PEX7

Refsum Disease, Adult

Clinical Characteristics
Ocular Features: 

A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease.  There is typical night blindness and visual field constriction.   Rod ERG responses are usually subnormal.  However, central acuity is also reduced due to a degenerative maculopathy.   Cataracts and optic atrophy are common.  The macula may undergo progressive degeneration and optic atrophy is not uncommon.  Some patients have defective pupillary responses.

Systemic Features: 

Onset of symptoms is usually late in the first decade and sometimes into the third decade.  There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs.  A progressive sensorineural hearing loss occurs in many patients.  Sensory deficits also occur.  Some have ataxia and skin changes of ichthyosis.  Anosmia is a near universal feature.  Heart failure may occur and cardiac abnormalities such as conduction defects can occur.  A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported.  There is considerable clinical heterogeneity even within families.

Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased.  The cerebrospinal fluid contains increased protein but no increase in cells.

Genetics

This disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. 

Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy.

There is also so-called infantile form of Refsum disease (266510).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease.  This approach may not be as beneficial for the visual or auditory symptoms.

References
Article Title: 

Rhizomelic Chondrodysplasia Punctata

Clinical Characteristics
Ocular Features: 

Congenital cataracts are the outstanding ocular feature of this syndrome and are present in over 70% of patients.  They are usually bilateral and symmetrical and may not be present for several months after birth.

Systemic Features: 

The name of this disorder comes from the punctate calcification seen in cartilage.   The vertebrae have coronal clefting.  The cartilage abnormalities result in defective bone growth with severe growth retardation, short stature, and joint contractures.  Many infants die during the neonatal period and few survive beyond the first decade of life. However, milder forms have been reported. The skin can be ichthyotic and severe mental retardation is often accompanied by seizures.  Red cells are deficient in plasmalogens while phytanic acid and very long chain fatty acids accumulate in the plasma, a biochemical profile characteristic of RCDP1.

Other types of chondrodysplasia punctata also exist (RCDP2 and RCDP3). The X-linked recessive (CDPX1; 302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

A phenocopy sometimes results from maternal ingestion of dicoumarol in early pregnancy.

Genetics

This rare autosomal recessive condition results from mutations in the PEX7 gene (6q22-q24) causing a peroxisomal biogenesis disorder.  Some clinical features overlap with those of Zellweger syndrome (214100) and infantile Refsum disease (266510), also peroxisomal biogenesis disorders. 

Mutations in the same gene are responsible for adult Refsum disease-2 (266500).  The latter, however, has other neurological symptoms as well as clinical features of retinitis pigmentosa with night blindness and restricted visual fields.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available beyond supportive measures. Cataract removal may improve vision but the poor prognosis for longevity requires caution be used.

References
Article Title: 
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