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🩺 Pathology
📋 Pharmacology
Adenosine deaminase deficiency
Adenosine deaminase deficiency

Severe combined immunodeficiency caused by toxic accumulation of deoxyadenosine and dATP.

  • 🟪 Overview
    Severe combined immunodeficiency caused by toxic accumulation of deoxyadenosine and dATP.
  • 🧠 Pathophysiology
    Autosomal‑recessive defect in ADA leads to failed degradation of adenosine → ↑dATP → inhibition of ribonucleotide reductase → ↓DNA synthesis → lymphocyte apoptosis.
  • 🩻 Clinical Presentation
    Recurrent viral, bacterial, fungal, and opportunistic infections within first months of life; chronic diarrhea; failure to thrive.
  • 🩺 Diagnosis
    Very low T‑, B‑, and NK‑cell counts; absent thymic shadow on CXR; undetectable ADA enzyme activity in leukocytes.
  • 💊 Management
    Hematopoietic stem‑cell transplant or gene therapy; prophylactic antimicrobials; IVIG; avoid live vaccines.
  • 📊 Epidemiology
    Incidence ≈1:200,000 births; accounts for ~15% of SCID cases.
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Lesch‑Nyhan syndrome
Lesch‑Nyhan syndrome

X‑linked disorder of purine metabolism characterized by hyperuricemia, neuropsychiatric disturbances, and self‑mutilation.

  • 🟪 Overview
    X‑linked disorder of purine metabolism characterized by hyperuricemia, neuropsychiatric disturbances, and self‑mutilation.
  • 🧠 Pathophysiology
    Absent hypoxanthine‑guanine phosphoribosyltransferase (HGPRT) → failure of purine salvage → ↑PRPP amidotransferase activity → excess de novo purine synthesis & uric acid.
  • 🩻 Clinical Presentation
    Self‑mutilating behavior (biting lips/fingers), dystonia, choreoathetosis, gouty arthritis, orange “sand” sodium urate crystals in diapers.
  • 🩺 Diagnosis
    Elevated serum uric acid, HGPRT enzyme assay, genetic testing of HPRT1 gene.
  • 💊 Management
    Allopurinol or febuxostat for hyperuricemia; behavioral & protective devices; dopamine agonists or intrathecal baclofen for dystonia.
  • 📊 Epidemiology
    Rare: ~1 in 380,000; exclusively in males.
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I‑Cell disease
I‑Cell disease

Congenital disorder of lysosomal enzyme targeting leading to intracellular inclusions and extracellular enzyme accumulation.

  • 🟪 Overview
    Congenital disorder of lysosomal enzyme targeting leading to intracellular inclusions and extracellular enzyme accumulation.
  • 🧠 Pathophysiology
    N‑acetylglucosaminyl‑1‑phosphotransferase deficiency → failure to add mannose‑6‑phosphate to lysosomal enzymes in Golgi → enzymes secreted instead of sent to lysosome.
  • 🩻 Clinical Presentation
    Coarse facial features, gingival hyperplasia, clouded corneas, restricted joint movement, claw hand deformities, developmental delay.
  • 🩺 Diagnosis
    ↑Plasma lysosomal hydrolases; inclusion bodies on fibroblast microscopy; genetic testing GNPTAB.
  • 💊 Management
    Supportive care: physical therapy, management of feeding and respiratory issues; no curative therapy.
  • 📊 Epidemiology
    Incidence ~1:640,000; autosomal recessive; fatal in childhood.
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Zellweger syndrome
Zellweger syndrome

Peroxisome biogenesis defect causing accumulation of very‑long‑chain and branched fatty acids.

  • 🟪 Overview
    Peroxisome biogenesis defect causing accumulation of very‑long‑chain and branched fatty acids.
  • 🧠 Pathophysiology
    PEX gene mutations → absent functional peroxisomes → impaired β‑ and α‑oxidation.
  • 🩻 Clinical Presentation
    Hypotonia, seizures, craniofacial dysmorphism (large anterior fontanelle, high forehead), hepatomegaly, developmental arrest.
  • 🩺 Diagnosis
    ↑VLCFA in plasma; PEX gene sequencing.
  • 💊 Management
    Supportive: seizure control, nutritional support, physical therapy.
  • 📊 Epidemiology
    Incidence 1:50,000; autosomal recessive; death within first year.
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Refsum disease
Refsum disease

Defect of α‑oxidation leading to phytanic acid accumulation and neurocutaneous findings.

  • 🟪 Overview
    Defect of α‑oxidation leading to phytanic acid accumulation and neurocutaneous findings.
  • 🧠 Pathophysiology
    Autosomal recessive mutation in PHYH (phytanoyl‑CoA hydroxylase) or PEX7 → inability to degrade phytanic acid.
  • 🩻 Clinical Presentation
    Scaly skin (ichthyosis), ataxia, hearing loss, cataracts, night blindness, shortening of 4th toe.
  • 🩺 Diagnosis
    ↑Serum phytanic acid; genetic testing.
  • 💊 Management
    Dietary restriction of chlorophyll (avoid dairy, ruminant fat, fish); plasmapheresis in severe cases.
  • 📊 Epidemiology
    Rare (<1:1,000,000).
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Adrenoleukodystrophy
Adrenoleukodystrophy

X‑linked disorder with accumulation of VLCFA causing adrenal insufficiency and neurologic decline.

  • 🟪 Overview
    X‑linked disorder with accumulation of VLCFA causing adrenal insufficiency and neurologic decline.
  • 🧠 Pathophysiology
    ABCD1 mutation → impaired transport of VLCFA into peroxisome → accumulation in adrenal cortex & white matter.
  • 🩻 Clinical Presentation
    Childhood cerebral form: behavioral changes, progressive spastic paresis, vision & hearing loss; adrenal crisis.
  • 🩺 Diagnosis
    ↑VLCFA; low cortisol with high ACTH; ABCD1 genetic test; brain MRI shows demyelination.
  • 💊 Management
    Lorenzo’s oil (oleic & erucic acids), hematopoietic stem‑cell transplant if early, adrenal hormone replacement.
  • 📊 Epidemiology
    1:20,000 males.
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Primary ciliary dyskinesia
Primary ciliary dyskinesia

Defective dynein arms impair mucociliary clearance and embryonic nodal flow.

  • 🟪 Overview
    Defective dynein arms impair mucociliary clearance and embryonic nodal flow.
  • 🧠 Pathophysiology
    Autosomal recessive mutations (DNAI1, DNAH5) disrupt axonemal dynein ATPase function.
  • 🩻 Clinical Presentation
    Chronic sinusitis, bronchiectasis, otitis media, infertility; 50% have situs inversus (Kartagener triad with sinusitis and bronchiectasis).
  • 🩺 Diagnosis
    ↓Nasal nitric oxide; biopsy shows absent dynein arms; genetic testing.
  • 💊 Management
    Airway clearance therapies, prophylactic antibiotics, IVF with intracytoplasmic sperm injection if desired.
  • 📊 Epidemiology
    Prevalence 1:15,000.
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Osteogenesis imperfecta
Osteogenesis imperfecta

Heritable bone fragility due to abnormal type I collagen.

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Ehlers‑Danlos syndrome
Ehlers‑Danlos syndrome

Connective‑tissue disorder with joint hypermobility and skin hyperextensibility.

  • 🟪 Overview
    Connective‑tissue disorder with joint hypermobility and skin hyperextensibility.
  • 🧠 Pathophysiology
    Heterogeneous; defects in COL5A1/2 (classical), COL3A1 (vascular), or TNXB.
  • 🩻 Clinical Presentation
    Hyperextensible skin, atrophic scars, joint laxity; vascular type—arterial/organ rupture.
  • 🩺 Diagnosis
    Clinical criteria; genetic panel; vascular imaging.
  • 💊 Management
    Physical therapy, joint protection, avoid high‑impact sports; vascular type needs routine angiography.
  • 📊 Epidemiology
    Prevalence 1:5,000; variable inheritance.
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Menkes disease
Menkes disease

Impaired copper absorption → defective cross‑linking of collagen & elastin.

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Marfan syndrome
Marfan syndrome

Autosomal dominant fibrillin-1 mutation leading to defective microfibrils.

  • 🟪 Overview
    Autosomal dominant fibrillin-1 mutation leading to defective microfibrils.
  • 🧠 Pathophysiology
    Loss of fibrillin scaffold → excess TGF‑β signalling → abnormal elastic tissue in aorta, periosteum, ocular zonules.
  • 🩻 Clinical Presentation
    Tall stature, long extremities, pectus deformity, joint hyper‑laxity, upward lens dislocation, aortic root dilation/dissection, spontaneous pneumothorax.
  • 🩺 Diagnosis
    Clinical ± FBN1 sequencing; echocardiography for aorta; slit‑lamp eye exam.
  • 💊 Management
    β‑blocker to lower aortic shear, elective aortic root graft, ophthalmology follow‑up, avoid contact sports. Lifelong surveillance.
  • 📊 Epidemiology
    1 : 5 000–1 : 10 000 births worldwide.
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Homocystinuria (classic CBS deficiency)
Homocystinuria (classic CBS deficiency)

Autosomal recessive cystathionine‑β‑synthase defect → homocysteine→methionine pathway block.

  • 🟪 Overview
    Autosomal recessive cystathionine‑β‑synthase defect → homocysteine→methionine pathway block.
  • 🧠 Pathophysiology
    Accumulation of homocysteine damages connective tissue and vascular endothelium; ↓ cysteine production.
  • 🩻 Clinical Presentation
    Marfanoid habitus, downward lens dislocation, osteoporosis, intellectual disability, vascular thrombosis.
  • 🩺 Diagnosis
    ↑ plasma homocysteine, ↑ methionine, + urinary homocystine; newborn screening with MS/MS.
  • 💊 Management
    High‑dose pyridoxine, methionine‑restricted cysteine‑supplemented diet, betaine, aspirin/anticoag.
  • 📊 Epidemiology
    ≈ 1 : 200 000 births; higher in Ireland and Qatar.
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McCune‑Albright syndrome
McCune‑Albright syndrome

Post‑zygotic activating mutation in GNAS (Gs‑alpha) causing constitutive cAMP/PKA signalling.

  • 🟪 Overview
    Post‑zygotic activating mutation in GNAS (Gs‑alpha) causing constitutive cAMP/PKA signalling.
  • 🧠 Pathophysiology
    Somatic mosaic; mutated cells hyper‑secrete hormones and induce fibrous dysplasia of bone.
  • 🩻 Clinical Presentation
    Triad: unilateral café‑au‑lait macules with irregular borders, polyostotic fibrous dysplasia → pathologic fractures, autonomous endocrine hyperfunction (precocious puberty, Cushing, thyrotoxicosis).
  • 🩺 Diagnosis
    Clinical + radiographs (ground‑glass bone), GNAS mutation in affected tissue.
  • 💊 Management
    Bisphosphonates for bone pain, endocrine‑specific treatments, orthopedic fixation.
  • 📊 Epidemiology
    Very rare (< 1 : 1 000 000); occurs sporadically.
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Prader‑Willi syndrome
Prader‑Willi syndrome

Loss of paternally expressed genes on 15q11‑q13 (maternal disomy or paternal deletion).

