Metabolic Disorders

A tall teenager with intellectual disability has downward lens dislocation (ectopia lentis). He had a stroke at age 15. Homocysteine is markedly elevated.

An infant is identified on newborn screening with elevated proline levels. The child is clinically asymptomatic. Family history reveals the mother also has elevated proline on plasma amino acids but is healthy.

A newborn becomes lethargic at day 3-5 of life with poor feeding and a sweet maple syrup odor. Amino acids show elevated leucine, isoleucine, and valine.

A newborn presents with severe hypotonia, apnea, and intractable seizures within the first days of life. CSF glycine is markedly elevated with an elevated CSF:plasma glycine ratio.

A newborn has an elevated phenylalanine on newborn screening. Without treatment, affected children develop intellectual disability, seizures, and musty body odor.

A newborn has intractable seizures unresponsive to standard anticonvulsants. Seizures stop dramatically after IV pyridoxine administration.

A term infant has congenital microcephaly, seizures beginning in the first weeks that do not respond to standard antiseizure medication, and profound developmental delay. Plasma amino acids are read as normal. Paired fasting CSF and plasma amino acids show **low CSF serine and low CSF glycine**.

An infant presents with liver failure, coagulopathy, and a cabbage-like odor. Succinylacetone is elevated in urine.

A child presents with progressive spastic diplegia and intellectual disability. Unlike other urea cycle disorders, hyperammonemia is mild or absent. Plasma arginine is markedly elevated.

A neonate presents within the first few days of life with poor feeding, lethargy, and hyperammonemia. Plasma citrulline is elevated and argininosuccinic acid is present in plasma and urine. Hair examination reveals trichorrhexis nodosa.

A male newborn becomes lethargic with poor feeding on day 2-3 of life. Ammonia is >1000 μmol/L. He has respiratory alkalosis progressing to coma.

A newborn screen flags an elevated C5-hydroxyacylcarnitine (C5-OH). The baby is feeding well and examining normally. Confirmatory testing on the infant is equivocal, and testing the **mother** shows the same biochemical abnormality: she has 3-MCC deficiency herself, has always been asymptomatic, and was identified only because her baby was screened.

A 4-month-old has myoclonic seizures that have not responded to two antiseizure medications, patchy hair loss, and a scaly rash around the mouth and eyes. Blood gas shows a metabolic acidosis with elevated lactate. Urine organic acids show 3-hydroxyisovaleric acid.

An infant with macrocephaly and hypotonia develops progressive spasticity, visual impairment, and seizures. MRI shows diffuse white matter involvement. N-acetylaspartic acid is elevated in urine.

A macrocephalic infant develops acute dystonia after a febrile illness. MRI shows frontotemporal atrophy and basal ganglia injury.

A newborn with vomiting and metabolic acidosis has a distinctive "sweaty feet" odor. Isovalerylglycine is elevated in urine.

A 9-month-old is brought in during a viral illness with vomiting and lethargy. Glucose is 32 mg/dL and there is a severe metabolic acidosis. **Urine ketones are negative.** Ammonia is mildly elevated. Urine organic acids show 3-hydroxy-3-methylglutaric acid.

A newborn becomes lethargic with metabolic acidosis, hyperammonemia, and ketosis. Urine organic acids show markedly elevated methylmalonic acid.

A newborn presents similarly to MMA with metabolic acidosis and hyperammonemia. Organic acids show elevated propionic acid and methylcitrate.

An infant of Inuit ancestry presents with hypoketotic hypoglycemia, hepatomegaly, and elevated transaminases after a viral illness. Newborn screening flagged a very high C0 (free carnitine) with low long-chain acylcarnitines.

A 22-year-old develops severe muscle pain and tea-colored urine after a long hike in cold weather. CK is >50,000. This is his third episode of rhabdomyolysis triggered by prolonged exertion or fasting.

A child presents with cardiomyopathy and hypoglycemia. Plasma carnitine is severely reduced. The condition is completely treatable with carnitine supplementation.

A neonate presents in the first 48 hours of life with seizures, cardiac arrhythmia, hypoketotic hypoglycemia, and hyperammonemia. Acylcarnitine profile shows markedly elevated C16, C18, and C18:1 with low free carnitine.

A child with recurrent rhabdomyolysis has cardiomyopathy and peripheral neuropathy. Mother had HELLP syndrome during pregnancy.

A previously healthy 14-month-old becomes unresponsive after an overnight fast during a viral illness. Labs show hypoketotic hypoglycemia.

