USMLE STEP 1- First AidDiseases/Disorders/Deficiencies/Syndromes

USMLE STEP 1- First AidDiseases/Disorders/Deficiencies/Syndromes Exam 2023 (A+) Adenosine deaminase (ADA) deficiency - ANS-An immunodeficiency disorder and one type of SCIDs that is caused by an *inborn error in the metabolism of adenine*. The accumulation of adenine destroys both B and T lymphocytes. Increase in dATP is lymphotoxic Lesch-Nyhan syndrome - ANS-*Defective purine salvage due to absent HGPRT*, which converts hypoxanthine to IMP and guanine to GMP. Results in *excess uric acid production and de novo purine synthesis*. X-linked recessive Findings: intellectual disability, self-mutilation, aggression, hyperuricemia (orange "sand" [sodium urate crystals] in diaper), gout, dystonia. Treatment: allopurinol or febuxostat (2nd line) Bloom Syndrome - ANS-Caused by mutations in the BLM gene leading to *mutated DNA helicase protein formation* Rare autosomal recessive disorder characterized by short stature, predisposition to the development of cancer and genomic instability Xeroderma pigmentosum (XP) - ANS-*Nucleotide Excision Repair Defect* Defect prevents repair of pyrimidine dimers because of ultraviolet light exposure Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) - ANS-Mismatch repair defect Ataxia Telangiectasia - ANS-Nonhomologous end joining defect *Defects in ATM gene = failure to repair DNA double strand breaks cell cycle arrest.* Triad: *cerebellar defects (Ataxia), spider Angiomas (telangiectasia), IgA deficiency.* Increased AFP. Decreased IgA, IgG, and IgE. Lymphopenia, cerebellar atrophy. Fanconi anemia - ANS-Nonhomologous end joining defect I-Cell Disease (Inclusion cell disease/mucolipidosis type II) - ANS-Inherited *lysosomal storage disorder* *Defect in N-acetylglucosaminyl-1-phosphotransferase = failure of the Golgi to phosphorylate mannose residues (ie, mannose-6-phosphate)* on glycoproteins = proteins are secreted extracellularly rather than delivered to lysosomes. Results in coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. Often fatal in childhood Zellweger syndrome - ANS-Autosomal Recessive disorder of *Peroxisome* biogenesis due to mutated PEX genes Results in hypotonia, seizures, hepatomegaly, early death Refsum disease - ANS-Autosomal recessive disorder of *alpha oxidation* *(peroxisome)* = *phytanic acid not metabolized to pristanic acid* Results in scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe, epiphyseal dysplasia Tx: diet, plasmaphoresis Adrenoleukodystrophy (ALD) - ANS-an X-linked disorder of *Beta oxidation (peroxisome)* in which dysfunction of the adrenal cortex and nervouse system demyelination are associated with high levels of saturated very-long-chain fatty acids (VLCFAs) Results in *VLCFAs buildup in adrenal glands, white matter of the brain, testes* Progressive disease that can lead to adrenal gland crisis, coma, death Kartagener syndrome (primary ciliary dyskinesia) - ANS-*Immotile cilia due to a dynein arm defect.* Results in male and female infertility due to immotile sperm and dysfunctional fallopian tube cilia, respectively; increased risk of ectopic pregnancy. Can cause bronchiectasis, recurrent sinusitis, and situs inversus (eg, dextrocardia on CXR = Defect in left-right Dynein can lead to Dextrocardia) Osteogenesis Imperfecta - ANS-Genetic bone disorder (brittle bone disease) caused by a variety of gene defects (most commonly *COL1A1 and COL1A2*). *Most common form is autosomal dominant with production of otherwise normal type I collagen*. Worst is type III = perinatal lethal Manifestations can include: -Multiple fractures with minimal trauma; may occur during the birth process -Blue sclerae due to the translucent connective tissue over choroidal veins -Hearing loss (abnormal ossicles) -Some forms have tooth abnormalities, including opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta) Tx: bisphosphonates to decrease fracture risk Ehlers-Danlos Syndrome (EDS) - ANS-Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints Multiple types. Inheritance and severity vary. Can be *autosomal dominant or recessive*. May be associated with *joint dislocation, berry and aortic aneurysms, organ rupture*. Hypermobility type (joint instability): most common type. Classical type (joint and skin symptoms): caused by a mutation in type V collagen (*COL5A1, COL5A2*) and I Vascular type (vascular and organ rupture): deficient *type III collagen* Ehlers-Danlos Syndrome: Hypermobility Type - ANS-Most common type of EDS. Ehlers-Danlos syndrome: Classical type (joint and skin symptoms) - ANS-EDS caused by a mutation in type V collagen (*COL5A1, COL5A2*) and type I Ehlers-Danlos syndrome: Vascular type (vascular and organ rupture) - ANS-EDS caused by deficient *type III collagen* Menkes Disease - ANS-*X-linked recessive* connective tissue disease caused by *impaired copper absorption and transport due to defective Menkes protein (ATP7A)*. *Leads to decreased activity of lysyl oxidase (copper is a necessary cofactor)*. CONTINUES...