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Infantile Refsum disease

ORPHA772
Synonym(s) IRD
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset All ages
ICD-10
  • G60.1
OMIM
UMLS
  • C0282527
MeSH
  • D052919
MedDRA -

Summary

Infantile Refsum disease (IRD) is the mildest variant of the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD- ZSS; see this term), characterized by hypotonia, retinitis pigmentosa, developmental delay, sensorineural hearing loss and liver dysfunction. Phenotypic overlap is seen between IRD and neonatal adrenoleukodystrophy (NALD) (see this term).

The birth prevalence of PBD-ZSS is estimated to be around 1/50,000 in North America and 1/500,000 in Japan. More than ½ of patients with PBD-ZSS have the NALD-IRD forms.

IRD has an onset at birth or early infancy but manifestations may be subtle enough that diagnosis is not until adulthood. In infancy, symptoms may include nystagmus, hypotonia, sensorineural hearing loss, growth retardation, mild facial dysmorphism, and hepatomegaly. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to coagulopathy. In childhood, progressive retinitis pigmentosa, developmental deficits and hypotonia are seen. Most achieve motor milestones, though delayed, and communicate in a few words or signs. Osteoporosis and fractures can occur in the less mobile. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Leukodystrophy with loss of previously acquired skills can occur at any age and may stabilize, or progress and be fatal. Atypical presentations (visual and hearing loss with preservation of intellect and cerebellar ataxia with/without peripheral neuropathy) have been described.

PBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.

IRD is suspected on physical exam and definitively confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are usually reduced, but can be normal. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Occasionally, VLCFA levels and enzymatic assays in fibroblasts can be within the normal range, requiring additional assessment in expert laboratories. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify myelin changes.

The main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. IRD should not be confused with adult Refsum disease (see this term).

Prenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis.

IRD is inherited autosomal recessively, so genetic counseling is possible.

There is no cure for IRD. Cataracts should be removed in early infancy and glasses used. Hearing aids should be provided to those with hearing impairment and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Standard epileptic drugs are used for seizures. Lifelong follow up monitors changes in hearing, vision and liver function.

Great variation is seen with respect to life expectancy, medical complications and preservation of neurological function. Many patients survive childhood, and survival to adulthood is possible.

Expert reviewer(s)

  • Dr Nancy BRAVERMAN

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Summary information
Clinical genetics review
  • EN (2012)
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