Medical Genetics and Metabolic Disorders: Clinical Features, Etiology, and Treatments

Lactose intolerance - Clinical presentation

GI distress; diarrhea, gas, bloating after consuming lactose/dairy

Lactose intolerance - Common molecular etiology

Decreased expression of lactase enzyme

Lactose intolerance - Treatment / prevention

Lactase enzyme pills; avoid dairy

Type 1 Diabetes - Clinical presentation

Hyperglycemia, polyuria, polydipsia, weight loss, retinopathy, nephropathy, neuropathy

Type 1 Diabetes - Common molecular etiology

Autoimmune destruction of pancreatic beta cells

Type 1 Diabetes - Treatment

Insulin replacement therapy (exogenous)

Type 1 Diabetes - Labs

HbA1c > 6.5; elevated C-peptide; elevated serum ketones

Type 2 Diabetes - Clinical presentation

Hyperglycemia, polyuria, polydipsia, weight loss, retinopathy, nephropathy, neuropathy

Type 2 Diabetes - Common molecular etiology

Insulin resistance due to GLUT4

Type 2 Diabetes - Treatment / prevention

Low glycemic index foods; lifestyle modifications

Type 2 Diabetes - Labs

HbA1c > 6.5; oral glucose tolerance test

GSD Type 0 - Clinical presentation

Hypoglycemia; hyperketonemia; early death

GSD Type 0 - Molecular etiology

Glycogen synthase deficiency

GSD Type IV (Andersen) - Clinical presentation

Hepatosplenomegaly

GSD Type IV (Andersen) - Molecular etiology

Amylo-4,6-glucosidase (branching enzyme) deficiency

GSD Type V (McArdle) - Clinical presentation

Exercise-induced muscle pain, cramps, progressive weakness

GSD Type V (McArdle) - Molecular etiology

Muscle glycogen phosphorylase deficiency

GSD Type VI (Hers) - Clinical presentation

Hepatomegaly; mild hypoglycemia

GSD Type VI (Hers) - Molecular etiology

Liver glycogen phosphorylase deficiency

GSD Type III (Cori) - Clinical presentation

Fasting hypoglycemia

GSD Type III (Cori) - Molecular etiology

Amylo-1,6-glucosidase (debranching enzyme) deficiency

GSD Type II (Pompe) - Clinical presentation

Early-onset progressive muscle hypotonia; cardiac failure

GSD Type II (Pompe) - Molecular etiology

Lysosomal alpha-glucosidase deficiency

GSD Type I (Von Gierke) - Clinical presentation

Enlarged liver and kidney; severe fasting hypoglycemia

GSD Type I (Von Gierke) - Molecular etiology

Glucose-6-phosphatase deficiency

Galactosemia - Clinical presentation

Lethargy; nausea; vomiting; poor vision; cataracts

Galactosemia - Molecular etiology

Defective Galactose-1-Phosphate uridylyltransferase

Galactosemia - Treatment / prevention

Avoid galactose and lactose from diet

Galactosemia - Labs

High galactitol levels

Hereditary Fructose Intolerance - Clinical presentation

Vomiting and hypoglycemia after fructose consumption

Hereditary Fructose Intolerance - Molecular etiology

Aldolase B deficiency

Hereditary Fructose Intolerance - Treatment

Avoid fructose, sucrose, sorbitol

Hereditary Fructose Intolerance - Labs

Elevated lactate; hypoglycemia

G6PD Deficiency - Clinical presentation

Hemolytic anemia; fatigue; SOB with exertion; dark urine

G6PD Deficiency - What precipitates an episode?