  • 🟪 Overview
    Loss of paternally expressed genes on 15q11‑q13 (maternal disomy or paternal deletion).
  • 🧠 Pathophysiology
    Hypothalamic dysfunction → hyperphagia, decreased GH, gonadotropins, dysregulation of satiety.
  • 🩻 Clinical Presentation
    Severe neonatal hypotonia, poor feeding → later hyperphagia, obesity, short stature, intellectual disability, hypogonadism, almond eyes.
  • 🩺 Diagnosis
    DNA methylation analysis for imprinting defect, FISH for deletion.
  • 💊 Management
    Caloric control, GH replacement, sex steroid therapy, behavioral support.
  • 📊 Epidemiology
    Prevalence ≈ 1 : 15 000.
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Angelman syndrome
Angelman syndrome

Loss of maternally expressed UBE3A on 15q11‑q13 (paternal disomy or maternal deletion).

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Phenylketonuria (PKU)
Phenylketonuria (PKU)

Autosomal‑recessive deficiency of phenylalanine hydroxylase or BH4 cofactor → inability to convert Phe to Tyr → accumulation of phenyl‑ketones.

  • 🟪 Overview
    Autosomal‑recessive deficiency of phenylalanine hydroxylase or BH4 cofactor → inability to convert Phe to Tyr → accumulation of phenyl‑ketones.
  • 🧠 Pathophysiology
    Accumulated phenylalanine is neurotoxic; deficiency of tyrosine leads to catecholamine and melanin shortage.
  • 🩻 Clinical Presentation
    Normal at birth → by few months: intellectual disability, seizures, eczema, ‘musty/mousy’ body odor, hypopigmented skin, hair & iris.
  • 🩺 Diagnosis
    Newborn screen: ↑ phenylalanine. Confirm with quantitative plasma amino‑acid analysis.
  • 💊 Management
    Life‑long low‑phenylalanine diet (avoid aspartame) + tyrosine supplementation; sapropterin for BH4‑responsive type.
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Maple Syrup Urine Disease
Maple Syrup Urine Disease

Autosomal‑recessive deficiency of branched‑chain α‑ketoacid dehydrogenase complex → blocked degradation of leucine, isoleucine, valine.

  • 🟪 Overview
    Autosomal‑recessive deficiency of branched‑chain α‑ketoacid dehydrogenase complex → blocked degradation of leucine, isoleucine, valine.
  • 🧠 Pathophysiology
    Accumulation of branched‑chain amino acids and toxic metabolites in plasma and urine.
  • 🩻 Clinical Presentation
    Within days: poor feeding, vomiting, dystonia, maple‑syrup/burnt sugar odor of urine; progressive neurologic decline and metabolic crisis.
  • 🩺 Diagnosis
    Plasma amino‑acid profile: ↑ Leu, Ile, Val; metabolic acidosis, ketonuria.
  • 💊 Management
    Dietary restriction of branched‑chain amino acids; thiamine (B1) cofactor high‑dose; dialysis during crises.
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Alkaptonuria
Alkaptonuria

AR deficiency of homogentisate oxidase in tyrosine degradation → ↑ homogentisic acid.

  • 🟪 Overview
    AR deficiency of homogentisate oxidase in tyrosine degradation → ↑ homogentisic acid.
  • 🧠 Pathophysiology
    Pigment polymer of homogentisic acid deposits in connective tissue (ochronosis) and cartilage; urine oxidizes on standing.
  • 🩻 Clinical Presentation
    Dark‑black urine on standing, bluish‑black discoloration of ear cartilage & sclera, arthropathy of spine & large joints after age 30.
  • 🩺 Diagnosis
    Clinical; urine homogentisic acid; genetic testing.
  • 💊 Management
    Low‑protein diet (↓ Phe & Tyr) may slow course; NSAIDs for pain; joint replacement.
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Cystinuria
Cystinuria

AR defect of PCT & intestinal AA transporter for COLA (Cys, Orn, Lys, Arg) → ↓ reabsorption → cystine kidney stones.

  • 🟪 Overview
    AR defect of PCT & intestinal AA transporter for COLA (Cys, Orn, Lys, Arg) → ↓ reabsorption → cystine kidney stones.
  • 🧠 Pathophysiology
    Poorly soluble cystine forms hexagonal crystals in urine and staghorn calculi.
  • 🩻 Clinical Presentation
    Recurrent flank pain, hematuria, urinary hexagonal crystals, nephrolithiasis in teens/20s.
  • 🩺 Diagnosis
    Cyanide‑nitroprusside urine test +; stone analysis; genetic testing.
  • 💊 Management
    High‑fluid intake, urinary alkalinization (potassium citrate, acetazolamide), chelation with penicillamine, low‑methionine diet.
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Propionic Acidemia
Propionic Acidemia

AR deficiency of propionyl‑CoA carboxylase → accumulation of propionic acid, ↓ gluconeogenesis & urea cycle.

  • 🟪 Overview
    AR deficiency of propionyl‑CoA carboxylase → accumulation of propionic acid, ↓ gluconeogenesis & urea cycle.
  • 🧠 Pathophysiology
    Toxic organic acids cause metabolic acidosis & hyperammonemia.
  • 🩻 Clinical Presentation
    Neonate: poor feeding, vomiting, hypotonia, anion‑gap metabolic acidosis, hepatomegaly, seizures.
  • 🩺 Diagnosis
    ↑ propionyl‑carnitine on newborn screen; labs: metabolic acidosis, hyper‑NH3, ketosis, ↓ glucose.
  • 💊 Management
    Low‑protein diet restricted in odd‑chain FAs & amino acids Val, Ile, Met, Thr; carnitine; emergency IV glucose/lipids.
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Methylmalonic Acidemia
Methylmalonic Acidemia

AR defect of methylmalonyl‑CoA mutase OR vitamin B12 metabolism → accumulation of methylmalonic acid.

  • 🟪 Overview
    AR defect of methylmalonyl‑CoA mutase OR vitamin B12 metabolism → accumulation of methylmalonic acid.
  • 🧠 Pathophysiology
    Disrupts myelin, Krebs cycle, urea cycle → neurologic damage, acidosis, hyperammonemia.
  • 🩻 Clinical Presentation
    Infancy: lethargy, vomiting, hypotonia, developmental delay, seizures.
  • 🩺 Diagnosis
    Newborn screen: ↑ C3 acylcarnitine; ↑ methylmalonic acid in serum/urine; test B12.
  • 💊 Management
    Protein‑restricted diet excluding offending AA, carnitine, hydroxocobalamin if B12‑responsive.
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Von Gierke Disease (GSD I)
Von Gierke Disease (GSD I)

AR deficiency of glucose‑6‑phosphatase in liver & kidney → impaired glycogenolysis & gluconeogenesis.

  • 🟪 Overview
    AR deficiency of glucose‑6‑phosphatase in liver & kidney → impaired glycogenolysis & gluconeogenesis.
  • 🧠 Pathophysiology
    Glycogen accumulates in liver, severe fasting hypoglycemia, ↑ lactic acid.
  • 🩻 Clinical Presentation
    3–4 mo: doll‑like face, hepatomegaly, severe fasting hypoglycemia → seizures, ↑ lactate, ↑ uric acid, ↑ TG; renal enlargement.
  • 🩺 Diagnosis
    Labs as above; enzyme assay / G6PC mutation.
  • 💊 Management
    Frequent oral glucose/cornstarch; avoid fructose & galactose; liver transplant for severe cases.
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Pompe Disease (GSD II)
Pompe Disease (GSD II)

AR deficiency of lysosomal acid α‑1,4‑glucosidase (acid maltase) → accumulation of glycogen in lysosomes.

  • 🟪 Overview
    AR deficiency of lysosomal acid α‑1,4‑glucosidase (acid maltase) → accumulation of glycogen in lysosomes.
  • 🧠 Pathophysiology
    Cardiomegaly, muscle weakness from glycogen buildup; diaphragm weakness → respiratory failure.
  • 🩻 Clinical Presentation
    Infantile: hypotonia, hypertrophic cardiomyopathy, macroglossia, hepatomegaly; death by 2 y if untreated. Late‑onset: limb‑girdle weakness, respiratory insufficiency.
  • 🩺 Diagnosis
    Acid maltase activity in fibroblasts; GAA gene test; elevated CK.
  • 💊 Management
    IV recombinant alglucosidase alfa; respiratory support.
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Cori Disease (GSD III)
Cori Disease (GSD III)

AR deficiency of debranching enzyme (α‑1,6‑glucosidase) → limit dextrin‑like cytosolic glycogen.

  • 🟪 Overview
    AR deficiency of debranching enzyme (α‑1,6‑glucosidase) → limit dextrin‑like cytosolic glycogen.
  • 🧠 Pathophysiology
    Gluconeogenesis intact → milder hypoglycemia but muscle, liver involvement.
  • 🩻 Clinical Presentation
    Infancy: hepatomegaly, moderate hypoglycemia, growth delay, cardiomyopathy, myopathy.
  • 🩺 Diagnosis
    Abnormal glycogen structure on biopsy; AGL gene test.
  • 💊 Management
    High‑protein diet, cornstarch, cardiac monitoring; liver transplant rarely.
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Andersen Disease (GSD IV)
Andersen Disease (GSD IV)

AR deficiency of branching enzyme (glycosyl‑4:6‑transferase) → long insoluble glycogen chains.

  • 🟪 Overview
    AR deficiency of branching enzyme (glycosyl‑4:6‑transferase) → long insoluble glycogen chains.
  • 🧠 Pathophysiology
    Poorly branched glycogen precipitates in hepatocytes → cirrhosis.
  • 🩻 Clinical Presentation
    Infant: failure to thrive, hypotonia, hepatosplenomegaly → progressive cirrhosis, portal HTN; death by age 5.
  • 🩺 Diagnosis
    Liver biopsy showing amylopectin‑like glycogen; GBE1 mutation.
  • 💊 Management
    Liver transplantation definitive; supportive care.
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McArdle Disease (GSD V)
McArdle Disease (GSD V)

AR deficiency of skeletal muscle glycogen phosphorylase (myophosphorylase) → impaired glycogenolysis in muscle.

  • 🟪 Overview
    AR deficiency of skeletal muscle glycogen phosphorylase (myophosphorylase) → impaired glycogenolysis in muscle.
  • 🧠 Pathophysiology
    Failure to generate ATP during exercise.
  • 🩻 Clinical Presentation
    Teen/adult: exercise‑induced muscle cramps, myoglobinuria, second‑wind phenomenon, ↑ CK.
  • 🩺 Diagnosis
    Forearm exercise test: flat lactate curve; PYGM gene.
  • 💊 Management
    Avoid strenuous exercise, oral sucrose before activity; vitamin B6 trial.
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Tay‑Sachs Disease
Tay‑Sachs Disease

AR deficiency of β‑hexosaminidase A → GM2 ganglioside accumulation in neurons.

