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Neonatal adrenoleukodystrophy

Synonym(s) NALD
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
  • E71.3
  • C0282525
  • D018901
MedDRA -


Disease definition

Neonatal adrenoleukodystrophy (NALD) is the variant of intermediate severity of the PBD-Zellweger syndrome spectrum (PBD-ZSS; see this term), charcterized by hypotonia, leukodystrophy, and vision and sensorineural hearing deficiencies. Phenotypic overlap is seen between NALD and infantile Refsum disease (IRD) (see this term).


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

Clinical description

NALD has an onset at birth or early infancy, but manifestations may be subtle enough that it is not diagnosed until late infancy or early childhood (or when a leukodystrophy develops). It is characterized by hypotonia, seizures, diffuse encephalopathy, sensorineural hearing loss, peripheral neuropathy, mild facial dysmorphism (hypertelorism and a flat midface), failure to thrive and severely delayed psychomotor development. Eye findings include chorioretinopathy, optic nerve dysplasia and cataracts. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to vitamin K-responsive coagulopathy. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Vision and hearing dysfunction are progressive and result in blindness and deafness. Osteoporosis and fractures can occur in patients who are less mobile. Neurological regression reflects a leukodystrophy, leading to the loss of previously acquired skills, dementia and ultimately death.


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

Diagnostic methods

NALD is suspected on physical examination and 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 reduced. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify leukodystrophy, neuronal migration defects or other brain malformations.

Differential diagnosis

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. X-linked adrenoleukodystrophy (see this term) should not be confused with NALD.

Antenatal diagnosis

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.

Genetic counseling

NALD is inherited in an autosomal recessive manner so genetic counseling is possible.

Management and treatment

There is no cure for NALD and treatment is symptomatic. Cataracts should be removed in early infancy and glasses used to improve vision. Hearing aids are 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. Docosahexanoic acid can be provided. Standard epileptic drugs are used for seizures. Lifelong follow up is needed to monitor changes in hearing, vision and liver function.


Prognosis is poor with most patients dying in infancy and early childhood. Some have lived until their teenage years.

Expert reviewer(s)

  • Dr Nancy BRAVERMAN

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