Background
Disease names and synonyms
History and definition
Epidemiology
Clinical features
Neonatal-infantile presentation
Childhood presentation
Adolescent-adult presentation
Etiology and pathophysiology
Peroxisome function | Biochemical consequence | Possible clinical relevance |
---|---|---|
β-oxidation of VLCFA (≥C22) | Impaired chain shortening of VLCFA, last step in DHA synthesis is impaired | Brain, nerve and adrenal damage due to VLCFA tissue accumulation, DHA deficiency affects brain function and vision |
β-oxidation of methyl-branched chain fatty acid, DHCA and THCA | Impaired chain shortening of DHCA, THCA and pristanic acid | Pristanic acid accumulation affects brain function, accumulation of DHCA and THCA causes liver toxicity and probably also brain damage |
α-oxidation of fatty acids | Impaired (pre-) degradation of methyl branched phytanic acid | Retinal degeneration, brain and nerve damage due to phytanic acid accumulation |
Fatty acid racemization | Reduced convertion of pristanoyl-CoA and C27-bile acyl-CoAs into stereoisomers before β-oxidation | Tissue accumulation of DHCA, THCA, pristanic- and phytanic acid |
Ether phospholipid (plasmalogen) biosynthesis | Impaired formation of ether phospholipids | Plasmalogen deficiency gives rise to growth- and psychomotor retardation, cataract and bone development anomalies |
Glyoxylate detoxification | Conversion of glyoxylate into oxalate, a toxic metabolite | Accumulation leads to calcium oxalate renal stones |
L-lysine oxidation | Impaired L-pipecolic acid degradation | Accumulation of pipecolic acid, no clinical consequences known [78] |
Hydrogen peroxide detoxification | Decreased catabolism of hydrogen peroxide | Increased reactive oxidant damage |
Diagnosis
Differential diagnosis
Main presenting symptom | Differential diagnosis |
---|---|
Hypotonia in newborns | Chromosomal abnormalities (Down syndrome, Prader-Willi syndrome) |
Congenital infections (cytomegalovirus, rubella, herpes simplex, toxoplasmosis) | |
Hypoxic ischemic encephalopathy | |
Cerebral malformations | |
Other metabolic disorders (acid maltase deficiency, carnitine deficiency, cytochrome-c-oxidase deficiency) | |
Other peroxisomal disorders (acyl-CoA oxidase type 1 deficiency, D-bifunctional protein deficiency) | |
Spinal muscular atrophy | |
Congenital muscular dystrophies | |
Congenital myopathies | |
Hereditary motor and sensory neuropathy | |
Bilateral cataract | Idiopathic |
Congenital infections | |
Other peroxisomal disorders (rhizomelic chondrodysplasia punctata, classical Refsum disease, 2-methylacyl-CoA racemase deficiency) | |
Other metabolic disorders (galactosemia) | |
Lowe syndrome | |
Sensorineural hearing loss with retinitis pigmentosa | Usher syndrome type I,II |
Other peroxisomal disorders (classical Refsum disease) | |
Mitochondrial disorders | |
Cockayne syndrome | |
Alport syndrome | |
Waardenburg syndrome | |
Adrenocorticol insufficiency | Autoimmune adrenalitis |
Infectious adrenalitis | |
Adrenal hemorrhage | |
Adrenal hypoplasia | |
X-linked adrenoleukodystrophy | |
Deficient cholesterol metabolism | |
Familial glucocorticoid deficiency |
ZSD | DBP-D | ACOX1-D | Remarks | |
---|---|---|---|---|
Plasma | ||||
Very long chain fatty acidsa
| ↑b
| ↑b
| ↑b
| False positives possible in ketogenic diets, hemolyzed samples and peanut rich diet. |
Di- and trihydroxycholestanoic acid | ↑b
| N-↑ | N | |
Phytanic acid | N-↑ | N-↑ | N | Derived from dietary sources only; dependent on dietary intake. Normal in newborns. |
Pristanic acid | N-↑ | N-↑ | N | Derived from dietary sources only (direct and indirectly via phytanic acid). Normal in newborns. |
Erythrocytes | ||||
Plasmalogen level | ↓-N | N | N | |
Blood spot | ||||
C26:0 lysophosphatidylcholine | ↑ | ↑ | ↑ | |
Fibroblasts | ||||
Plasmalogen synthesis | ↓ | N | N | |
DHAPAT | ↓ | N | N | |
Alkyl DHAP synthase | ↓ | N | N | |
C26:0 β-oxidation | ↓ | ↓ | ↓ | |
Pristanic acid β-oxidation | ↓ | ↓ | N | |
Acyl-CoA oxidase 1 | ↓-N | N | ↓ | |
D-Bifunctional protein | ↓-N | ↓ | N | |
Phytanic acid α-oxidation | ↓ | N | N | |
Phytanoyl CoA hydroxylase | ↓ | N | N | |
Peroxisomes | ↓ | N | N | Peroxisomal mosaicism can be present in ZSD. In DBP- and ACOX1-deficiency abnormal peroxisomal morphology may be present. |
Mutant gene |
PEX1,2,3,5,6,10,11β,12,13,14,16,19,26 |
HSD17B4
|
ACOX
|
Genetic counseling and antenatal diagnosis
Clinical management and treatment
Symptom/disease | Treatment/intervention |
---|---|
Adrenal insufficiency | Cortisone |
Coagulopathy | Vitamin K suppletion |
Enamel hypoplasia | Dentist referral |
Epilepsy | Standard antiepileptic drugs |
Hearing impairment | Hearing aids, cochlear implant |
High phytanic acid plasma level | Phytanic acid restricted diet |
Hyperoxaluria | Oral citrate treatment Sufficient fluid intake |
Insufficient calory intake | Gastrostomy |
Low levels of fat-soluble vitamins (A, D, E) | Vitamin suppletion |
Visual impairment | Cataract removal, glasses and ophthalmologist referral |