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Information for clinicians

4 Clinical description

4a Natural history

Onset of symptoms ranges from 7 months to greater than 50 years of age. However, because the onset is insidious, it is difficult for many individuals to know exactly when symptoms first started. A few individuals remain asymptomatic until adulthood [Skjeldal et al 1987].

Retinitis pigmentosa is, in most cases, an early clinical feature. If a detailed past medical history is obtained, many individuals confirm the onset of night blindness in childhood. Virtually every individual ultimately diagnosed to have adult Refsum's disease experiences visual symptoms first. The delay between first ophthalmologic evaluation and diagnosis ranged between one and 28 years (mean: 11 years) in one study of 23 patients [Claridge et al 1992].
Anosmia is also considered an early symptom [Wierzbicki et al 2002].

Other findings that may occur in the following 10 to 15 years in decreasing order of frequency are anosmia, neuropathy, deafness, ataxia, and ichthyosis [Skjeldal & Stokke 1987, Wierzbicki et al 2002]. The four cardinal features, originally described by Refsum [1946] (retinitis pigmentosa, a chronic polyneuropathy, ataxia, and raised CSF protein) are rarely seen in a single individual. In a few instances, psychiatric disturbances have been observed.

An early onset of the disease does not necessarily indicate a particularly poor prognosis as to life span.

4a(i) Ophthalmologic signs

Retinitis pigmentosa (pigmentary retinal degeneration, tapeto-retinal degeneration) is present in all individuals with biochemical findings of adult Refsum's disease and therefore, appears to be an obligatory finding. In a series of 17 patients, retinitis pigmentosa was present in all [Skjeldal et al 1987]. Typically, individuals with adult Refsum's disease experience night-blindness years before the progressive chnages changes of constricted visual fields and decreased central visual acuity appear. Because night-blindness can be difficult to ascertain, particularly in children, electroretinography, which shows either a reduction or a complete absence of rod and cone responses can help support the diagnosis in early stages. (See GeneReview: Retinitis Pigmentosa Overview.)

4a(ii) Anosmia

This is the absence of smell. Although the sense of smell and the sense of taste have their own specific receptors, they are intimately related. The sense of smell (and thus indirectly the taste of food) is always reduced in adult Refum's disease. The five subgroups of the sensation of taste are unaffected.

4a(iii) Polyneuropathy

The polyneuropathy is a mixed motor and sensory neuropathy that is asymmetric, chronic, and progressive in untreated individuals. It may not be clinically apparent at the start of the illness. Initially, symptoms often wax and wane. Later, the distal lower limbs are affected with resulting muscular atrophy and weakness. Over the course of years, muscular weakness can become widespread and disabling, involving not only the limbs, but also the trunk. Almost without exception, individuals with adult Refsum's disease have peripheral sensory disturbances, most often impairment of deep sensation, particularly perception of vibration and position-motion in the distal legs.

4a(iv) Hearing loss

Bilaterally symmetric mild to profound sensorineural hearing loss affects the high frequencies or middle to high frequencies [Oysu et al 2001, Bamiou et al 2003]. Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brainstem evoked responses (ABR) [Oysu et al 2001, Bamiou et al 2003]. Individuals with auditory nerve involvement may experience hearing difficulty even in the presence of a normal audiogram.

4a(v) Ataxia

Although cerebellar dysfunction is considered to be a main clinical sign of adult Refsum's disease, onset is nevertheless relatively late, particularly when compared with the onset of retinopathy and neuropathy. Unsteadiness of gait is the main symptom related to cerebellar dysfunction. Ataxia is thus characteristically more marked than the degree of muscular weakness and sensory loss would indicate.

4a(vi) Ichthyosis

Mild generalized scaling may occur in childhood, but usually begins in adolescence. This finding is present in a minority of affected individuals.

4a(vii) Cardiac arrhythmias

Cardiac arrhythmia and heart failure due to cardiomyopathy are frequent causes of death in acute adult Refsum's disease. Arrhythmias are rare except in the most severe acute cases and are usually precipitated by classical stressors causing acute phytanic acid release in ill patients. Arrhythmias are a known complication of plasmapheresis/apheresis for adult Refsum's disease in patients with highly elevated levels of phytanic acid. Cardiomyopathy is rare but may develop in some patients after 20-40 years.

Next: Prevalence

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Page last updated 26 June 2006