  • 🟪 Overview
    AR deficiency of β‑hexosaminidase A → GM2 ganglioside accumulation in neurons.
  • 🧠 Pathophysiology
    Lysosomal swelling damages CNS.
  • 🩻 Clinical Presentation
    3–6 mo: progressive neurodegeneration, developmental regression, hyperacusis, seizures, ‘cherry‑red’ macula, hypotonia; no hepatosplenomegaly.
  • 🩺 Diagnosis
    Enzyme assay; HEXA mutation; prenatal screening in Ashkenazi Jews.
  • 💊 Management
    Supportive; seizure control; feeding tube.
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Fabry Disease
Fabry Disease

X‑linked recessive α‑galactosidase A deficiency → ceramide trihexoside (Gb3) accumulation.

  • 🟪 Overview
    X‑linked recessive α‑galactosidase A deficiency → ceramide trihexoside (Gb3) accumulation.
  • 🧠 Pathophysiology
    Gb3 deposits in vascular endothelium, kidney, heart, nerves.
  • 🩻 Clinical Presentation
    Childhood: episodic neuropathic pain, angiokeratomas, hypohidrosis. Adult: progressive CKD, LVH, TIAs.
  • 🩺 Diagnosis
    Enzyme activity (males), GLA gene testing, urine Gb3.
  • 💊 Management
    IV agalsidase‑β ERT, chaperone migalastat, ACEi for proteinuria.
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Metachromatic Leukodystrophy
Metachromatic Leukodystrophy

AR arylsulfatase A deficiency → cerebroside sulfate accumulation → demyelination.

  • 🟪 Overview
    AR arylsulfatase A deficiency → cerebroside sulfate accumulation → demyelination.
  • 🧠 Pathophysiology
    Sulphatide storage destroys oligodendrocytes & Schwann cells.
  • 🩻 Clinical Presentation
    After 1 y: developmental regression, ataxia, hypotonia, peripheral neuropathy, seizures.
  • 🩺 Diagnosis
    Low arylsulfatase A activity in leukocytes; MRI diffuse white‑matter loss.
  • 💊 Management
    HSCT in presymptomatic stage; supportive thereafter.
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Gaucher Disease
Gaucher Disease

AR β‑glucocerebrosidase deficiency → glucocerebroside accumulation in macrophages (Gaucher cells).

  • 🟪 Overview
    AR β‑glucocerebrosidase deficiency → glucocerebroside accumulation in macrophages (Gaucher cells).
  • 🧠 Pathophysiology
    Lipid‑laden macrophages infiltrate spleen, bone marrow.
  • 🩻 Clinical Presentation
    Hepatosplenomegaly, pancytopenia, bone crises, avascular necrosis of femur; ‘crumpled tissue paper’ cells.
  • 🩺 Diagnosis
    Enzyme assay; GBA gene; radiographs.
  • 💊 Management
    IV imiglucerase or velaglucerase alfa ERT; substrate reducer eliglustat.
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Niemann‑Pick Disease
Niemann‑Pick Disease

AR sphingomyelinase deficiency → sphingomyelin accumulation.

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Hurler Syndrome
Hurler Syndrome

AR deficiency of α‑L‑iduronidase → heparan & dermatan sulfate accumulation.

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Hunter Syndrome
Hunter Syndrome

X‑linked recessive deficiency of iduronate‑2‑sulfatase → heparan & dermatan sulfate accumulation.

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Systemic Primary Carnitine Deficiency
Systemic Primary Carnitine Deficiency

AR defect in OCTN2 carnitine transporter on plasma membrane → ↓ intracellular carnitine → impaired LCFA entry into mitochondria.

  • 🟪 Overview
    AR defect in OCTN2 carnitine transporter on plasma membrane → ↓ intracellular carnitine → impaired LCFA entry into mitochondria.
  • 🧠 Pathophysiology
    Unable to generate acetyl‑CoA → ↓ ketogenesis & gluconeogenesis during fasting.
  • 🩻 Clinical Presentation
    Infancy: hypoketotic hypoglycemia, hypotonia, cardiomyopathy, hepatomegaly, hyperammonemia.
  • 🩺 Diagnosis
    Low carnitine on newborn screen; acylcarnitine profile.
  • 💊 Management
    High‑carb, low‑fat diet; L‑carnitine supplementation; avoid fasting.
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Medium‑Chain Acyl‑CoA Dehydrogenase Deficiency
Medium‑Chain Acyl‑CoA Dehydrogenase Deficiency

AR deficiency of MCAD → accumulation of medium‑chain acyl‑carnitines → impaired β‑oxidation.

  • 🟪 Overview
    AR deficiency of MCAD → accumulation of medium‑chain acyl‑carnitines → impaired β‑oxidation.
  • 🧠 Pathophysiology
    No ketones during fasting; ↑ dicarboxylic acids.
  • 🩻 Clinical Presentation
    3–24 mo: vomiting, seizures, coma, sudden death in overnight fast; hypoketotic hypoglycemia.
  • 🩺 Diagnosis
    Newborn screen: ↑ C8‑C10 acylcarnitines; confirm ACADM mutation.
  • 💊 Management
    Avoid prolonged fasting; high‑carb intake during illness; carnitine.
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Osteogenesis Imperfecta (Type I Collagen Defect)
Osteogenesis Imperfecta (Type I Collagen Defect)

Inherited connective‑tissue disorder characterized by defective synthesis of type I collagen.

  • 🟪 Overview
    Inherited connective‑tissue disorder characterized by defective synthesis of type I collagen.
  • 🧠 Pathophysiology
    AD loss‑of‑function mutations in COL1A1 or COL1A2 -> ↓ quantity/quality of type I collagen triple helices. Leads to decreased osteoid production & brittle bone matrix with normal mineralization.
  • 🩻 Clinical Presentation
    Multiple fractures at different stages of healing after minimal trauma or during birth; blue sclerae due to underlying choroidal veins; conductive hearing loss (abnormal ossicles); dentinogenesis imperfecta with opalescent teeth.
  • 🩺 Diagnosis
    Clinical findings ± COL1A1/2 genetic testing; bone biopsy shows thin cortical bone & few trabeculae.
  • 💊 Management
    Bisphosphonates to ↓ fracture risk, surgical rodding, physical therapy, vitamin D & Ca²⁺ supplementation.
  • 📊 Epidemiology
    ≈ 1 : 15 000–20 000 live births; Type I is most common & mildest form.
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Ehlers‑Danlos Syndrome
Ehlers‑Danlos Syndrome

Group of hereditary disorders affecting collagen III or V maturation leading to hyperextensible skin and hypermobile joints.

  • 🟪 Overview
    Group of hereditary disorders affecting collagen III or V maturation leading to hyperextensible skin and hypermobile joints.
  • 🧠 Pathophysiology
    Defects in COL3A1 (vascular type) or COL5A1/5A2 (classic type) or in procollagen peptidase/lysyl‑hydroxylase -> impaired collagen cross‑linking & tensile strength.
  • 🩻 Clinical Presentation
    Skin hyperelasticity, atrophic scars, easy bruising, joint dislocations, chronic pain; vascular type: arterial/organ rupture.
  • 🩺 Diagnosis
    Clinical criteria + molecular testing; decreased tensile strength on skin biopsy.
  • 💊 Management
    Protect joints, physiotherapy; avoid high‑impact sports; vascular type needs routine vascular imaging & β‑blockers.
  • 📊 Epidemiology
    1 : 5 000; most AD, some AR.
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Menkes Disease
Menkes Disease

X‑linked recessive disorder of copper absorption/transport.

  • 🟪 Overview
    X‑linked recessive disorder of copper absorption/transport.
  • 🧠 Pathophysiology
    ATP7A mutation → defective intestinal copper efflux → ↓ copper in blood & brain → ↓ lysyl oxidase activity → impaired collagen cross‑linking.
  • 🩻 Clinical Presentation
    Hypotonia, seizures, growth retardation, intellectual disability, brittle ‘kinky’ hair, hypopigmentation, early death.
  • 🩺 Diagnosis
    Low serum copper & ceruloplasmin; molecular testing of ATP7A.
  • 💊 Management
    Parenteral copper histidinate may slow neurodegeneration if started neonatally.
  • 📊 Epidemiology
    ≈ 1 : 100 000 male births.
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McCune‑Albright Syndrome
McCune‑Albright Syndrome

Sporadic mosaic G‑protein signaling mutation causing endocrine hyperfunction.

  • 🟪 Overview
    Sporadic mosaic G‑protein signaling mutation causing endocrine hyperfunction.
  • 🧠 Pathophysiology
    Post‑zygotic activating mutation in GNAS (Gs‑alpha) in some cell lines → ↑ cAMP → autonomous hormone secretion & fibrous bone.
  • 🩻 Clinical Presentation
    Triad: café‑au‑lait skin spots with ‘coast of Maine’ borders, polyostotic fibrous dysplasia, and at least one endocrinopathy (precocious puberty, thyrotoxicosis, Cushing).
  • 🩺 Diagnosis
    Clinical; mosaic GNAS mutation on lesional biopsy.
  • 💊 Management
    Bisphosphonates for bone pain, aromatase inhibitors for precocious puberty, surgical fixation of weight‑bearing deformities.
  • 📊 Epidemiology
    Rare; affects girls > boys; lethal if mutation occurs before fertilization (non‑mosaic).
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Prader‑Willi Syndrome
Prader‑Willi Syndrome

Loss of paternally expressed genes on chromosome 15q11‑q13.

  • 🟪 Overview
    Loss of paternally expressed genes on chromosome 15q11‑q13.
  • 🧠 Pathophysiology
    70 % paternal deletion; 25 % maternal uniparental disomy; remainder imprinting defects → ↓ hypothalamic satiety signals & endocrine dysfunction.
  • 🩻 Clinical Presentation
    Neonatal hypotonia, feeding difficulty → hyperphagia & obesity in childhood, short stature, hypogonadism, intellectual disability, almond‑shaped eyes.
  • 🩺 Diagnosis
    Methylation‑specific PCR or FISH for 15q11‑q13.
  • 💊 Management
    Caloric restriction, growth hormone therapy, behavioral support.
  • 📊 Epidemiology
    ≈ 1 : 15 000 births.
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Angelman Syndrome
Angelman Syndrome

Loss of maternally expressed UBE3A gene on chromosome 15q11‑q13.