A child presents with cardiomyopathy, peripheral neuropathy, and pigmentary retinopathy. Acylcarnitine profile shows elevated long-chain hydroxy-acylcarnitines (C16-OH, C18-OH). The mother had HELLP syndrome during pregnancy.

A neonate is hypotonic with hepatomegaly and a peculiar "sweaty feet" odor. Imaging shows polycystic kidneys and dysmorphic facial features. Acylcarnitine profile is broadly abnormal across short-, medium-, and long-chain species; urine organic acids show elevated glutaric, ethylmalonic, and multiple dicarboxylic acids.

A newborn screen flags elevated C4 (butyrylcarnitine). The infant is asymptomatic. Urine organic acids show elevated ethylmalonic acid. Sequencing identifies two _ACADS_ variants, including the common c.625G>A susceptibility variant.

A newborn presents with cardiomyopathy and hypoglycemia. Acylcarnitine profile shows elevated C14:1.

A young adult with intellectual disability has bilateral cataracts and progressive ataxia. MRI shows white matter abnormalities. Serum cholestanol is elevated.

A 35-year-old has a heart attack. His LDL cholesterol is 350 mg/dL. He has tendon xanthomas on his Achilles tendons and a corneal arcus. His father died of MI at age 42.

A newborn male has 2-3 toe syndactyly, ambiguous genitalia (undervirilization), microcephaly, and cleft palate. 7-dehydrocholesterol is markedly elevated.

A child has strikingly enlarged, yellow-orange tonsils. A fasting lipid panel shows HDL cholesterol near zero and a markedly reduced apolipoprotein A-I. He also has mild hepatosplenomegaly and patchy sensory loss consistent with peripheral neuropathy.

A newborn presents at 1 week of age with jaundice, hepatomegaly, and E. coli sepsis after starting breast milk or formula. Cataracts are noted on exam.

An infant with hepatomegaly has severe hypoglycemia not responding to glucagon. Labs show lactic acidosis, hyperuricemia, and hyperlipidemia.

An infant with severe hypotonia has cardiomegaly with short PR interval. CK is elevated. Acid alpha-glucosidase activity is deficient.

A child with hepatomegaly has fasting hypoglycemia similar to GSD1 but responds to glucagon and has elevated CK due to myopathy.

A teenager experiences muscle cramps and fatigue during exercise. He notices dark urine after intense activity. He describes a "second wind" phenomenon where exercise becomes easier after initial fatigue.

An infant develops vomiting, hypoglycemia, and liver dysfunction after introduction of fruit/juice. Symptoms resolve when fructose is removed.

A teenage boy has painful burning in hands and feet (acroparesthesias), inability to sweat, and angiokeratomas on his trunk. His mother has mild symptoms.

A child of Ashkenazi Jewish ancestry has hepatosplenomegaly, thrombocytopenia, and bone pain. Bone marrow shows "Gaucher cells" with wrinkled tissue paper appearance.

A 6-month-old of non-Ashkenazi background has progressive loss of motor milestones, exaggerated startle to sound, hypotonia, and hepatosplenomegaly. Fundoscopy shows a cherry-red macular spot. Hexosaminidase A activity is reduced; **total hexosaminidase (A + B) is also reduced**, distinguishing this from Tay-Sachs.

An infant with irritability and feeding difficulties develops progressive spasticity, blindness, and peripheral neuropathy. CSF protein is elevated.

A toddler who was walking normally begins to fall frequently. He develops progressive spasticity, peripheral neuropathy, and cognitive decline.

An infant with hepatosplenomegaly has progressive neurological decline. Bone marrow shows "foam cells." Cherry-red spot is present.

A 6-month-old of Ashkenazi Jewish ancestry has developmental regression, exaggerated startle response, and cherry-red spot on fundoscopy. Hexosaminidase A is deficient.

A child develops coarse facial features, corneal clouding, hepatosplenomegaly, and developmental delay. Urine shows elevated dermatan and heparan sulfate.

A boy has features similar to Hurler but without corneal clouding. He has distinctive ivory-colored skin lesions (pebbling) on the upper back and shoulders.

A child with normal appearance develops severe behavioral problems, sleep disturbance, and progressive dementia. Mild coarse features develop later.

A child with severe skeletal abnormalities has short trunk, odontoid hypoplasia, and corneal clouding but normal intelligence.

An infant presents with vomiting, diarrhea, failure to thrive, and massive hepatosplenomegaly. Abdominal X-ray reveals bilateral adrenal calcifications. Liver biopsy shows lipid-laden macrophages.

An infant presents with coarse facial features, skeletal abnormalities, and severe developmental delay. Serum lysosomal enzyme levels are markedly elevated, but intracellular enzyme activity is deficient. Fibroblasts show dense cytoplasmic inclusions on microscopy.

