even when the baby looks well, because the first episode can be fatal.

• Contact the family the same day; a result received after hours means evaluation in the emergency department that night.
• Ask about feeding and lethargy, and make sure the baby is not fasting.
• First labs: glucose, electrolytes and liver tests.
• Confirm with a plasma acylcarnitine profile (high C8) and urine organic acids; ACADM gene testing follows.
• Involve the metabolic (biochemical genetics) team right away.

Acute treatment of an MCAD crisis

• A child with MCAD deficiency who is vomiting, lethargic or hypoglycemic needs IV dextrose at once.
• Give D10 with electrolytes at about 1.5 times maintenance to stop fat breakdown, not just to correct the glucose.
• Do not wait for oral intake to fail repeatedly; children who cannot keep down fluids should come in early.

Preventing MCAD episodes

• Avoid prolonged fasting, with age-appropriate limits on time between feeds.
• A written sick-day (emergency) plan for families, schools and emergency departments.
• Free carnitine can be low because it is lost in the urine as acylcarnitines; add L-carnitine only when free carnitine is low.
• Outcomes are excellent when episodes are prevented.

Mitochondrial disease: inheritance and CPEO

When the respiratory chain fails, too little ATP is made and tissues with high energy needs suffer most: brain, muscle, eye, ear and heart. NADH builds up, pyruvate is shunted to lactate, and blood lactate and the lactate-to-pyruvate ratio rise.

• Variants in mitochondrial DNA (mtDNA) are passed on by the mother.
• Not every mitochondrial disease is maternal: many are caused by nuclear genes (often autosomal recessive), and some variants arise de novo.
• Chronic progressive external ophthalmoplegia (CPEO): ptosis and weak eye movements, with ragged-red fibers on muscle biopsy.
• In mitochondrial ophthalmoplegia with multisystem disease, screen hearing, cerebellar function, endocrine function (including diabetes) and the heart.

MELAS

MELAS stands for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. It is maternally inherited through mtDNA.

• Onset usually in childhood, about 2–15 years.
• Short stature, hearing loss, migraine-like headaches and vomiting, then seizures and stroke-like episodes.
• MRI: stroke-like lesions in the posterior cortex (temporal, parietal, occipital) that do not follow a vascular territory.
• High lactate; ragged-red fibers on muscle biopsy (Gomori trichrome stain).
• Confirm with mtDNA testing; the most common variant is m.3243A>G.
• Stroke-like episode: IV L-arginine (expert consensus). Avoid mitochondrial toxins such as valproate.

Kearns–Sayre syndrome

• CPEO beginning before age 20, plus pigmentary retinopathy, plus heart block.
• The key cardiac risk is conduction block, which can cause sudden death.
• Do regular ECG and Holter monitoring; place a pacemaker for conduction block.

Common questions

Sources

• GeneReviews: Medium-chain acyl-CoA dehydrogenase deficiency
• Pediatric Endocrine Society: Recommendations for evaluation of persistent hypoglycemia (J Pediatr 2015)
• Mitochondrial Medicine Society: Patient care standards for primary mitochondrial disease (Genet Med 2017)
• Mitochondrial Medicine Society: Diagnosis and management consensus (Genet Med 2015)
• GeneReviews: MELAS

Written for Pedemy in our own words from the sources above; checked November 2026. For education only, not medical advice; check doses and local protocols before treating a patient. Pedemy is independent and not affiliated with or endorsed by the organizations cited.