  • 🟪 Overview
    Loss of maternally expressed UBE3A gene on chromosome 15q11‑q13.
  • 🧠 Pathophysiology
    70 % maternal deletion; 5 % paternal uniparental disomy; rest imprinting center/UBE3A mutations → loss of ubiquitin ligase in brain.
  • 🩻 Clinical Presentation
    Severe intellectual disability, seizures, ataxic gait, inappropriate laughter (‘happy puppet’), microcephaly.
  • 🩺 Diagnosis
    Methylation PCR/FISH; EEG high‑amplitude slow‑spike waves.
  • 💊 Management
    Seizure control, PT/OT, communication therapy.
  • 📊 Epidemiology
    ≈ 1 : 20 000 births.
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Rett Syndrome
Rett Syndrome

Neurodevelopmental disorder almost exclusively in girls due to MECP2 mutation.

  • 🟪 Overview
    Neurodevelopmental disorder almost exclusively in girls due to MECP2 mutation.
  • 🧠 Pathophysiology
    De novo MECP2 loss‑of‑function on X chromosome in paternal germline → defective methyl‑CpG‑binding protein 2 → dysregulated gene silencing.
  • 🩻 Clinical Presentation
    Normal early development followed by regression at 6‑18 mo: loss of speech and purposeful hand use, stereotypic hand‑wringing, seizures, ataxia, intellectual disability.
  • 🩺 Diagnosis
    MECP2 sequencing; exclusion of metabolic errors.
  • 💊 Management
    Supportive: seizure control, physiotherapy, communication aids.
  • 📊 Epidemiology
    ≈ 1 : 10 000 female births; lethal in hemizygous males.
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Fragile X Syndrome
Fragile X Syndrome

Most common inherited cause of intellectual disability and 2nd overall after Down syndrome.

  • 🟪 Overview
    Most common inherited cause of intellectual disability and 2nd overall after Down syndrome.
  • 🧠 Pathophysiology
    CGG expansion (> 200) in FMR1 on X chromosome → hypermethylation and silencing → ↓ FMRP protein → defective synaptic plasticity.
  • 🩻 Clinical Presentation
    Intellectual disability, post‑pubertal macro‑orchidism, long face with large jaw & ears, autism, mitral valve prolapse.
  • 🩺 Diagnosis
    PCR with repeat‑size analysis, Southern blot for methylation status.
  • 💊 Management
    Early educational intervention, manage ADHD/anxiety; FXTAS & POI surveillance in premutation carriers.
  • 📊 Epidemiology
    1 : 4000 males; anticipation via maternal meiosis.
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Down Syndrome (Trisomy 21)
Down Syndrome (Trisomy 21)

Most common viable chromosomal disorder with intellectual disability.

  • 🟪 Overview
    Most common viable chromosomal disorder with intellectual disability.
  • 🧠 Pathophysiology
    95 % meiotic nondisjunction (↑ maternal age); 4 % unbalanced Robertsonian translocation (usually 14;21); 1 % mosaicism.
  • 🩻 Clinical Presentation
    Flat facies, upslanting palpebral fissures, epicanthal folds, single palmar crease, gap between 1st‑2nd toes, duodenal/jejunal atresia, Hirschsprung, congenital heart disease (AVSD), early Alzheimer disease, ALL/AML risk.
  • 🩺 Diagnosis
    ↓ PAPP‑A & ↑ β‑hCG (1st tri); quad screen: ↓ AFP, ↑ hCG, ↓ estriol, ↑ inhibin A; confirm with karyotype.
  • 💊 Management
    Early intervention, repair heart defects, screen thyroid and hearing yearly.
  • 📊 Epidemiology
    1 : 700 births; risk rises exponentially after maternal age 35.
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Edwards Syndrome (Trisomy 18)
Edwards Syndrome (Trisomy 18)

Second‑most common autosomal trisomy resulting in live birth.

  • 🟪 Overview
    Second‑most common autosomal trisomy resulting in live birth.
  • 🧠 Pathophysiology
    Trisomy of chromosome 18 usually due to maternal nondisjunction.
  • 🩻 Clinical Presentation
    Severe ID, rocker‑bottom feet, clenched fists with overlapping fingers, low‑set ears, micrognathia, prominent occiput, VSD, death < 1 yr.
  • 🩺 Diagnosis
    1st tri: ↓ PAPP‑A & β‑hCG; quad screen: ↓ AFP, ↓ hCG, ↓ estriol, ↓/normal inhibin A.
  • 💊 Management
    Palliative; discuss goals of care early.
  • 📊 Epidemiology
    1 : 6000; majority female; ↑ maternal age.
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Patau Syndrome (Trisomy 13)
Patau Syndrome (Trisomy 13)

Severe congenital malformation syndrome with median survival < 1 yr.

  • 🟪 Overview
    Severe congenital malformation syndrome with median survival < 1 yr.
  • 🧠 Pathophysiology
    Trisomy of chromosome 13 from maternal nondisjunction; rarely translocation.
  • 🩻 Clinical Presentation
    Severe ID, rocker‑bottom feet, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, PKD, death < 1 yr.
  • 🩺 Diagnosis
    1st tri: ↓ PAPP‑A & β‑hCG; quad screen often normal.
  • 💊 Management
    Supportive; comfort care.
  • 📊 Epidemiology
    1 : 10 000; ↑ maternal age.
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Cri‑du‑chat Syndrome
Cri‑du‑chat Syndrome

Congenital deletion of short arm of chromosome 5 (46,XX/XY,5p−).

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Williams Syndrome
Williams Syndrome

Microdeletion of chromosome 7q11.23 including elastin gene.

  • 🟪 Overview
    Microdeletion of chromosome 7q11.23 including elastin gene.
  • 🧠 Pathophysiology
    Deletion results in elastin deficiency → vascular/connective tissue anomalies; loss of neighboring genes → neurocognitive defects.
  • 🩻 Clinical Presentation
    Elfin facies, well‑developed verbal skills, extreme friendliness, hypercalcemia (↑ vitamin D sensitivity), supravalvular aortic stenosis, renal artery stenosis.
  • 🩺 Diagnosis
    FISH or microarray showing 7q11.23 deletion.
  • 💊 Management
    Treat hypercalcemia; surgical repair of vascular lesions; educational therapy.
  • 📊 Epidemiology
    1 : 10 000–20 000; usually sporadic.
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Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy

Severe X‑linked recessive myopathy with early childhood onset.

  • 🟪 Overview
    Severe X‑linked recessive myopathy with early childhood onset.
  • 🧠 Pathophysiology
    Frameshift or nonsense mutations in DMD → absent dystrophin → myofiber membrane fragility, myonecrosis.
  • 🩻 Clinical Presentation
    Delayed motor milestones, Gowers sign, pseudohypertrophy of calves, cardiomyopathy, respiratory failure by teens.
  • 🩺 Diagnosis
    Marked ↑ CK & aldolase; absent dystrophin on muscle biopsy or multiplex PCR.
  • 💊 Management
    Glucocorticoids slow progression; ACE‑I/β‑blockers for cardiomyopathy; nocturnal ventilation.
  • 📊 Epidemiology
    1 : 3500 male births.
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Becker Muscular Dystrophy
Becker Muscular Dystrophy

Milder X‑linked recessive dystrophinopathy with later onset.

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Myotonic Dystrophy Type 1
Myotonic Dystrophy Type 1

AD CTG repeat expansion in DMPK gene causing myotonia & multisystem involvement.

  • 🟪 Overview
    AD CTG repeat expansion in DMPK gene causing myotonia & multisystem involvement.
  • 🧠 Pathophysiology
    CTG expansion → abnormal RNA binding proteins → splicing defects (eg, CLCN1) → myotonia, endocrine issues.
  • 🩻 Clinical Presentation
    Difficulty releasing handshake (grip myotonia), cataracts, balding, testicular atrophy, arrhythmias.
  • 🩺 Diagnosis
    PCR repeat sizing; electromyography: myotonic discharges.
  • 💊 Management
    Mexiletine for myotonia, slit‑lamp for cataracts, pacemaker for heart block.
  • 📊 Epidemiology
    1 : 8000; anticipation via maternal transmission.
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Cystic Fibrosis
Cystic Fibrosis

Autosomal recessive multisystem disease due to CFTR Cl⁻ channel defect.

  • 🟪 Overview
    Autosomal recessive multisystem disease due to CFTR Cl⁻ channel defect.
  • 🧠 Pathophysiology
    ΔF508 (Phe508del) misfolding → ↓ Cl⁻ secretion & ↑ Na⁺ absorption → thick mucus in lungs, pancreas, GI, GU.
  • 🩻 Clinical Presentation
    Recurrent pulmonary infections (S aureus, Pseudomonas), pancreatic insufficiency, meconium ileus, infertility (absent vas deferens), nasal polyps, digital clubbing.
  • 🩺 Diagnosis
    Sweat chloride ≥ 60 mEq/L twice, abnormal CFTR genotyping, or nasal potential difference.
  • 💊 Management
    Pancreatic enzyme + ADEK, chest physiotherapy, dornase alfa, hypertonic saline, CFTR modulators (ivacaftor, elexacaftor/tezacaftor/ivacaftor).
  • 📊 Epidemiology
    1 : 2500 Caucasian births; carrier freq 1 : 25.
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Primary Ciliary Dyskinesia (Kartagener Syndrome)
Primary Ciliary Dyskinesia (Kartagener Syndrome)

Autosomal recessive dynein arm defect leading to immotile cilia.

  • 🟪 Overview
    Autosomal recessive dynein arm defect leading to immotile cilia.
  • 🧠 Pathophysiology
    Mutations in dynein‑arm genes (DNAH5/11) → lack of ATPase activity → absent mucociliary clearance & nodal flow.
  • 🩻 Clinical Presentation
    Chronic sinusitis, bronchiectasis, otitis media, infertility, ectopic pregnancy risk; 50 % situs inversus (Kartagener).
  • 🩺 Diagnosis
    Low nasal NO; EM shows absent dynein arms; genetic testing.
  • 💊 Management
    Chest physiotherapy, macrolides, IVF with ICSI for infertility.
  • 📊 Epidemiology
    1 : 15 000; half have organ laterality defects.
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Adenosine Deaminase Deficiency (SCID)
Adenosine Deaminase Deficiency (SCID)

Autosomal recessive cause of severe combined immunodeficiency.

  • 🟪 Overview
    Autosomal recessive cause of severe combined immunodeficiency.
  • 🧠 Pathophysiology
    ADA deficiency → ↑ dATP → feedback inhibition of ribonucleotide reductase → ↓ lymphocyte DNA synthesis.
  • 🩻 Clinical Presentation
    Failure to thrive, chronic diarrhea, thrush, recurrent viral/bacterial/fungal infections starting in infancy.
  • 🩺 Diagnosis
    Very low T/B/NK cells, absent thymic shadow; low ADA activity in RBCs.
  • 💊 Management
    Hematopoietic stem‑cell transplant, gene therapy approved, lifelong IgG replacement.
  • 📊 Epidemiology
    ≈ 15 % of SCID cases worldwide.
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Lesch‑Nyhan Syndrome
Lesch‑Nyhan Syndrome

X‑linked recessive HGPRT deficiency causing uric acid overproduction & neurobehavioral issues.

