Table 4.

Genes of Interest in the Differential Diagnosis of Adult Refsum Disease

Gene(s)DisorderMOIClinical FeaturesDistinguishing Features / Comment
Disorders w/elevated phytanic acid
AMACR Alpha-methylacyl-CoA racemase (AMACR) deficiency 1 (OMIM 614307)ARTypically adult-onset sensory motor neuropathy ± assoc pigmentary retinopathy.2 Other presentations are dominated by early-onset liver failure w/cholestasis, hepatomegaly, & ↑ liver enzymes.Distinguished from ARD by screening peroxisome metabolites in plasma
PEX1
PEX6
PEX12
PEX26
PEX10
PEX2
(13 genes) 3		Zellweger spectrum disorder (ZSD)ARAffected persons usually present in newborn period or later in childhood. Newborns are hypotonic, feed poorly, & have distinctive facies, congenital malformations, & liver disease that can be severe. Infants w/severe ZSD are significantly impaired & typically die during 1st yr of life, usually having made no developmental progress.Persons w/ARD have a biochemical profile distinct from ZSD & are developmentally normal before presenting in their late teens, 20s, or even later.
Disorders w/retinitis pigmentosa (RP) ± sensorineural hearing loss (SNHL)
~90 genes 4 RP AD
AR
XL
Digenic		RP refers to a group of inherited retinal disorders in which abnormalities of the photoreceptors (rods & cones) of the retina → progressive visual loss. RP is classified as nonsyndromic, or "simple" (not affecting other organs or tissues); syndromic (affecting other neurosensory systems, e.g., hearing); or systemic (affecting multiple tissues).Because visual deterioration is almost always the 1st symptom of ARD, plasma phytanic acid concentration should be measured in any person w/RP, esp when combined w/other features suggestive of ARD (e.g., anosmia, shortened metacarpals & metatarsals, impaired hearing).
ADGRV1
CDH23
CIB2
CLRN1
HARS1
MYO7A
PCDH15
USH1C
USH1G
USH2A
WHRN 		Usher syndrome (USH) type I, type II, & type III (OMIM 276902, 614504)ARUSH1: Congenital bilateral profound SNHL, vestibular areflexia, & adolescent-onset RP
USH2: Congenital bilateral SNHL (mild-moderate in low frequencies & severe-profound in higher frequencies); intact or variable vestibular responses; & RP
USH3: Postingual progressive SNHL, late-onset RP, & variable impairment of vestibular function		ARD can be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.
ALMS1

Alström syndrome

ARSevere cone-rod dystrophy (typically early-onset), obesity, progressive SNHL, cardiomyopathy, insulin resistance/type 2 diabetes mellitus, nonalcoholic fatty liver disease, & chronic progressive kidney diseaseARD is assoc w/rod-cone dystrophy (not cone-rod dystrophy). ARD can also be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.
BBS1
BBS2
BBS4
BBS10
BBS12
MKKS
(~26 genes) 5

Bardet-Biedl syndrome

ARCone-rod or rod-cone dystrophy, obesity & related complications, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism &/or genitourinary malformations, & renal malformations &/or renal parenchymal diseaseRP in BBS is generally more severe than that seen in ARD. ARD can also be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.
mtDNA (single large-scale deletion)Kearns-Sayre syndrome (KSS) (See Mitochondrial DNA Deletion Syndromes.)MatDefined by triad of onset before age 20 yrs, pigmentary retinopathy, & PEO. Addl features: cerebellar ataxia, impaired intellect, SNHL, ptosis, oropharyngeal & esophageal dysfunction, exercise intolerance, muscle weakness, cardiac conduction block, & endocrinopathy.The RP in ARD is characterized by intraretinal pigment migration rather than the hyperpigmentation at the level of the retinal pigment epithelium as seen in KSS. ARD can also be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.
Disorder w/ataxia (see also Hereditary Ataxia Overview )
FXN Friedreich ataxia ARSlowly progressive ataxia w/mean onset at age 10-15 yrs (usually before age 25 yrs). Typically assoc w/dysarthria, muscle weakness, spasticity in lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, & loss of position & vibration sense. Hearing loss is uncommon.ARD is frequently assoc w/progressive SNHL. ARD can also be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.
Disorder w/ichthyosis
ALDH3A2 Sjögren-Larsson syndrome (OMIM 270200)ARCongenital ichthyosis & onset of ataxia in early childhoodARD can be distinguished by screening peroxisome metabolites (phytanic acid) in plasma.

AD = autosomal dominant; AR = autosomal recessive; ARD = adult Refsum disease; CSF = cerebrospinal fluid; MOI = mode of inheritance; PEO = progressive external ophthalmoplegia; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; VLCFA = very-long-chain fatty acids; XL = X-linked

1.

The enzyme AMACR plays a key role in the breakdown of pristanic acid and the C27-bile acid intermediates di- and trihydroxycholestanoic acid. As a consequence of the impaired degradation of pristanic acid, both pristanic acid and phytanic acid accumulate with pristanic concentrations much more elevated than phytanic acid concentrations (see Table 1).

2.
3.

>90% of ZSD is attributed to pathogenic variants in the listed genes. ZSD is also associated with pathogenic variants in PEX11β, PEX13, PEX14, PEX16, PEX19, PEX3, and PEX5.

4.
5.

~65% of BBS is attributed to pathogenic variants in the listed genes. See Bardet-Biedl syndrome for additional associated genes.

From: Adult Refsum Disease

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