What is Refsum disease?

Refsum Disease: A Rare Autosomal Recessive Metabolic Disorder

Refsum disease is a rare autosomal recessive disorder characterized by deficiency of phytanoyl-CoA hydroxylase (PhyH) enzyme, resulting in accumulation of phytanic acid that causes progressive neurological damage, retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and other multisystem complications.

Definition and Pathophysiology

• Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase (PHYH) gene, resulting in deficiency of the enzyme that catalyzes the first step in alpha-oxidation of phytanic acid 1
• The metabolic defect leads to accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) in blood and tissues, particularly those rich in lipids such as myelin sheaths and internal organs 2
• Phytanic acid is derived from dietary sources and cannot be properly metabolized due to the enzyme deficiency 1

Clinical Manifestations

Primary Clinical Tetrad

• Retinitis pigmentosa (often the earliest manifestation) 3
• Peripheral polyneuropathy 2
• Cerebellar ataxia 2
• Elevated protein levels in cerebrospinal fluid without increased cell count 1

Additional Common Manifestations

• Sensorineural hearing loss 2, 4
• Anosmia (loss of smell) 4
• Ichthyosis (scaly, dry skin) 4
• Cardiac abnormalities and arrhythmias 3, 4
• Skeletal malformations 4
• Cataracts 3

Diagnosis

Laboratory Findings

• Elevated plasma phytanic acid levels (>300 mg/L in severe cases) 2
• Genetic testing for mutations in the PHYH gene 1

Clinical Evaluation

• Ophthalmologic examination showing retinitis pigmentosa, which typically precedes biochemical diagnosis by several years (average delay of 11 years) 3
• Neurological assessment for peripheral neuropathy and cerebellar ataxia 5
• Audiometric testing for sensorineural hearing loss 4

Treatment Strategies

Dietary Management

• Primary treatment is a diet low in phytanic acid 4
• Dietary restriction can improve neurological symptoms (polyneuropathy and ataxia) and slow or stop progression of other manifestations 4

Therapeutic Apheresis

• Lipid apheresis is effective for removing lipoprotein-phytanic acid complexes in severe cases 2
• Long-term lipid apheresis (5-13 years) has shown:
  • Reduction of phytanic acid levels by approximately 59% per treatment 2
  • Improvement in motor nerve conduction velocity 2
  • Stabilization of eye involvement 2
  • Prevention of disease extension to previously unaffected organs 2

Prognosis

• Without treatment, the disease follows a progressive course with worsening neurological and sensory symptoms 2
• Early diagnosis is crucial to prevent development of severe neurological disease 3
• With appropriate dietary management and/or lipid apheresis, many symptoms can be stabilized or improved 2, 4
• Visual deterioration may not show definite improvement with treatment once retinal damage is severe 3

Genetic Considerations

• Autosomal recessive inheritance pattern 1
• Should be considered in the differential diagnosis of children and adolescents with unexplained retinitis pigmentosa, especially when accompanied by neurological symptoms 6
• When evaluating patients with unexplained fatty liver disease, Refsum disease should be included in the differential diagnosis along with other genetic disorders 6

Animal Models

• Mouse models of Refsum disease (Phyh knockout mice) demonstrate:
  • Unsteady gait with reduced paw print area 5
  • Loss of Purkinje cells in the cerebellum 5
  • Peripheral neuropathy 5
  • Additional findings including hepatic steatosis and testicular atrophy 5