Fava beans, severe illness, trauma, oxidative stress

G6PD Deficiency - Impact / prevention

RBCs damaged due to oxidative stress and low NADPH; avoid triggers

MCAD Deficiency - Clinical presentation

Hepatomegaly; nausea; vomiting; headache; seizure

MCAD Deficiency - Impact

Less ATP; reduced gluconeogenesis; reduced ketone body production; reduced ureagenesis

MCAD Deficiency - Treatment / prevention

High-carb, low-fat diet; avoid fasting; frequent meals

MCAD Deficiency - Labs

Elevated medium-chain fatty acids in blood

Jaundice & Gallstones (secondary to sickle cell) - Clinical presentation

RUQ pain; vomiting; dark urine; clay-colored stool; jaundice

Jaundice & Gallstones - Pathophysiology

Accumulation of unconjugated bilirubin; excess bilirubin → gallstone formation

Jaundice & Gallstones - Treatment

Hydration

Jaundice & Gallstones - Labs

Elevated bilirubin

CPT II Deficiency - Clinical presentation

Myoglobinuria, muscle pain, weakness, mild hypoglycemia, hypoketosis

CPT II Deficiency - Impact

Reduced fatty acid oxidation

CPT II Deficiency - Treatment

High-carbohydrate diet; avoid prolonged fasting

CPT II Deficiency - Labs

CPT II and myoglobin in urine

Kwashiorkor - Clinical presentation

Edema; hypoalbuminemia; anemia; hyperpigmented skin; fatty liver

Kwashiorkor - Molecular etiology

Lack of essential amino acids; negative nitrogen balance

Kwashiorkor - Treatment

High-protein diet

Kwashiorkor - Labs

Decreased albumin

Hartnup Disease - Clinical presentation

Increased amino acids in urine; red rash; possible pellagra

Hartnup Disease - Molecular etiology

B⁰ transport system defect

Hartnup Disease - Treatment

High-protein diet; niacin supplement

Cystinuria - Clinical presentation

Renal stones

Cystinuria - Molecular etiology

B⁰,+ transport system defect

Cystinuria - Treatment

Increase fluids; medication to raise urine pH

Cystinuria - Labs

Elevated cystine and arginine; cystine stones in urine

Urea Cycle Defect (OTC) - Clinical presentation

Hyperammonemia; brain damage; intellectual disability

Urea Cycle Defect - Molecular etiology

Ornithine transcarbamylase deficiency

Urea Cycle Defect - Treatment

Low-protein diet

Urea Cycle Defect - Labs

Elevated carbamoyl phosphate

PKU - Clinical presentation

Musty urine odor; intellectual disability; seizures

PKU - Molecular etiology

Phenylalanine hydroxylase deficiency

PKU - Treatment

Lifelong dietary modification

PKU - Labs

Newborn screening positive

MSUD - Clinical presentation

Sweet-smelling urine; poor feeding; vomiting; lethargy

MSUD - Molecular etiology

Defective branched-chain alpha-keto acid dehydrogenase

MSUD - Treatment

Dietary modification

MSUD - Labs

Elevated amino acids and alpha-keto acids in urine

Homocystinuria - Clinical presentation

Myopia; lens dislocation; osteoporosis; developmental delay

Homocystinuria - Molecular etiology

Cystathionine beta-synthase deficiency

Homocystinuria - Treatment

Low-methionine diet; high pyridoxine (B6)

Homocystinuria - Labs

High methionine and homocysteine; low cysteine

Alcaptonuria - Clinical presentation

Ochronosis (dark cartilage); arthritis

Alcaptonuria - Molecular etiology

Homogentisate oxidase deficiency

Alcaptonuria - Labs

Dark urine

Tyrosinemia Type II - Clinical presentation

Eye pain; eye redness; thick painful skin on palms and soles

Tyrosinemia Type II - Molecular etiology

Tyrosine aminotransferase deficiency

Tyrosinemia Type II - Treatment

No specific treatment

Tyrosinemia Type II - Labs

Elevated tyrosine

Lesch-Nyhan Syndrome - Clinical presentation

Intellectual disability; self-mutilation (lip/finger chewing)

Lesch-Nyhan Syndrome - Molecular etiology

HGPRT deficiency

Lesch-Nyhan Syndrome - Labs

Elevated uric acid

Gouty Arthritis - Clinical presentation

Swollen and inflamed joint

Gouty Arthritis - Molecular etiology

Xanthine oxidase involvement

Gouty Arthritis - Treatment

Allopurinol