Summary of the clinical features, diagnosis, and treatment of the major peroxisomal disorders (excluding X-linked adrenoleukodystrophy and primary hyperoxaluria)

Disorder	Type of disorder (PBD versus single enzyme deficiency)	Gene(s) involved	Clinical features	Age at presentation	Radiographic findings	Initial diagnostic biochemical test	Confirmatory tests	Treatment
Zellweger spectrum disorders (ZSD)^*	PBD	PEX1 PEX6 Other PEX genes (uncommon)	Craniofacial dysmorphisms (high forehead, epicanthal folds, hypoplasia of supraorbital ridges and midface) Neurodevelopmental impairment, which can be profound Seizures Cataracts Pigmentary retinopathy Sensorineural hearing loss Liver disease (hepatomegaly, cholestasis, cirrhosis) Cortical kidney cysts Adrenal insufficiency Amelogenesis imperfecta (dental enamel defect)	Variable; severe forms present in newborn period	Brain MRI may show cortical and white matter abnormalities Skeletal radiographs may show calcific stippling of the epiphyses and/or osteopenia Abdominal imaging may show cortical kidney cysts and/or kidney stones	Plasma C26:0-LPC level (where available)^¶ or Standard plasma VLCFA analysis^¶ (if plasma C26:0-LPC testing is not available)	Genetic testing^Δ	No specific treatment; supportive care
ACOX1 deficiency	Enzyme deficiency	ACOX1	Clinically indistinguishable from ZSD			Same as for ZSD	Genetic testing	No specific treatment; supportive care
DBP deficiency	Enzyme deficiency	HSD17B4	Clinically indistinguishable from ZSD			Same as for ZSD	Genetic testing	No specific treatment; supportive care
Rhizomelic chondrodysplasia punctata (RCDP)	PBD (RCDP types 1 and 5) Enzyme deficiency (RCDP types 2, 3, and 4)	RCDP type 1: PEX7 RCDP type 2: GNPAT RCDP type 3: AGPS RCDP type 4: FAR1 RCDP type 5: PEX5	Growth failure with shortened proximal long bones (rhizomelia) Global developmental delay, which can be profound Dysmorphic facies Congenital cataracts Congenital heart disease Ichthyosis Joint contractures	Variable; severe forms present in newborn period	Skeletal radiographs typically show stippled calcification in epiphyses of long bones and vertebrae; cervical stenosis an/or thoracolumbar kyphoscoliosis may be present Brain MRI may show white matter abnormalities, pachygyria and polymicrogyria, ventriculomegaly, and/or cerebellar atrophy	Erythrocyte plasmalogen analysis	Genetic testing^Δ	No specific treatment; supportive care
Refsum disease	Enzyme deficiency	PHYH	Progressive vision loss due to pigmentary retinopathy Anosmia Sensorineural hearing loss Peripheral neuropathy Ataxia Ichthyosis Cardiac arrhythmias	Adolescence or early adulthood	Brain MRI may be abnormal but there is no characteristic pattern	Plasma phytanic acid level	Genetic testing^Δ	Dietary restriction to eliminate phytol-containing foods Plasmapheresis can be used to rapidly reduce phytanic acid levels in patients with acute severe neurologic symptoms

This table summarizes the major peroxisomal disorders, including ZSD, ACOX1 deficiency, DBP deficiency, RCDPs, and Refsum disease. Other major peroxisomal disorders include X-linked adrenoleukodystrophy (X-ALD) and primary hyperoxaluria type 1 (PH1), which are described in detail in separate UpToDate topics and tables. Other rare peroxisomal disorders that have been described in small case series or single case reports include ACOX2 deficiency, AMACR deficiency, BAAT deficiency, ACBD5 deficiency, SCPX deficiency, PMP70 deficiency, glycolate oxidase deficiency, ACOX1 upregulation, and FAR1 upregulation. For additional information, refer to UpToDate topic on peroxisomal disorders. For information on X-ALD or PH1, refer to separate topics on those conditions.

ACBD5: acyl-CoA-binding domain type 5; ACOX1: Acyl CoA oxidase-1; ACOX2: Acyl CoA oxidase-2; AMACR: 2 methylacyl-CoA racemase; BAAT: bile acid-CoA: amino acid N-acyltransferase; C26:0-LPC: C26:0-lysophosphatidylcholine; DBP: D-bifunctional protein; FAR1: fatty acyl-CoA reductase 1; MRI: magnetic resonance imaging; PBD: peroxisome biogenesis disorder; PMP70: peroxisomal membrane protein 70; SCPX: sterol carrier protein-X; VLCFA: very long-chain fatty acid; VUS: variant of uncertain significance.

* ZSD represents a spectrum of disorders that includes classical Zellweger syndrome (the most severe form) and other milder variants. Some conditions included in this category were previously considered separate disorders (eg, neonatal adrenoleukodystophy [NALD] and infantile Refsum disease [IRD]). However, since NALD and IRD are caused by the same genetic variants as ZSD (PEX1 and PEX6) with a similar constellation of clinical and laboratory findings, they are now considered part of ZSD.

¶ If plasma C26:0-LPC or VLCFA analysis is abnormal, additional testing is performed in the same blood sample, including analysis of peroxisomal biomarkers in plasma (bile acid intermediates, phytanic acid, pristanic acid, pipecolic acid) and peroxisomal biomarkers in erythrocytes (plasmalogens).

Δ Additional confirmatory testing with functional assays using fibroblasts can sometimes be useful in the diagnostic evaluation for these disorders (eg, if genetic testing identifies a VUS).

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Summary of the clinical features, diagnosis, and treatment of the major peroxisomal disorders (excluding X-linked adrenoleukodystrophy and primary hyperoxaluria)