A school-age child develops progressive vision loss, seizures, and cognitive decline. Fundoscopy shows retinal degeneration.

A child presents with bilateral congenital cataracts, severe global developmental delay, spastic paraparesis, and seizures. Plasma plasmalogens are reduced and dihydroxyacetone phosphate acyltransferase (DHAP-AT) activity in fibroblasts is normal, pointing away from RCDP and toward an isolated downstream block.

An adult with progressive night blindness (retinitis pigmentosa) develops peripheral neuropathy, ataxia, and anosmia. Phytanic acid is elevated.

A newborn with severe proximal limb shortening has cataracts and ichthyosis. X-rays show stippled calcifications in the epiphyses. Plasmalogen levels are severely reduced.

A 7-year-old boy with behavior changes and declining school performance develops vision and hearing loss. MRI shows posterior white matter changes. He has adrenal insufficiency.

A hypotonic newborn with distinctive facial features (high forehead, large fontanelles) has hepatomegaly, seizures, and stippled calcifications in the epiphyses.

A male infant presents with dilated cardiomyopathy, neutropenia, and failure to thrive. He has recurrent bacterial infections. Urine organic acids show elevated 3-methylglutaconic acid. His maternal uncle died in infancy from heart failure.

An infant with developmental regression and hypotonia has elevated lactate. MRI shows symmetric basal ganglia and brainstem lesions.

A teenager with short stature, diabetes, and sensorineural hearing loss has recurrent episodes resembling strokes that don't follow vascular territories. Lactate is elevated.

A patient with myoclonic seizures, ataxia, and myopathy has multiple lipomas. Muscle biopsy shows ragged red fibers.

An infant with refractory sideroblastic anemia and pancreatic insufficiency (Pearson) later develops ptosis, ophthalmoplegia, and cardiac conduction defects (Kearns-Sayre).

A young adult with progressive external ophthalmoplegia has severe GI dysmotility, cachexia, and peripheral neuropathy.

A young adult with developmental delay has progressive ataxia, peripheral neuropathy, and night blindness. Retinitis pigmentosa is found on fundoscopy.

An infant with refractory seizures and developmental regression develops liver failure. Valproate administration causes acute hepatotoxicity.

A newborn with lactic acidosis and hypotonia has agenesis of the corpus callosum on MRI. Lactate:pyruvate ratio is normal (distinguishing from respiratory chain defects).

An infant with recurrent severe infections (pneumonia, chronic diarrhea, candidiasis) has absent T, B, and NK cells. Skeletal abnormalities are present on X-ray.

A 6-month-old has failure to thrive and a **megaloblastic anemia that has not responded to vitamin B12 or folate**. Serum ammonia is normal. Urine contains orange-brown crystals, and urine organic acids show massively elevated orotic acid.

A boy with developmental delay and choreoathetosis exhibits self-injurious behavior including lip and finger biting. Uric acid is elevated and he has gout and kidney stones.

A young woman taking oral contraceptives develops severe abdominal pain, vomiting, and constipation. She becomes confused and has a seizure. Urine turns dark on standing. PBG is elevated.

A 40-year-old presents with premature arthritis of the spine and large joints. His urine turns dark when left standing. On exam, his ear cartilage appears bluish-black (ochronosis).

A 5-year-old boy has intellectual disability with **expressive speech far more impaired than comprehension**, autistic features, and seizures. Metabolic and genetic first-tier testing is unrevealing. Brain MR spectroscopy shows an **absent creatine peak**.

A newborn presents with poor feeding, lethargy, and failure to thrive. Labs show elevated methylmalonic acid AND homocysteine, with megaloblastic anemia. Ophthalmologic exam reveals progressive macular degeneration.

An infant with failure to thrive has inverted nipples and abnormal fat pads. He has hypotonia, developmental delay, and strabismus. Transferrin isoelectric focusing shows an abnormal pattern.

A term newborn feeds poorly and develops intractable seizures on day 2. Glucose, ammonia, and lactate are normal, so the workup moves away from the usual metabolic causes. Brain MRI at the end of the first week shows diffuse cystic encephalomalacia resembling severe hypoxic-ischemic injury, though the delivery was uncomplicated. **Serum uric acid is very low.**

A 28-year-old woman with a history of recurrent first-trimester pregnancy losses is found to be homozygous for the *MTHFR* c.677C>T (p.Ala222Val) variant on a "thrombophilia panel" ordered by her OB/GYN. She is referred to genetics to discuss the implications. She has no personal or family history of thrombosis.