  • 🟪 Overview
    X‑linked recessive HGPRT deficiency causing uric acid overproduction & neurobehavioral issues.
  • 🧠 Pathophysiology
    Absent hypoxanthine‑guanine phosphoribosyltransferase → ↑ de novo purine synthesis & uric acid.
  • 🩻 Clinical Presentation
    Intellectual disability, self‑mutilation, aggression, orange ‘sand’ sodium urate crystals in diaper, gout, dystonia.
  • 🩺 Diagnosis
    Hyperuricemia; HGPRT enzyme assay; genetic testing.
  • 💊 Management
    Allopurinol or febuxostat for hyperuricemia; gabapentin/clonazepam for dystonia; dental guards for self‑injury.
  • 📊 Epidemiology
    1 : 380 000; males primarily.
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I‑Cell Disease (Mucolipidosis II)
I‑Cell Disease (Mucolipidosis II)

AR lysosomal storage disorder due to failure of Golgi to tag enzymes with mannose‑6‑phosphate.

  • 🟪 Overview
    AR lysosomal storage disorder due to failure of Golgi to tag enzymes with mannose‑6‑phosphate.
  • 🧠 Pathophysiology
    N‑acetylglucosaminyl‑1‑phosphotransferase deficiency → enzymes secreted extracellularly → lysosomal inclusions of undigested material.
  • 🩻 Clinical Presentation
    Coarse facial features, gingival hyperplasia, restricted joints, claw hand, corneal clouding, ↑ plasma lysosomal enzymes, death in childhood.
  • 🩺 Diagnosis
    Inclusion bodies on fibroblast EM; absent M6P tagging assays.
  • 💊 Management
    Supportive; PT/OT, respiratory care.
  • 📊 Epidemiology
    1 : 640 000; more common in Quebec.
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Vitamin B6 deficiency
Vitamin B6 deficiency

Insufficient pyridoxine (vitamin B6) leading to impaired transamination, decarboxylation, and heme synthesis reactions.

  • 🟪 Overview
    Insufficient pyridoxine (vitamin B6) leading to impaired transamination, decarboxylation, and heme synthesis reactions.
  • 🧠 Pathophysiology
    Pyridoxal‑5′‑phosphate is required cofactor for aminotransferases (eg, ALT, AST), cystathionine β‑synthase, ALA‑synthase, and neurotransmitter synthesis (dopamine, serotonin, GABA). Isoniazid or oral contraceptives ↑ urinary excretion and ↓ activation of vitamin B6.
  • 🩻 Clinical Presentation
    Peripheral neuropathy, sideroblastic anemia, cheilosis, glossitis, conjunctivitis, seborrheic dermatitis, irritability and confusion.
  • 🩺 Diagnosis
    ↓ PLP level; sideroblastic anemia with ring sideroblasts on marrow smear; ↑ serum homocysteine with normal methylmalonic acid (distinguishes from B12 deficiency).
  • 💊 Management
    Pyridoxine 50–100 mg/day orally; higher doses (up to 200 mg) if on isoniazid.
  • 📊 Epidemiology
    Seen in TB patients on isoniazid without supplementation; chronic alcohol use; malabsorption.
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Vitamin B7 deficiency
Vitamin B7 deficiency

Biotin deficiency resulting in dysfunctional carboxylase enzymes.

  • 🟪 Overview
    Biotin deficiency resulting in dysfunctional carboxylase enzymes.
  • 🧠 Pathophysiology
    Biotin is cofactor for pyruvate, acetyl‑CoA and propionyl‑CoA carboxylases. Avidin in raw egg whites binds biotin; long‑term antibiotic use decreases gut flora biotin production.
  • 🩻 Clinical Presentation
    Periorificial dermatitis, alopecia, brittle nails, conjunctivitis, myalgias, lethargy, paresthesias.
  • 🩺 Diagnosis
    ↑ Plasma lactate + ↑ organic acids; measurement of urinary 3‑hydroxyisovalerate. Clinical response to supplementation is confirmatory.
  • 💊 Management
    Biotin 5–10 mg/day orally; stop raw egg white consumption; treat underlying malabsorption or antibiotic overuse.
  • 📊 Epidemiology
    Rare; most cases iatrogenic (parenteral nutrition without biotin).
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Vitamin B9 deficiency
Vitamin B9 deficiency

Folate deficiency impairing purine/pyrimidine synthesis and DNA methylation.

  • 🟪 Overview
    Folate deficiency impairing purine/pyrimidine synthesis and DNA methylation.
  • 🧠 Pathophysiology
    Folate absorbed in jejunum; deficiency from malnutrition (alcoholism), malabsorption, methotrexate, trimethoprim, phenytoin, or ↑ requirement in pregnancy.
  • 🩻 Clinical Presentation
    Macrocytic megaloblastic anemia, hypersegmented neutrophils, glossitis. No neurologic deficits (vs B12).
  • 🩺 Diagnosis
    ↑ Homocysteine, normal methylmalonic acid, ↓ serum and RBC folate. Elevated RDW.
  • 💊 Management
    Oral folic acid 1 mg daily; parenteral if severe malabsorption; give prophylactically in pregnancy.
  • 📊 Epidemiology
    Most common vitamin deficiency in US; neural tube defects risk in fetus.
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Vitamin B12 deficiency
Vitamin B12 deficiency

Cobalamin deficiency leading to defective DNA synthesis and abnormal myelin.

  • 🟪 Overview
    Cobalamin deficiency leading to defective DNA synthesis and abnormal myelin.
  • 🧠 Pathophysiology
    Lack of intrinsic factor (pernicious anemia, gastrectomy), pancreatic insufficiency, ileal resection/Crohn, vegan diet. Needed for methylmalonyl‑CoA mutase and methionine synthase.
  • 🩻 Clinical Presentation
    Macrocytic megaloblastic anemia, peripheral neuropathy, ataxia, cognitive decline, glossitis.
  • 🩺 Diagnosis
    ↑ Homocysteine and methylmalonic acid, ↓ serum B12; anti‑IF antibodies; Schilling test historically.
  • 💊 Management
    IM or high‑dose oral cyanocobalamin 1000 µg monthly; treat reversible causes.
  • 📊 Epidemiology
    More common in elderly; irreversible neurologic damage if untreated.
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Vitamin C deficiency (Scurvy)
Vitamin C deficiency (Scurvy)

Lack of ascorbic acid impairing collagen hydroxylation and norepinephrine synthesis.

  • 🟪 Overview
    Lack of ascorbic acid impairing collagen hydroxylation and norepinephrine synthesis.
  • 🧠 Pathophysiology
    Poor diet, alcoholism, elderly, tea‑and‑toast diets. ↓ Prolyl and lysyl hydroxylase activity ‑> weakened connective tissue.
  • 🩻 Clinical Presentation
    Perifollicular hemorrhages, corkscrew hairs, bleeding gums, tooth loss, impaired wound healing, anemia, arthralgias.
  • 🩺 Diagnosis
    Clinical; plasma ascorbate < 0.2 mg/dL.
  • 💊 Management
    Oral vitamin C 100‑500 mg tid for 1 week then maintenance; diet rich in fruits/vegetables.
  • 📊 Epidemiology
    Rare in developed countries; occurs in infants on evaporated milk.
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Vitamin C excess
Vitamin C excess

Over‑supplementation with ascorbic acid.

  • 🟪 Overview
    Over‑supplementation with ascorbic acid.
  • 🧠 Pathophysiology
    High‑dose vitamin C ↑ iron absorption and conversion to oxalate; osmotic diarrhea.
  • 🩻 Clinical Presentation
    Nausea, vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis, ↑ risk of iron overload in hemochromatosis.
  • 🩺 Diagnosis
    History of > 2 g/day supplementation; ↑ serum ascorbate.
  • 💊 Management
    Discontinue supplements; hydrate; monitor renal function.
  • 📊 Epidemiology
    Seen in fad diets, megadose cold prevention.
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Vitamin D deficiency
Vitamin D deficiency

Insufficient calcitriol activity resulting in defective bone mineralization.

  • 🟪 Overview
    Insufficient calcitriol activity resulting in defective bone mineralization.
  • 🧠 Pathophysiology
    Low sun exposure, malabsorption, chronic kidney or liver disease preventing 1α‑hydroxylation, exclusive breastfeeding without supplementation.
  • 🩻 Clinical Presentation
    Rickets in children, osteomalacia in adults: bone pain, fractures, bowed legs, rachitic rosary.
  • 🩺 Diagnosis
    ↓ 25‑OH vitamin D, ↓ Ca²⁺, ↑ PTH, ↓ phosphate; Looser zones on X‑ray.
  • 💊 Management
    Cholecalciferol 600‑1000 IU daily; calcitriol if renal failure; ensure calcium intake.
  • 📊 Epidemiology
    Common worldwide; resurgence with sunscreen and indoor lifestyle.
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Rickets
Rickets

Vitamin D deficiency in growing bone leading to defective mineralization of osteoid.

  • 🟪 Overview
    Vitamin D deficiency in growing bone leading to defective mineralization of osteoid.
  • 🧠 Pathophysiology
    Low calcitriol leads to ↓ Ca‑Pi product impairing endochondral ossification at growth plates.
  • 🩻 Clinical Presentation
    Bowing of legs, frontal bossing, craniotabes, widening of wrist, rachitic rosary, delayed fontanelle closure.
  • 🩺 Diagnosis
    Same labs as vit D deficiency; wrist X‑ray shows cupping and fraying metaphyses.
  • 💊 Management
    Vitamin D 1000‑2000 IU/day, calcium; treat underlying malabsorption or renal disease.
  • 📊 Epidemiology
    Exclusively breast‑fed infants without supplementation at highest risk.
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Osteomalacia
Osteomalacia

Defective bone mineralization in adults due to vitamin D deficiency.

  • 🟪 Overview
    Defective bone mineralization in adults due to vitamin D deficiency.
  • 🧠 Pathophysiology
    Decreased Ca/Pi absorption → secondary hyperparathyroidism; osteoid persists.
  • 🩻 Clinical Presentation
    Bone pain, muscle weakness, pseudo‑fractures (Looser zones), waddling gait.
  • 🩺 Diagnosis
    ↓ Vitamin D, ↓ Ca²⁺, ↓ Pi, ↑ ALP, ↑ PTH; x‑ray shows cortical thinning.
  • 💊 Management
    Cholecalciferol 2000 IU/day and calcium carbonate; ergocalciferol IM monthly if severe.
  • 📊 Epidemiology
    Elderly, malabsorption, bariatric surgery, anticonvulsants.
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Vitamin D excess
Vitamin D excess

Hypervitaminosis D causing hypercalcemia.

