Which is not a feature of G6PD deficiency?

Males and females are equally affected

A 4-year-old boy is brought to a pediatrician by his parents for a consultation after his teacher complained about his inability to focus or make friends at school. They mention that the boy does not interact well with others at home, school, or daycare. On physical examination, his vital signs are stable with normal weight, height, and head circumference for his age and sex. His general examination and neurologic examination are completely normal. A recent audiological evaluation shows normal hearing, and intellectual disability has been ruled out by a clinical psychologist. Which of the following investigations is indicated as part of his diagnostic evaluation at present?

Autism spectrum disorder screening and developmental assessment

Magnetic resonance imaging (MRI) of brain

Positron Emission Tomography (PET) scanning of head

A 16-year-old male presents to an ophthalmologist as a new patient with a complaint of blurry vision. He reports that over the past several months he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His past medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type II diabetes mellitus, and a father who underwent aortic valve replacement last year. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses. Which of the following is the most likely etiology of this patient’s presentation?

Mutation of gene on chromosome 15

Defective metabolism of methionine

A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?

Abnormally decreased expression of the gene from the maternal chromosome

Abnormally increased expression of the gene from the maternal chromosome

Abnormally decreased expression of the gene from both chromosomes

Abnormally decreased expression of the gene from the paternal chromosome

Abnormally increased expression of the gene from the paternal chromosome

Single Gene Disorders for USMLE Step 3: High-Yield Psychiatry Lessons

Single Gene Disorders - Gene Transmission Tactics

Standard Pedigree Nomenclature

Pattern	Risk	Trans.	Notes	Examples
AD	50%	Vertical; M=F		Marfan, Achondroplasia
AR	25%	Horizontal; M=F	Consang. ↑	CF, PKU, Sickle Cell
XLR	Varies	No M-M; M > F	Carrier F	Hemophilia A, DMD
XLD	Varies	No M-M; F > M	Lethal M	Rett, Incontinentia Pigmenti
Mito.	100% (mother)	Maternal	Heteroplasmy	MELAS, LHON

Expressivity: Variable severity of phenotype.
Pleiotropy: 1 gene → multiple effects.
Locus Heterogeneity: Same disease, different genes.
Allelic Heterogeneity: Different mutations, same gene.
New Mutation: Fresh gene change; no family Hx.
Germline Mosaicism: Mutation in germline only; parent unaffected.

⭐ Lyonization/X-inactivation in females explains variable expression in female carriers of X-linked recessive traits and manifestation in X-linked dominant traits.

Single Gene Disorders - Autosomal Aces & Recessive Risks

Disorder	Gene	Key Features	Dx Hint/Screening
Marfan Syndrome (AD)	FBN1	Tall, Arachnodactyly, Lens up, Aortic dissection. 📌 FBN1	Ghent criteria
Neurofibromatosis 1 (AD)	NF1	≥6 Café-au-lait, Lisch nodules, Neurofibromas, Optic glioma	NIH criteria
Achondroplasia (AD)	FGFR3	Short limbs, Macrocephaly, Trident hand	X-ray
Cystic Fibrosis (AR)	CFTR	Lung disease, Pancreatic insufficiency, ↑Sweat Cl⁻ > 60 mmol/L, Meconium ileus	Sweat test, NBS
Phenylketonuria (AR)	PAH	ID (untreated), Musty odor, Eczema	NBS (↑Phe); Diet: Phe 120-360 µmol/L
Sickle Cell Anemia (AR)	HBB	Vaso-occlusion, Anemia, Dactylitis	Hb electrophoresis, NBS

PKU Management:

⭐ High spontaneous mutation rate, often linked to advanced paternal age, is characteristic for Autosomal Dominant disorders like Achondroplasia and NF1.

Single Gene Disorders - Chromosome X-Files & More

Disorder	Gene	Defect	Key Features	Note (X-linked Recessive unless stated)
Duchenne MD (DMD)	DMD	Dystrophin (absent)	Gower's sign, calf pseudohypertrophy, ↑CK. Onset <5 yrs. 📌 DMD: Dystrophin Defect → Muscle Destruction.	Wheelchair by 12 yrs.
Becker MD (BMD)	DMD	Dystrophin (reduced/altered)	Milder DMD, onset >5 yrs.	Ambulatory >15 yrs.
Hemophilia A	F8	Factor VIII deficiency	Bleeding (joints, muscles). Severity: Mild (>5%), Mod (1-5%), Severe (<1% FVIII).
Hemophilia B	F9	Factor IX deficiency	Similar to Hemophilia A (Christmas Disease). Severity: Mild (>5%), Mod (1-5%), Severe (<1% FIX).
G6PD Deficiency	G6PD	↓G6PD enzyme	Hemolytic anemia (oxidative stress: drugs, fava beans). Heinz bodies, bite cells.	📌 G6PD: Bite cells & Heinz bodies.
Fragile X Syndrome	FMR1	CGG repeat expansion (>200)	Intellectual disability, long face, large ears, macroorchidism. Premutation (55-200 repeats): FXTAS, FXPOI.	X-linked Dominant (anticipation).

High‑Yield Points - ⚡ Biggest Takeaways

Autosomal Dominant: Vertical transmission, 50% risk to offspring (e.g., Marfan syndrome, Achondroplasia).

Autosomal Recessive: Horizontal transmission (sibs), 25% risk, consanguinity is key (e.g., Cystic Fibrosis, PKU).

X-Linked Recessive: Affects mainly males; no male-to-male transmission (e.g., DMD, Hemophilia).

X-Linked Dominant: Affected fathers transmit to all daughters, no sons (e.g., Vitamin D-resistant rickets).

Mitochondrial Inheritance: Maternal transmission only, to all offspring (e.g., LHON, MELAS).

Cystic Fibrosis: CFTR gene defect, sweat chloride test, recurrent sinopulmonary infections.

Duchenne Muscular Dystrophy (DMD): Dystrophin gene, Gower's sign, progressive muscle weakness_._

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