Retinitis pigmentosa

A patient (often a child or young adult) with progressive rod-cone retinal degeneration. The classic triad on funduscopy is bone-spicule pigmentation in the mid-periphery, attenuated retinal vessels, and a waxy pale optic disc. The symptoms map onto rod loss first: nyctalopia (night blindness) and concentric peripheral visual field loss ("tunnel vision"), with central acuity preserved until late. ERG shows reduced or extinguished rod responses early, cone responses later. RP is the diagnosis; the clinical work is figuring out whether it is isolated or part of a syndrome, because several syndromic forms are treatable or require organ-specific surveillance.

Three questions structure the work-up:

1. Isolated or syndromic? Isolated RP is the largest bucket (>100 genes; all inheritance patterns including mitochondrial). Syndromic RP is a smaller fraction but disproportionately high yield because of comorbidity and treatability.
2. Inheritance pattern. Three-generation pedigree: AD (milder, later onset), AR (more severe, often consanguineous), X-linked (males severe, female carriers may have patchy fundus changes), mitochondrial (maternal transmission, multisystem).
3. Extraocular features that direct testing. Hearing, obesity, polydactyly, renal disease, ataxia, cardiac conduction abnormalities, cognitive issues, gait, skin. Any one of these points to a specific syndrome.

Isolated RP

• Autosomal dominant (~30%): RHO (rhodopsin) is the prototype; usually milder, later onset.
• Autosomal recessive (~50-60%): USH2A is the most common single gene (even outside Usher); RPE65-associated Leber congenital amaurosis spectrum (treatable with voretigene neparvovec subretinal gene therapy, the first FDA-approved gene therapy for an inherited eye disease).
• X-linked (~10-15%): RPGR, RP2. Males severe with early central involvement; female carriers show a "tapetal" sheen.
• Mitochondrial: maternal inheritance, often part of a multisystem mitochondrial disorder.

Syndromic RP (the high-yield differential)

• Usher syndrome (AR; multiple genes including MYO7A, USH2A, CDH23, CLRN1): RP + congenital sensorineural hearing loss ± vestibular dysfunction. Three clinical types: type 1 (profound congenital deafness + vestibular areflexia + early RP), type 2 (moderate to severe deafness with normal vestibular function + later RP onset), type 3 (progressive hearing loss + variable RP). Most common cause of combined deaf-blindness in adults.
• Bardet-Biedl syndrome (AR ciliopathy; >20 BBS genes): RP + post-axial polydactyly + truncal obesity + cognitive impairment + renal anomalies + hypogonadism. A primary ciliopathy; renal disease is a leading cause of mortality.
• Refsum disease (PHYH, less commonly PEX7; AR): RP + cerebellar ataxia + peripheral neuropathy + anosmia + ichthyosis + cardiomyopathy. Treatable: dietary restriction of phytanic acid (no dairy fat, no ruminant meat) halts progression. Always include serum phytanic acid in the RP work-up.
• Kearns-Sayre syndrome (large mitochondrial DNA deletion, usually sporadic): RP + progressive external ophthalmoplegia + cardiac conduction block (the pacemaker is the life-saving intervention) + onset before age 20. Ragged-red fibers on muscle biopsy.
• Alstrom syndrome (ALMS1, AR ciliopathy): looks like BBS without polydactyly; adds cone-rod dystrophy + sensorineural hearing loss + dilated cardiomyopathy + insulin resistance + truncal obesity. Cardiac and hepatic involvement drive prognosis.
• Joubert syndrome (ciliopathy; AHI1, CEP290, others): RP in a subset, plus the molar tooth sign on brain MRI + episodic tachypnea + cerebellar ataxia.
• Senior-Loken syndrome (NPHP1, NPHP4, IQCB1, CEP290; AR): RP + nephronophthisis (juvenile interstitial nephritis progressing to ESRD).
• Abetalipoproteinemia (Bassen-Kornzweig) (MTTP, AR): RP + acanthocytes + fat-soluble vitamin deficiency. Treatable with high-dose vitamins A and E.

1. Full ophthalmologic evaluation: dilated fundus exam, fundus photos, OCT, full-field ERG, visual fields, fundus autofluorescence.
2. Audiology in every RP patient (Usher rule-out), regardless of reported hearing.
3. Renal evaluation (urinalysis, BUN/creatinine, renal ultrasound) for BBS, Senior-Loken, Alstrom.
4. Serum phytanic acid in every RP patient (Refsum is treatable; missing it costs decades of preventable disease).
5. Echocardiogram and ECG for Kearns-Sayre and Alstrom; consider cardiac MRI.
6. Lipid panel + peripheral smear for acanthocytes + fat-soluble vitamins if abetalipoproteinemia is on the differential.
7. Three-generation pedigree with attention to consanguinity, X-linked patterns, maternal transmission, sudden death, deafness.
8. Inherited retinal disease gene panel (covers >250 genes; preferred first genetic test in most centers). Exome with mitochondrial coverage if the panel is unrevealing or mitochondrial disease is suspected.