  • 🟪 Overview
    Hypervitaminosis D causing hypercalcemia.
  • 🧠 Pathophysiology
    Granulomatous diseases (sarcoidosis) with ↑ 1α‑hydroxylase, high‑dose supplements, Williams syndrome.
  • 🩻 Clinical Presentation
    Hypercalcemia, hypercalciuria, kidney stones, bone pain, metastatic calcifications, confusion.
  • 🩺 Diagnosis
    ↑ 25‑OH and 1,25‑OH Vit D, ↑ Ca²⁺, ↓ PTH.
  • 💊 Management
    Stop supplements, low Ca diet, hydration, glucocorticoids or bisphosphonates if severe.
  • 📊 Epidemiology
    Rare; infants given erroneous high‑dose drops.
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Vitamin E deficiency
Vitamin E deficiency

Deficiency of tocopherol leading to oxidative damage to RBCs and neurons.

  • 🟪 Overview
    Deficiency of tocopherol leading to oxidative damage to RBCs and neurons.
  • 🧠 Pathophysiology
    Fat‑malabsorption (CF, cholestasis), abetalipoproteinemia. ↓ antioxidant protection, RBC hemolysis, axonal degeneration.
  • 🩻 Clinical Presentation
    Hemolytic anemia, acanthocytosis, spinocerebellar ataxia, loss of dorsal column and spinocerebellar tract sensation, muscle weakness.
  • 🩺 Diagnosis
    ↓ Serum α‑tocopherol; ↑ plasma hemolysis with H₂O₂ test.
  • 💊 Management
    Fat‑soluble vitamin formulation 100‑400 IU/day; address malabsorption etiology.
  • 📊 Epidemiology
    Rare; preterm infants at risk.
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Vitamin E excess
Vitamin E excess

High‑dose tocopherol supplementation causing coagulopathy.

  • 🟪 Overview
    High‑dose tocopherol supplementation causing coagulopathy.
  • 🧠 Pathophysiology
    Vitamin E interferes with vitamin K–dependent γ‑carboxylation of coagulation factors II, VII, IX, X.
  • 🩻 Clinical Presentation
    ↑ Bleeding risk, bruising, hemorrhagic stroke in adults; necrotizing enterocolitis in infants.
  • 🩺 Diagnosis
    Prolonged PT/INR, normal PTT, normal platelets; ↑ serum tocopherol.
  • 💊 Management
    Discontinue supplements; vitamin K 10 mg IM if significant bleeding.
  • 📊 Epidemiology
    Supplement use for cardiovascular health despite lack of benefit.
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Vitamin K deficiency
Vitamin K deficiency

Deficiency of phylloquinone leading to impaired γ‑carboxylation of clotting factors.

  • 🟪 Overview
    Deficiency of phylloquinone leading to impaired γ‑carboxylation of clotting factors.
  • 🧠 Pathophysiology
    Newborns without gut flora, chronic broad‑spectrum antibiotics, fat malabsorption, warfarin.
  • 🩻 Clinical Presentation
    Neonatal hemorrhage (intracranial, GI, umbilical), easy bruising, mucosal bleeding, ↑ PT and PTT.
  • 🩺 Diagnosis
    Prolonged PT > PTT, normal bleeding time, low factor II, VII, IX, X levels.
  • 💊 Management
    Phytonadione 1 mg IM at birth; oral/IV vitamin K and FFP for active bleeding.
  • 📊 Epidemiology
    Routine prophylaxis prevents classic hemorrhagic disease of newborn.
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Zinc deficiency
Zinc deficiency

Hypozincemia impairing metalloproteins and transcription factors.

  • 🟪 Overview
    Hypozincemia impairing metalloproteins and transcription factors.
  • 🧠 Pathophysiology
    Malabsorption (IBD), parenteral nutrition without trace elements, high phytate diet, acrodermatitis enteropathica (ZIP4 mutation).
  • 🩻 Clinical Presentation
    Perioral and acral dermatitis, alopecia, impaired wound healing, anosmia, dysgeusia, hypogonadism, impaired night vision.
  • 🩺 Diagnosis
    ↓ Plasma zinc < 70 µg/dL; alkaline phosphatase may be low.
  • 💊 Management
    Oral zinc sulfate 2 mg/kg/day; lifelong in genetic forms.
  • 📊 Epidemiology
    Common micronutrient deficiency worldwide.
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Acrodermatitis enteropathica
Acrodermatitis enteropathica

Autosomal recessive ZIP4 transporter defect leading to impaired intestinal zinc uptake.

  • 🟪 Overview
    Autosomal recessive ZIP4 transporter defect leading to impaired intestinal zinc uptake.
  • 🧠 Pathophysiology
    SLC39A4 mutation prevents absorption of zinc in jejunum and ileum → systemic deficiency.
  • 🩻 Clinical Presentation
    Periorificial and acral eczematous dermatitis, diarrhea, alopecia, growth failure, recurrent infections in infancy.
  • 🩺 Diagnosis
    ↓ Serum zinc, ↑ alkaline phosphatase; genetic testing confirms.
  • 💊 Management
    High‑dose oral zinc (2‑3 mg/kg/d elemental) lifelong; topical emollients for dermatitis.
  • 📊 Epidemiology
    1:500,000; presents after weaning from breast milk (low zinc binding ligand).
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Kwashiorkor
Kwashiorkor

Dietary protein deficiency with adequate caloric intake.

  • 🟪 Overview
    Dietary protein deficiency with adequate caloric intake.
  • 🧠 Pathophysiology
    ↓ Oncotic pressure from hypoalbuminemia leads to edema; ↓ apolipoprotein synthesis causes fatty liver.
  • 🩻 Clinical Presentation
    Pitting edema, distended abdomen, flag‑sign hair depigmentation, dermatosis, growth retardation.
  • 🩺 Diagnosis
    Albumin < 2.8 g/dL, ↓ transferrin; normal or ↑ weight‑for‑age.
  • 💊 Management
    Slow protein repletion (F‑75, F‑100 formulas), treat infections, vitamin/mineral supplementation.
  • 📊 Epidemiology
    Weaning children in developing countries during famines.
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Marasmus
Marasmus

Inadequate total caloric intake causing tissue wasting.

  • 🟪 Overview
    Inadequate total caloric intake causing tissue wasting.
  • 🧠 Pathophysiology
    Body adapts by mobilizing fat and muscle; no edema due to relatively preserved albumin.
  • 🩻 Clinical Presentation
    Severe wasting, loss of subcutaneous fat, ravenous appetite, stunted growth, immune suppression.
  • 🩺 Diagnosis
    Weight < 60% expected, albumin usually normal.
  • 💊 Management
    Gradual caloric refeeding with micronutrients; treat infections; psychosocial support.
  • 📊 Epidemiology
    Famine, severe neglect, cachexia in chronic disease (cancer, COPD).
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Glucokinase deficiency
Glucokinase deficiency

Heterozygous loss‑of‑function GCK mutation causing mild chronic hyperglycemia (MODY‑2).

  • 🟪 Overview
    Heterozygous loss‑of‑function GCK mutation causing mild chronic hyperglycemia (MODY‑2).
  • 🧠 Pathophysiology
    Glucokinase acts as β‑cell glucose sensor. Loss increases glucose threshold for insulin release.
  • 🩻 Clinical Presentation
    Fasting glucose 100‑145 mg/dL, mild gestational diabetes; microvascular complications rare.
  • 🩺 Diagnosis
    Family history of mild diabetes, stable HbA1c < 7.5%; confirmed by GCK sequencing.
  • 💊 Management
    Usually none; diet/exercise; insulin in pregnancy if fetal overgrowth.
  • 📊 Epidemiology
    1–2% of gestational diabetes cases.
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Pyruvate dehydrogenase complex deficiency
Pyruvate dehydrogenase complex deficiency

X‑linked defect in PDHA1 leading to inability to convert pyruvate to acetyl‑CoA.

  • 🟪 Overview
    X‑linked defect in PDHA1 leading to inability to convert pyruvate to acetyl‑CoA.
  • 🧠 Pathophysiology
    Shunts pyruvate to lactate and alanine causing lactic acidosis and neuro deficits.
  • 🩻 Clinical Presentation
    Infant with hypotonia, seizures, lactic acidosis, developmental delay, brainstem malformations.
  • 🩺 Diagnosis
    ↑ Serum lactate, alanine; genetic testing for PDHA1.
  • 💊 Management
    High‑fat (ketogenic) diet, thiamine, lipoic acid, biotin, dichloroacetate; supportive care.
  • 📊 Epidemiology
    Rare; females may have milder disease due to lyonization.
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Glucose‑6‑phosphate dehydrogenase (G6PD) deficiency
Glucose‑6‑phosphate dehydrogenase (G6PD) deficiency

X‑linked recessive defect in G6PD causing episodic hemolytic anemia.

  • 🟪 Overview
    X‑linked recessive defect in G6PD causing episodic hemolytic anemia.
  • 🧠 Pathophysiology
    ↓ NADPH impairs glutathione reduction → RBCs susceptible to oxidative stress from fava beans, sulfa drugs, primaquine, dapsone, infections.
  • 🩻 Clinical Presentation
    Jaundice, back pain, dark urine after trigger; peripheral smear shows Heinz bodies and bite cells.
  • 🩺 Diagnosis
    ↓ G6PD activity (avoid testing during acute hemolysis), ↑ LDH, ↓ haptoglobin, reticulocytosis.
  • 💊 Management
    Avoid triggers; folic acid; transfusion in severe crisis.
  • 📊 Epidemiology
    Common in African, Mediterranean, Middle Eastern descent; confers malaria protection.
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Essential fructosuria
Essential fructosuria

Benign AR deficiency of hepatic fructokinase.

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Hereditary Fructose Intolerance
Hereditary Fructose Intolerance

Autosomal‑recessive deficiency of hepatic aldolase B leading to the toxic accumulation of fructose‑1‑phosphate after fructose ingestion.

  • 🟪 Overview
    Autosomal‑recessive deficiency of hepatic aldolase B leading to the toxic accumulation of fructose‑1‑phosphate after fructose ingestion.
  • 🧠 Pathophysiology
    Phosphate trapping by fructose‑1‑P depletes intracellular phosphate and ATP, inhibiting glycogenolysis and gluconeogenesis. Hypoglycemia and hepatocellular injury ensue.
  • 🩻 Clinical Presentation
    Appears after weaning when fruit or sucrose is introduced. Minutes‑to‑hours post‑ingestion: profuse vomiting, hypoglycemic seizures, irritability. Chronic exposure → failure to thrive, jaundice, hepatomegaly, renal Fanconi‑like syndrome.
  • 🩺 Diagnosis
    Hypoglycemia with low glucose and reducing sugars (+) in urine. Quantitative enzyme assay or genetic testing (ALDOB).
  • 💊 Management
    Strict lifelong avoidance of fructose, sucrose, and sorbitol. Parenteral glucose for acute episodes.
  • 📊 Epidemiology
    ≈1 : 20 000 in Europeans; usually diagnosed in infancy.
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Galactokinase Deficiency
Galactokinase Deficiency

Autosomal‑recessive deficiency of galactokinase causing accumulation of galactitol.

