Mark the false statement regarding mitochondrial DNA:

AGA and AGG are stop codons in mitochondrial DNA

Kearns-Sayre Syndrome is a large deletion in mitochondrial DNA

1% of cellular DNA, 13 proteins of respiratory chain

Which disorder is associated with NARP syndrome, characterized by neuropathy, ataxia, and retinitis pigmentosa?

Mitochondrial function disorder

A 3-month-old girl with an immunodeficiency syndrome has been hospitalized for 1 month due to a severe pulmonary infection. Her family came to visit her daily in the beginning of her hospital stay; however, since their car broke down they have been unable to visit for the last 2 weeks. While the infection has now been resolved with proper treatment and supportive care, the girl's nurse is concerned that the patient is becoming increasingly withdrawn. Specifically, the nurse has noticed that since the family has stopped visiting, the girl seems to shy away from contact and sometimes even becomes unresponsive to verbal or visual cues. Which of the following is most likely true about this infant's condition?

The condition can be diagnosed in adults if it lasts > 6 months

The condition is significantly more common in boys

The condition is exclusively seen in girls

The condition should be reported to state authorities

A 59-year-old man comes to the clinic for an annual well-exam. He was lost to follow-up for the past 3 years due to marital issues but reports that he feels fine. The patient reports, “I feel tired but it is probably because I am getting old. I do feel a little feverish today - I think I got a cold.” His past medical history is significant for hypertension that is controlled with hydrochlorothiazide. He reports fatigue, congestion, cough, and night sweats. He denies any sick contacts, recent travel, weight changes, chest pain, or dizziness. His temperature is 101°F (38.3°C), blood pressure is 151/98 mmHg, pulse is 97/min, and respirations are 15/min. His laboratory values are shown below: Hemoglobin: 13.5 g/dL Hematocrit: 41% Leukocyte count: 25,000/mm^3 Segmented neutrophils: 73% Bands: 8% Eosinophils: 1% Basophils: 2% Lymphocytes: 15% Monocytes: 2% Platelet count: 200,000/mm^3 What diagnostic test would be helpful in distinguishing this patient’s condition from pneumonia?

Magnetic resonance imaging of the chest

A 19-year-old woman is brought to the emergency room by her mother. She found her daughter pale, cold to the touch, and collapsed next to her bed earlier this morning. The patient has no previous medical or psychiatric history, but the mother does report that her daughter has not had her periods for the last 3 months. In the emergency department, the patient is alert and oriented. Her vitals include: blood pressure 80/60 mm Hg supine, heart rate 55/min. On physical examination, the patient appears pale and emaciated. A urine pregnancy test is negative. She is suspected of having an eating disorder. Which of the following treatment options would be contraindicated in this patient?

Selective serotonin reuptake inhibitors

A 66-year-old woman comes to the physician because of a 1-week history of pruritic blister formation. Physical examination shows multiple 1–3 cm bullae on the palms, soles, lower legs, and inguinal folds. Gentle rubbing of the skin does not result in sloughing of the epidermis. Immunofluorescence studies of a perilesional skin biopsy specimen are most likely to show deposition of antibodies in which of the following areas?

Between epidermal keratinocytes

Mitochondrial Disorders for USMLE Step 3: High-Yield Psychiatry Lessons

Mitochondrial Disorders: Mito Basics - Tiny Powerhouse Troubles

Mitochondria: "Cell's powerhouses"; generate ATP via Oxidative Phosphorylation (OXPHOS).
Dual Genome:
- mtDNA: Small, circular, maternally inherited. Encodes 13 essential OXPHOS protein subunits, tRNAs, rRNAs.
- nDNA: Nuclear DNA; encodes vast majority (~1500) of mitochondrial proteins.
Unique Genetic Principles:
- Heteroplasmy: Presence of both mutant and wild-type mtDNA in cells/tissues.
- Threshold Effect: Clinical disease manifests when mutant mtDNA proportion exceeds a critical level.
- Replicative Segregation: Random distribution of mtDNA during cell division, affecting tissue involvement.

⭐ Maternal inheritance is a key characteristic for disorders caused by mtDNA defects.

Mitochondrial dysfunction in brain disorders

Mitochondrial Disorders: Clinical Clues - Energy Crisis Manifestations

Mitochondrial dysfunction leads to impaired ATP production, causing an "energy crisis." This primarily affects organs with high energy requirements.

