Systemic Associations in Retinitis Pigmentosa
Retinitis pigmentosa (RP) presents with systemic associations in 20-30% of cases, requiring evaluation for ciliopathies, inherited metabolic disorders, mitochondrial disorders, and miscellaneous syndromes to guide prognosis and management. 1
Syndromic RP: Major Categories
Ciliopathies (Most Common Systemic Associations)
Usher Syndrome and Bardet-Biedl Syndrome are the most prevalent ciliopathies associated with RP 1:
- Usher Syndrome: Progressive sensorineural hearing loss (congenital or early-onset) combined with RP; vestibular dysfunction may be present depending on subtype 1
- Bardet-Biedl Syndrome: Obesity, polydactyly, renal abnormalities, hypogonadism, cognitive impairment, and RP 1
Less Common Ciliopathies include 1:
- Cohen syndrome
- Joubert syndrome (cerebellar vermis hypoplasia, developmental delay, abnormal breathing patterns)
- Cranioectodermal dysplasia
- Asphyxiating thoracic dystrophy (Jeune syndrome)
- Mainzer-Saldino syndrome
- RHYNS syndrome
Inherited Metabolic Disorders
Peroxisomal Disorders 1:
- Zellweger spectrum disorders: Craniofacial abnormalities, hepatomegaly, hypotonia, seizures
- Adult Refsum disease: Peripheral neuropathy, cerebellar ataxia, elevated phytanic acid levels, anosmia
- α-methylacyl-CoA racemase deficiency: Adult-onset sensory motor neuropathy
Storage and Metabolic Diseases 1:
- Mucopolysaccharidoses (certain types): Coarse facial features, skeletal abnormalities, organomegaly
- Neuronal ceroid lipofuscinoses: Progressive cognitive decline, seizures, motor deterioration
- Abetalipoproteinemia: Fat malabsorption, acanthocytosis, ataxia, low cholesterol
- Ataxia with vitamin E deficiency: Progressive ataxia, proprioceptive loss
Other Metabolic Associations 1:
- Mevalonic aciduria: Recurrent fevers, developmental delay, cerebellar ataxia
- PKAN/HARP syndrome: Dystonia, rigidity, iron accumulation in basal ganglia
- PHARC syndrome: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataracts
- Methylmalonic acidaemia with homocystinuria (cblC disease): Developmental delay, megaloblastic anemia
Mitochondrial Disorders
The retina's high metabolic demand makes it vulnerable to mitochondrial dysfunction 1:
- Kearns-Sayre Syndrome: Progressive external ophthalmoplegia, cardiac conduction defects, onset before age 20, elevated CSF protein 1
- NARP Syndrome: Neuropathy, ataxia, retinitis pigmentosa; maternal inheritance pattern 1
- Primary Coenzyme Q10 Deficiency: Variable presentation with encephalomyopathy, ataxia, seizures 1
- SSBP1-Associated Disease: Optic atrophy, progressive external ophthalmoplegia 1
- Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Hypoglycemia, cardiomyopathy, neuropathy 1
Miscellaneous Syndromes
- Cockayne Syndrome: Premature aging, photosensitivity, cachexia, microcephaly, developmental delay 1
- PERCHING Syndrome: Does not fit standard classification hierarchy 1
Clinical Implications and Management Approach
Diagnostic Evaluation
When RP is diagnosed, systematically assess for 1:
- Hearing loss (audiometry for Usher syndrome)
- Obesity, polydactyly, renal function (Bardet-Biedl syndrome)
- Ataxia, peripheral neuropathy (Refsum disease, mitochondrial disorders)
- Developmental delay, cognitive impairment (multiple syndromes)
- Cardiac conduction abnormalities (Kearns-Sayre syndrome)
- Metabolic screening: Phytanic acid, very long chain fatty acids, plasma amino acids, acylcarnitine profile
Impact on Prognosis and Treatment
Accurate syndromic diagnosis is essential because 2, 1:
- Systemic manifestations may be life-threatening (cardiac conduction defects in Kearns-Sayre, renal disease in Bardet-Biedl)
- Some conditions have specific dietary interventions (phytanic acid restriction in Refsum disease)
- Genetic counseling differs based on inheritance pattern (autosomal recessive vs. mitochondrial)
- Several first-in-human clinical trials are underway for specific syndromic forms of RP 1
Quality of Life Considerations
RP causes greater emotional and psychological impact than diabetic retinopathy or age-related macular degeneration, with progressive vision loss severely affecting daily tasks, employment, and independence 2. The addition of systemic manifestations in syndromic RP compounds this burden significantly 2, 1.
Common Pitfalls
- Failing to screen for hearing loss: Usher syndrome may present with RP before hearing loss is recognized as progressive 1
- Missing cardiac screening in Kearns-Sayre syndrome: Cardiac conduction defects can be fatal if undetected 1
- Overlooking metabolic screening: Treatable conditions like Refsum disease require specific dietary modifications 1
- Assuming isolated RP: 20-30% of RP cases are syndromic, requiring systematic evaluation even when no obvious systemic features are initially apparent 1