  • 🟪 Overview
    Autosomal‑recessive deficiency of galactokinase causing accumulation of galactitol.
  • 🧠 Pathophysiology
    Absent galactokinase blocks galactose → galactose‑1‑P step. Aldose reductase converts excess galactose to galactitol → osmotic damage in lens & retina.
  • 🩻 Clinical Presentation
    Infantile cataracts (failure to track objects, no social smile), occasional pseudotumor cerebri; otherwise mild.
  • 🩺 Diagnosis
    Reducing substances in urine, normal plasma galactose‑1‑P; enzymatic or GALK1 genetic testing.
  • 💊 Management
    Dietary restriction of galactose and lactose. Early treatment prevents cataracts.
  • 📊 Epidemiology
    Rare (<1 : 100 000). Higher prevalence in Roma populations.
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Classic Galactosemia
Classic Galactosemia

Life‑threatening AR deficiency of galactose‑1‑phosphate uridyltransferase (GALT).

  • 🟪 Overview
    Life‑threatening AR deficiency of galactose‑1‑phosphate uridyltransferase (GALT).
  • 🧠 Pathophysiology
    Galactose‑1‑P accumulation in liver, brain, kidney → phosphate trapping, organ dysfunction; galactitol → cataracts.
  • 🩻 Clinical Presentation
    Breast‑fed neonate with jaundice, vomiting, E. coli sepsis, cataracts, renal Fanconi syndrome.
  • 🩺 Diagnosis
    ↑ galactose‑1‑P in RBCs, positive newborn screen, GALT assay or gene sequencing.
  • 💊 Management
    Eliminate galactose & lactose; urgent IV fluids & broad‑spectrum antibiotics for sepsis.
  • 📊 Epidemiology
    ≈1 : 60 000; newborn screening in many countries.
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Lactase Deficiency
Lactase Deficiency

Inability to hydrolyze lactose into glucose + galactose in brush border.

  • 🟪 Overview
    Inability to hydrolyze lactose into glucose + galactose in brush border.
  • 🧠 Pathophysiology
    Primary (age‑related loss of LCT gene expression) or secondary (post‑gastroenteritis, IBD); unabsorbed lactose → osmotic diarrhea, colonic bacterial fermentation.
  • 🩻 Clinical Presentation
    Bloating, crampy abdominal pain, flatulence, watery diarrhea after dairy.
  • 🩺 Diagnosis
    Lactose hydrogen breath test: ↑ H₂. Stool: ↓ pH. Small bowel biopsy normal (rules out celiac).
  • 💊 Management
    Lactose‑free diet, lactase enzyme supplements.
  • 📊 Epidemiology
    Common worldwide; ↑ in Asian, African, Native American ancestry.
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Hyperammonemia (Acquired)
Hyperammonemia (Acquired)

Excess plasma NH₃ due to hepatic failure or portosystemic shunting.

  • 🟪 Overview
    Excess plasma NH₃ due to hepatic failure or portosystemic shunting.
  • 🧠 Pathophysiology
    NH₃ crosses BBB → astrocyte swelling, ↑ Gln, ↓ α‑ketoglutarate → TCA inhibition and cerebral edema.
  • 🩻 Clinical Presentation
    Confusion, asterixis, slurred speech, vomiting, cerebral edema → coma.
  • 🩺 Diagnosis
    Plasma ammonia > 80 µmol/L, normal anion gap metabolic alkalosis.
  • 💊 Management
    Lactulose, rifaximin, benzoate/phenylbutyrate, dialysis in fulminant liver failure.
  • 📊 Epidemiology
    Seen in advanced cirrhosis, post‑TIPS.
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Ornithine Transcarbamylase Deficiency
Ornithine Transcarbamylase Deficiency

X‑linked recessive deficiency of mitochondrial OTC leading to hyperammonemia.

  • 🟪 Overview
    X‑linked recessive deficiency of mitochondrial OTC leading to hyperammonemia.
  • 🧠 Pathophysiology
    Carbamoyl‑P accumulates → orotic acid in pyrimidine pathway; ↓ BUN, ↑ NH₃.
  • 🩻 Clinical Presentation
    Healthy neonate develops lethargy, vomiting, seizures after protein feeding; respiratory alkalosis.
  • 🩺 Diagnosis
    ↑ orotic acid in urine w/ hyperammonemia; molecular testing of OTC gene.
  • 💊 Management
    Protein restriction, nitrogen‑scavenging agents, arginine supplementation, liver transplant curative.
  • 📊 Epidemiology
    Most common urea cycle defect (≈1 : 50 000).
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Phenylketonuria
Phenylketonuria

AR deficiency of phenylalanine hydroxylase or BH₄ cofactor leading to ↑ Phe & ↓ Tyr.

  • 🟪 Overview
    AR deficiency of phenylalanine hydroxylase or BH₄ cofactor leading to ↑ Phe & ↓ Tyr.
  • 🧠 Pathophysiology
    Excess Phe competes with neutral AAs at BBB → impaired neurotransmitter synthesis & myelination.
  • 🩻 Clinical Presentation
    Intellectual disability, growth delay, seizures, fair complexion, eczema, musty body odor.
  • 🩺 Diagnosis
    Newborn screen (tandem MS) after protein feeding; ↑ Phe/Tyr ratio in plasma.
  • 💊 Management
    Lifetime restriction of Phe (avoid aspartame) with Tyrosine supplementation; BH₄ (sapropterin).
  • 📊 Epidemiology
    ≈1 : 10 000 Caucasian births.
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Maple Syrup Urine Disease
Maple Syrup Urine Disease

AR deficiency of branched‑chain α‑ketoacid dehydrogenase complex.

  • 🟪 Overview
    AR deficiency of branched‑chain α‑ketoacid dehydrogenase complex.
  • 🧠 Pathophysiology
    Unable to degrade Leu, Ile, Val → neurotoxic α‑ketoacids accumulate.
  • 🩻 Clinical Presentation
    First days of life: poor feeding, vomiting, dystonia, opisthotonus, maple‑syrup odor urine.
  • 🩺 Diagnosis
    ↑ leucine & alloisoleucine on newborn screen; enzyme assay or BCKDHA/B genes.
  • 💊 Management
    Lifelong restriction of Leu/Ile/Val; thiamine (cofactor) trial; dialysis in crises.
  • 📊 Epidemiology
    Higher in Mennonite population (~1 : 200).
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Alkaptonuria
Alkaptonuria

AR deficiency of homogentisate oxidase → accumulation of homogentisic acid.

  • 🟪 Overview
    AR deficiency of homogentisate oxidase → accumulation of homogentisic acid.
  • 🧠 Pathophysiology
    Pigment deposits in connective tissue (ochronosis); polymer deposition in cartilage & heart valves.
  • 🩻 Clinical Presentation
    Bluish‑black sclerae & ear cartilage, dark urine on standing, arthropathy of large joints in adulthood.
  • 🩺 Diagnosis
    ↑ homogentisic acid in urine/plasma; HGD gene sequencing.
  • 💊 Management
    Low‑protein diet restricting Phe & Tyr; nitisinone inhibits upstream pathway; NSAIDs for pain.
  • 📊 Epidemiology
    Rare; higher in Slovakia & Dominican Republic.
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Homocystinuria
Homocystinuria

AR cystathionine β‑synthase (most common) or methionine synthase defects → ↑ homocysteine.

  • 🟪 Overview
    AR cystathionine β‑synthase (most common) or methionine synthase defects → ↑ homocysteine.
  • 🧠 Pathophysiology
    Homocysteine damages endothelium & connective tissue → thrombosis & Marfanoid habitus.
  • 🩻 Clinical Presentation
    Tall stature, lens subluxation (down/in), intellectual disability, osteoporosis, recurrent DVT/TE.
  • 🩺 Diagnosis
    ↑ homocysteine & methionine; positive cyanide‑nitroprusside urine test; CBS sequencing.
  • 💊 Management
    Pyridoxine high dose, restriction of Met, supplement B₁₂ and folate; betaine for remethylation.
  • 📊 Epidemiology
    ≈1 : 200 000; B₆‑responsive in 50 %.
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Hereditary fructose intolerance
Hereditary fructose intolerance

Autosomal‑recessive deficiency of aldolase B leading to toxic buildup of fructose‑1‑phosphate; traps phosphate, blocks glycogenolysis & gluconeogenesis → profound fasting hypoglycemia.

  • 🟪 Overview
    Autosomal‑recessive deficiency of aldolase B leading to toxic buildup of fructose‑1‑phosphate; traps phosphate, blocks glycogenolysis & gluconeogenesis → profound fasting hypoglycemia.
  • 🧠 Pathophysiology
    Lack of hepatic aldolase B prevents cleavage of fructose‑1‑P → intracellular phosphate sequestration, ↓ ATP, inhibition of glycogen phosphorylase & fructose‑1,6‑bisphosphatase; hepatocellular injury & metabolic crisis on fructose ingestion.
  • 🩻 Clinical Presentation
    Healthy breast‑fed infant develops vomiting, lethargy, diaphoresis, seizures, jaundice, hepatomegaly minutes–hours after first exposure to fructose‑ or sucrose‑containing foods (eg, fruit juice, honey, baby food). May progress to liver failure & renal Fanconi‑like syndrome.
  • 🩺 Diagnosis
    Hypoglycemia with ↓ phosphate after fructose load, positive urinary reducing sugars with negative glucose oxidase dipstick; genetic testing of ALDOB or enzymatic assay in cultured fibroblasts.
  • 💊 Management
    Strict lifelong elimination of fructose, sucrose, and sorbitol; rapid IV dextrose during crises; dietary counselling and emergency plan for accidental ingestion.
  • 📊 Epidemiology
    ≈1 : 20 000 live births; presents after weaning; carrier frequency highest in Europeans.
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Galactokinase deficiency
Galactokinase deficiency

Autosomal recessive error of galactose metabolism due to absent or severely reduced galactokinase (GALK).

  • 🟪 Overview
    Autosomal recessive error of galactose metabolism due to absent or severely reduced galactokinase (GALK).
  • 🧠 Pathophysiology
    Mutation in GALK gene → inability to phosphorylate galactose to galactose‑1‑phosphate → galactose accumulates in blood (galactosemia) and spills into urine (galactosuria). Aldose reductase converts excess galactose to galactitol in lens → osmotic cataracts. Unlike classic galactosemia, no accumulation of galactose‑1‑phosphate in tissues, so hepatotoxicity and sepsis do not occur.
  • 🩻 Clinical Presentation
    Infant with failure to track objects or develop a social smile; bilateral cataracts often early infancy; otherwise generally benign.
  • 🩺 Diagnosis
    Reducing substances in urine; ↑ serum galactose; normal/low galactose‑1‑phosphate; molecular GALK testing.
  • 💊 Management
    Exclude galactose and lactose (galactose + glucose) from diet; cataract surgery if visual axis obscured.
  • 📊 Epidemiology
    Rare; prevalence ~1 : 30 000–60 000 live births; more common in Roma population.
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Classic galactosemia
Classic galactosemia

Life‑threatening AR disorder caused by galactose‑1‑phosphate uridyltransferase (GALT) deficiency.