Multi-systemic involvement is characteristic.
Neurological: Encephalopathy, seizures, ataxia, stroke-like episodes, migraines, developmental delay/regression.
Muscular: Myopathy, exercise intolerance, fatigue, ptosis, progressive external ophthalmoplegia (PEO).
Cardiac: Cardiomyopathy (often hypertrophic), conduction defects.
Ocular: Optic atrophy, pigmentary retinopathy, ophthalmoplegia.
Auditory: Sensorineural hearing loss (SNHL).
Endocrine: Diabetes mellitus, short stature, hypoparathyroidism.
Renal: Fanconi syndrome, tubulopathy.
Gastrointestinal: Dysmotility, pseudo-obstruction, liver dysfunction.
Other: Persistent lactic acidosis, failure to thrive.

📌 Mnemonic: "My Brain Hates Exercise" - Myopathy - Brain: Encephalopathy, seizures, ataxia - Heart: Cardiomyopathy - Eyes: Ophthalmoplegia, optic atrophy - Endocrine: Diabetes mellitus - Ears: Sensorineural hearing loss (SNHL)

⭐ Tissues with high energy demand (brain, muscle, heart, retina, cochlea) are most severely affected.

Mitochondrial Disorders: Syndrome Showcase - Rogues' Gallery

Syndrome	Key Features (📌 Mnemonic)	Gene (Common)	Specific Findings
MELAS	📌 Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes	MT-TL1 ($tRNA^{Leu}$)	Stroke-like episodes (non-vascular), RRF, hearing loss, diabetes
MERRF	📌 Myoclonic Epilepsy, Ragged Red Fibers	MT-TK ($tRNA^{Lys}$)	Ataxia, dementia, myopathy, RRF, optic atrophy
KSS	Ophthalmoplegia, Retinitis Pigmentosa, Cardiac conduction defects (onset < 20 yrs)	Large mtDNA deletions	Ptosis, complete heart block, ↑CSF protein (>100 mg/dL)
Leigh Syndrome	Progressive neurodegeneration, psychomotor delay, brainstem & basal ganglia involvement	Multiple (mtDNA/nDNA)	Symmetrical necrotic lesions (basal ganglia, brainstem), hypotonia, optic atrophy

⭐ MELAS often presents with stroke-like episodes, typically before age 40, not conforming to vascular territories.

Other Notable Syndromes:
- Pearson Syndrome: Infantile pancreatic exocrine dysfunction, sideroblastic anemia, pancytopenia. Large mtDNA deletions. May evolve to KSS.
- LHON (Leber Hereditary Optic Neuropathy): Acute/subacute bilateral central vision loss. Primarily MT-ND gene mutations.

Mitochondrial Disorders: Diagnosis & Care - Unmasking & Managing

Diagnosis: Suspect with unexplained multi-systemic disease (neuro, myopathy).
- Initial tests: ↑ Plasma/CSF lactate, $L/P \text{ ratio} > \mathbf{20}$, urine organic acids, plasma amino acids.
- Muscle biopsy: Key for histochemistry (Ragged-Red Fibers, COX-deficiency) & enzyme assays.
- Genetic testing: mtDNA (e.g., MELAS, MERRF) & nDNA (e.g., Leigh syndrome) targeted panels or exome.
Management:
- Supportive: Symptomatic relief, avoid mitochondrial toxins (valproate, statins).
- Mitochondrial cocktail (empirical): CoQ10, L-carnitine, riboflavin, thiamine.
- Physiotherapy, genetic counseling.

⭐ Muscle biopsy showing ragged-red fibers (RRF) is a classic finding but not pathognomonic; may be absent in some disorders or early stages.

High‑Yield Points - ⚡ Biggest Takeaways

Mitochondrial disorders typically show maternal inheritance (mtDNA); some from nuclear DNA.

Primarily affect high-energy organs (brain, muscle, heart, eyes), causing varied symptoms.

Clinical presentation is highly variable due to heteroplasmy (mixed mutant/normal mtDNA).

Lactic acidosis, often with ↑ lactate/pyruvate ratio, is a key biochemical marker.

Key syndromes: MELAS, MERRF, LHON, and Kearns-Sayre syndrome.

Ragged red fibers on muscle biopsy (Gomori trichrome) are characteristic.

Management is supportive; cofactor therapy (e.g., CoQ10) is often tried.

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