Metabolic Diseases (will overlap with rare inherited) Flashcards
What enzyme is deficient in homocystinuria?
Cystathionine beta-synthase (CBS)
What is the genetic inheritance of homocystinuria?
Autosomal recessive
What substrate accumulates in homocystinuria?
Homocysteine and its metabolites
What are the clinical features of homocystinuria?
Intellectual disability, Thromboembolic events, Ectopia lentis (lens dislocation), Marfanoid body habitus, Osteoporosis
How is homocystinuria treated?
Vitamin B6 (pyridoxine) supplementation, Methionine-restricted diet, Folate and B12 supplementation
What is the treatment response to vitamin B6 in homocystinuria?
Some patients are responsive to high doses of vitamin B6, leading to reduced homocysteine levels
What other diseases should be considered in the differential diagnosis of homocystinuria?
Marfan syndrome, Ehlers-Danlos syndrome
What is the effect of homocystinuria on the cardiovascular system?
Increased risk of thromboembolism (stroke, deep vein thrombosis, pulmonary embolism)
What is the characteristic ocular finding in homocystinuria?
Ectopia lentis (dislocated lens)
What are the skeletal findings in homocystinuria?
Marfanoid features (tall, long limbs, hypermobile joints), Osteoporosis
What enzyme is deficient in phenylketonuria (PKU)?
Phenylalanine hydroxylase (PAH)
What cofactor deficiency can also cause PKU?
Tetrahydrobiopterin (BH4) deficiency
What is the genetic inheritance pattern of PKU?
Autosomal recessive
What substrate accumulates in PKU?
Phenylalanine
What amino acid becomes essential in PKU?
Tyrosine
What are the clinical features of PKU?
Intellectual disability, Seizures, Musty body odor, Eczema, Light skin and hair, Growth retardation
Why do PKU patients have light skin and hair?
Lack of tyrosine, which is needed for melanin synthesis
What is the characteristic odor in PKU and why does it occur?
Musty/mousy body odor due to phenylacetate accumulation
How is PKU diagnosed?
Newborn screening (elevated phenylalanine levels)
What is the treatment for PKU?
Phenylalanine-restricted diet, Tyrosine supplementation, BH4 supplementation in BH4-responsive cases
What foods must be avoided in PKU?
High-protein foods (meat, dairy, eggs), Aspartame (artificial sweetener)
What is maternal PKU syndrome?
Teratogenic effects of high phenylalanine levels in a pregnant woman with PKU
What are the clinical features of maternal PKU syndrome?
Microcephaly, Congenital heart defects, Intellectual disability, Growth restriction
What is the function of tetrahydrobiopterin (BH4) in amino acid metabolism?
Cofactor for phenylalanine hydroxylase (PAH) and tyrosine hydroxylase
How does PKU differ from alkaptonuria?
PKU involves phenylalanine metabolism, while alkaptonuria involves tyrosine metabolism
What enzyme is deficient in maple syrup urine disease (MSUD)?
Branched-chain alpha-ketoacid dehydrogenase (BCKD) complex
What is the inheritance pattern of MSUD?
Autosomal recessive
What amino acids accumulate in MSUD?
Branched-chain amino acids (Leucine, Isoleucine, Valine)
What toxic metabolites accumulate in MSUD?
Alpha-ketoacids of branched-chain amino acids, especially α-ketoisocaproate (from leucine)
What are the clinical features of MSUD?
Poor feeding, Vomiting, Lethargy, Hypotonia, Seizures, Sweet/maple syrup-smelling urine, Intellectual disability
Why does urine in MSUD have a sweet smell?
Due to the accumulation of branched-chain keto acids
What severe complication can result from MSUD if left untreated?
Life-threatening metabolic crisis with ketoacidosis, coma, and death
How is MSUD diagnosed?
Newborn screening (elevated branched-chain amino acids in blood, organic acid analysis in urine)
What is the primary treatment for MSUD?
Dietary restriction of branched-chain amino acids (leucine, isoleucine, valine)
What supplement can be given in some cases of MSUD?
Thiamine (Vitamin B1), as BCKD requires it as a cofactor
What is the role of thiamine (B1) in MSUD treatment?
Some milder cases (thiamine-responsive MSUD) improve with high-dose B1 supplementation
What is the metabolic consequence of leucine accumulation in MSUD?
Neurotoxicity leading to cerebral edema and neurological damage
What dietary restrictions must be maintained lifelong in MSUD?
Avoidance of high-protein foods (meat, dairy, eggs, nuts) to prevent metabolic crises
What enzyme is deficient in classic galactosemia?
Galactose-1-phosphate uridyltransferase (GALT)
What are the symptoms of classic galactosemia?
Jaundice, Hepatomegaly, Vomiting, Cataracts, Failure to thrive, Intellectual disability
What enzyme is deficient in hereditary fructose intolerance?
Aldolase B
What metabolite accumulates in hereditary fructose intolerance?
Fructose-1-phosphate
What are the symptoms of hereditary fructose intolerance?
Hypoglycemia, Jaundice, Hepatomegaly, Vomiting after fructose consumption
What enzyme is deficient in fructokinase deficiency (essential fructosuria)?
Fructokinase
What is the clinical presentation of essential fructosuria?
Benign, Asymptomatic, Fructose in urine
What enzyme is deficient in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency?
Medium-chain acyl-CoA dehydrogenase
What are the symptoms of MCAD deficiency?
Hypoketotic hypoglycemia, Vomiting, Lethargy, Seizures, Sudden death in infants
What enzyme is defective in Hunter syndrome?
Iduronate-2-sulfatase
What are the clinical features of Hunter syndrome?
Developmental delay, Hepatosplenomegaly, Aggressive behavior, No corneal clouding
What enzyme is deficient in Hurler syndrome?
Alpha-L-iduronidase
What are the clinical features of Hurler syndrome?
Gargoylism, Corneal clouding, Hepatosplenomegaly, Developmental delay
What gene is mutated in Wilson disease?
ATP7B
What are the clinical features of Wilson disease?
Hepatic dysfunction, Neurologic symptoms (dystonia, tremors), Kayser-Fleischer rings
What mineral accumulates in Menkes disease?
Copper
What is the inheritance pattern of Menkes disease?
X-linked recessive
What are the symptoms of Menkes disease?
Brittle ‘kinky’ hair, Developmental delay, Hypotonia, Seizures
What are the key features of Waardenburg syndrome?
Sensorineural hearing loss, White forelock, Heterochromia, Dystopia canthorum
What is the genetic cause of Smith-Magenis syndrome?
Deletion of 17p11.2
What are the clinical features of Smith-Magenis syndrome?
Intellectual disability, Self-injury, Sleep disturbances, Behavioral problems
What gene is mutated in Charcot-Marie-Tooth disease?
PMP22 (most common)
What are the clinical features of Charcot-Marie-Tooth disease?
Progressive distal muscle weakness, Foot drop, High-arched feet (pes cavus)
What gene is mutated in Cornelia de Lange syndrome?
NIPBL (most common)
What are the clinical features of Cornelia de Lange syndrome?
Growth delay, Intellectual disability, Synophrys (unibrow), Limb abnormalities
What mutation causes McCune-Albright syndrome?
GNAS gene (activating mutation in G-protein signaling)
What are the clinical features of McCune-Albright syndrome?
Café-au-lait spots, Polyostotic fibrous dysplasia, Precocious puberty, Endocrinopathies
Cataracts, cant track pen, no social smile
GALK, galatokinase def
Infantile cataracts, failure to thrive, e coli sepsis
GALT, galatose 1 phosphate uridyltransferase