  • 🟪 Overview
    Life‑threatening AR disorder caused by galactose‑1‑phosphate uridyltransferase (GALT) deficiency.
  • 🧠 Pathophysiology
    No conversion of galactose‑1‑phosphate to UDP‑galactose → accumulation of galactose‑1‑phosphate in liver, kidneys, brain → cell dysfunction from phosphate trapping and osmotic damage. Secondary galactitol deposition in lens.
  • 🩻 Clinical Presentation
    Onset days after breast‑/formula‑feeding: vomiting, jaundice, hepatomegaly, hypoglycemia, neonatal E. coli sepsis, cataracts, failure to thrive, intellectual disability.
  • 🩺 Diagnosis
    Newborn screen: ↑ total galactose ± ↓ GALT activity on dried blood spot; confirm with enzyme assay or GALT gene sequencing.
  • 💊 Management
    Strict lifelong avoidance of galactose & lactose; prompt IV glucose for hypoglycemia; treat sepsis; vitamin K for coagulopathy.
  • 📊 Epidemiology
    Incidence ≈1 : 30 000–60 000; classic founder mutation Q188R common in Europeans.
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Lactase deficiency
Lactase deficiency

Inability to hydrolyze lactose into glucose and galactose → osmotic diarrhea and malabsorption.

  • 🟪 Overview
    Inability to hydrolyze lactose into glucose and galactose → osmotic diarrhea and malabsorption.
  • 🧠 Pathophysiology
    Primary: age‑dependent decline after childhood (lactase non‑persistence) due to down‑regulation of LCT gene (common in Asians, Africans). Secondary: loss of brush border enzymes (eg, viral gastroenteritis, celiac sprue, IBD). Congenital: rare AR mutation in LCT gene; complete absence of lactase from birth.
  • 🩻 Clinical Presentation
    Bloating, crampy abdominal pain, flatulence, osmotic (high‑volume) watery diarrhea after milk products.
  • 🩺 Diagnosis
    Stool pH <5, ↑ breath hydrogen after lactose tolerance test; normal intestinal biopsy; symptom relief on lactose‑free diet.
  • 💊 Management
    Lactose‑restricted diet; lactase enzyme replacement tablets; ensure calcium & vitamin D intake.
  • 📊 Epidemiology
    Up to 65 % of world population has some degree of lactase non‑persistence; higher prevalence in non‑European ancestry.
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Hyperammonemia
Hyperammonemia

Elevated blood ammonia leading to neurotoxicity

  • 🟪 Overview
    Elevated blood ammonia leading to neurotoxicity
  • 🧠 Pathophysiology
    Deficiency of urea cycle enzymes or liver failure prevents conversion of NH3 to urea → excess NH3 crosses BBB causing astrocyte swelling and ↑ glutamine
  • 🩻 Clinical Presentation
    Lethargy, vomiting, cerebral edema, seizures, coma, respiratory alkalosis in neonate or altered mental status in adult with liver disease
  • 🩺 Diagnosis
    Plasma ammonia >80 µmol/L, ↑glutamine, ↓BUN, respiratory alkalosis; all amino acids in urine
  • 💊 Management
    Limit protein; give lactulose, rifaximin, benzoate/phenylacetate/phenylbutyrate to trap NH3; liver transplant if severe
  • 📊 Epidemiology
    Incidence ~1:30 000; all ethnicities; presents in first days of life for inherited forms
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Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency

Most common urea‑cycle disorder causing hyperammonemia with orotic aciduria

  • 🟪 Overview
    Most common urea‑cycle disorder causing hyperammonemia with orotic aciduria
  • 🧠 Pathophysiology
    X‑linked recessive deficiency of mitochondrial OTC blocks conversion of carbamoyl phosphate + ornithine → citrulline; carbamoyl phosphate → orotic acid in pyrimidine pathway
  • 🩻 Clinical Presentation
    Neonatal catastrophic hyperammonemia or later episodic vomiting & confusion; no megaloblastic anemia
  • 🩺 Diagnosis
    ↑Orotic acid in urine/plasma, ↑NH3, ↓citrulline, normal CBC
  • 💊 Management
    Protein restriction, nitrogen‑scavenger drugs, arginine supplementation, liver transplant definitive
  • 📊 Epidemiology
    1:40 000 male births; female heterozygotes symptomatic during catabolic stress
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Phenylketonuria
Phenylketonuria

Failure to convert phenylalanine to tyrosine results in toxic phenylketone accumulation causing intellectual disability

  • 🟪 Overview
    Failure to convert phenylalanine to tyrosine results in toxic phenylketone accumulation causing intellectual disability
  • 🧠 Pathophysiology
    Autosomal recessive PAH (phenylalanine hydroxylase) deficiency or BH4 cofactor deficiency
  • 🩻 Clinical Presentation
    Intellectual disability, microcephaly, seizures, eczema, musty body odor, hypopigmented skin & hair
  • 🩺 Diagnosis
    Newborn screen (tandem mass‑spec); ↑Phe, ↓tyrosine
  • 💊 Management
    Life‑long low‑phenylalanine diet, BH4 supplementation in some, tyrosine supplementation
  • 📊 Epidemiology
    1:10 000 in U.S.; detected on newborn screen
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Maple syrup urine disease
Maple syrup urine disease

Accumulation of branched‑chain amino acids and ketoacids

  • 🟪 Overview
    Accumulation of branched‑chain amino acids and ketoacids
  • 🧠 Pathophysiology
    Autosomal recessive deficiency of branched‑chain α‑ketoacid dehydrogenase complex (requires thiamine)
  • 🩻 Clinical Presentation
    Poor feeding, vomiting, dystonia, hypotonia, seizures, maple‑syrup odor urine within first days
  • 🩺 Diagnosis
    ↑Leucine/isoleucine/valine, ↑ketoacids in plasma/urine
  • 💊 Management
    BCAA‑restricted diet, thiamine supplementation, dialysis during crises
  • 📊 Epidemiology
    Incidence 1:200 000; ↑ in Mennonite population
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Alkaptonuria
Alkaptonuria

Benign in childhood, causes ochronosis & arthritis later

  • 🟪 Overview
    Benign in childhood, causes ochronosis & arthritis later
  • 🧠 Pathophysiology
    Autosomal recessive homogentisate oxidase deficiency in tyrosine degradation → ↑homogentisic acid
  • 🩻 Clinical Presentation
    Dark urine on standing, bluish‑black connective tissue pigmentation (ochronosis), arthropathy of spine & large joints
  • 🩺 Diagnosis
    Clinical; homogentisic acid in urine; CT shows calcified discs
  • 💊 Management
    Symptomatic; nitisinone blocks upstream steps; low‑protein diet
  • 📊 Epidemiology
    Rare (~1:250 000)
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Cystinuria
Cystinuria

Defective renal reabsorption of COLA dibasic AAs → cystine stones

  • 🟪 Overview
    Defective renal reabsorption of COLA dibasic AAs → cystine stones
  • 🧠 Pathophysiology
    Autosomal recessive mutation in SLC3A1/SLC7A9 causing PCT & intestine transport defect for cystine, ornithine, lysine, arginine
  • 🩻 Clinical Presentation
    Recurrent hexagonal cystine nephrolithiasis in childhood/teens
  • 🩺 Diagnosis
    Urinary cyanide‑nitroprusside test; stone analysis; genetic testing
  • 💊 Management
    High‑fluid intake, urinary alkalinization (K‑citrate, acetazolamide), chelators (penicillamine), low‑methionine diet
  • 📊 Epidemiology
    Prevalence 1:7000; ↑ in Mediterranean
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Propionic acidemia
Propionic acidemia

Accumulation of propionic acid causes anion‑gap metabolic acidosis

  • 🟪 Overview
    Accumulation of propionic acid causes anion‑gap metabolic acidosis
  • 🧠 Pathophysiology
    Autosomal recessive deficiency of propionyl‑CoA carboxylase (biotin cofactor) in catabolism of odd‑chain FA, Val, Ile, Met, Thr
  • 🩻 Clinical Presentation
    Neonatal poor feeding, vomiting, hypotonia, seizures, hyperammonemia, AG acidosis
  • 🩺 Diagnosis
    ↑Propionic acid, ↑3‑OH‑propionate, ↑glycine in plasma; metabolic acidosis
  • 💊 Management
    Protein‑restricted diet (low VOMIT AAs), biotin; emergency IV glucose/lipids during catabolism
  • 📊 Epidemiology
    Incidence 1:100 000
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Methylmalonic acidemia
Methylmalonic acidemia

Build‑up of methylmalonic acid due to impaired conversion to succinyl‑CoA

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Systemic primary carnitine deficiency
Systemic primary carnitine deficiency

Impaired long‑chain FA transport into mitochondria → hypoketotic hypoglycemia

  • 🟪 Overview
    Impaired long‑chain FA transport into mitochondria → hypoketotic hypoglycemia
  • 🧠 Pathophysiology
    AR defect in SLC22A5 (OCTN2) carnitine transporter; ↓carnitine uptake
  • 🩻 Clinical Presentation
    Infantile encephalopathy, hepatomegaly, cardiomyopathy, hypotonia, hypoketotic hypoglycemia during fasting
  • 🩺 Diagnosis
    ↓Plasma carnitine, ↓ketones despite hypoglycemia, ↑dicarboxylic acids
  • 💊 Management
    Oral L‑carnitine, avoid fasting, high‑carb low‑fat diet
  • 📊 Epidemiology
    Rare; reported worldwide
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Medium‑chain acyl‑CoA dehydrogenase deficiency
Medium‑chain acyl‑CoA dehydrogenase deficiency

Inability to break down medium‑chain FAs → hypoketotic hypoglycemia

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Abetalipoproteinemia
Abetalipoproteinemia

Inability to form chylomicrons & VLDL → fat malabsorption & neuro deficits

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Familial hyperchylomicronemia (Type I)
Familial hyperchylomicronemia (Type I)

Severe elevation of chylomicrons & TGs due to LPL pathway defect

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Familial hypercholesterolemia (Type IIa)
Familial hypercholesterolemia (Type IIa)

Elevated LDL due to LDL receptor or ApoB‑100 defect

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Familial dysbetalipoproteinemia (Type III)
Familial dysbetalipoproteinemia (Type III)

Accumulation of remnants due to ApoE2 homozygosity

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Familial hypertriglyceridemia (Type IV)
Familial hypertriglyceridemia (Type IV)

Hepatic VLDL overproduction causes isolated ↑TG

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