What is Refsum disease and how is it characterized, diagnosed, and managed?

Refsum Disease: Diagnosis, Clinical Features, and Management

Refsum disease is a rare autosomal recessive disorder caused by deficiency of phytanoyl-CoA hydroxylase (PhyH) enzyme, resulting in accumulation of phytanic acid that causes progressive neurological damage and multisystem complications. Primary treatment involves a diet low in phytanic acid, with plasmapheresis indicated for severe cases. 1, 2

Background and Pathophysiology

• Refsum disease is characterized by mutations in the PHYH gene (also called PAHX), resulting in deficiency of the enzyme that catalyzes the first step in alpha-oxidation of phytanic acid 1, 3
• Phytanic acid is derived from dietary sources and accumulates in fatty tissues including myelin sheaths and internal organs due to impaired metabolism 2, 4
• The condition follows an autosomal recessive inheritance pattern 1

Clinical Features

Primary Clinical Tetrad

• Retinitis pigmentosa (often the earliest manifestation):
  • Progressive hereditary dystrophy of the retina
  • Presents with visual changes including night blindness and tunnel vision 5, 4
• Peripheral polyneuropathy (symmetrical ascending polyneuropathy) 1, 2
• Cerebellar ataxia 1, 3
• Elevated protein levels in cerebrospinal fluid (CSF) without increased cell count 1, 3

Additional Common Manifestations

• Sensorineural hearing loss 2, 4
• Anosmia (loss of smell) 2, 4
• Ichthyosis (scaly, dry skin) 4
• Cardiac abnormalities and arrhythmias 2, 4
• Skeletal malformations 4
• Cataracts 5

Diagnosis

• Primary diagnostic test: Detection of elevated phytanic acid in plasma 1, 2
• Molecular genetic analysis of the PHYH gene to identify disease-causing mutations 1, 3
• Clinical diagnosis based on the characteristic tetrad of symptoms 1, 3
• Average delay of 11 years between initial presentation to ophthalmologists and diagnosis, highlighting the need for increased awareness 5, 4

Management

Dietary Intervention

• Primary treatment is a diet low in phytanic acid 2, 4
  • Restricts foods containing phytanic acid
  • Can lead to improvement in neurological symptoms (polyneuropathy and ataxia)
  • May slow or even stop progression of other manifestations 4

Therapeutic Apheresis

• Plasmapheresis/lipid apheresis is indicated for severe cases or acute attacks 2
• Effectively removes phytanic acid bound to lipoproteins from circulation 2
• Long-term lipid apheresis has shown:
  • Mean reduction rate of 59% per treatment for phytanic acid levels
  • Improvement in motor nerve conduction velocity
  • Morphological and functional stabilization of eye involvement
  • Prevention of disease extension to previously unaffected organs 2

Monitoring and Follow-up

• Regular monitoring of plasma phytanic acid levels to assess treatment efficacy 2
• Ophthalmological examinations to monitor retinal status 5, 4
• Neurological assessments to evaluate polyneuropathy and ataxia 2

Clinical Course and Prognosis

• Early diagnosis is crucial to prevent development of severe neurological disease 5, 4
• Without treatment, progressive neurological damage occurs 2
• With appropriate dietary management and therapeutic apheresis when needed, long-term improvement or stabilization can be achieved 2
• Visual deterioration may be difficult to reverse once established, emphasizing the importance of early diagnosis 5

Common Pitfalls and Caveats

• Delayed diagnosis is common (average 11 years from initial symptoms), leading to irreversible damage 5, 4
• Dietary restriction alone may not be sufficient to prevent acute attacks in some patients 2
• Ophthalmologists play a crucial role in early identification as retinitis pigmentosa is often the first manifestation 4
• The condition should be considered in the differential diagnosis of unexplained retinitis pigmentosa, especially when accompanied by neurological symptoms 6