Neonatal adrenoleukodystrophy

Other Names: Adrenoleukodystrophy autosomal neonatal form; NALD A rare metabolic disorder that affects neonates. It is characterized by damage of the white matter in the brain and degeneration of the adrenal glands. It manifests with hyperactivity, paralysis, muscular weakness, crossed eyes, hearing loss, seizures, and coma.

Epidemiology

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.

Cause

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

Inheritance

Autosomal recessive inheritance, a 25% chance

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

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal palate morphology(Abnormality of the palate)
• Abnormality of metabolism/homeostasis(Laboratory abnormality)
• Abnormality of the liver(Abnormal liver)
• Anteverted nares(Nasal tip, upturned)
• Developmental regression(Loss of developmental milestones)
• Dolichocephaly(Long, narrow head)
• EEG abnormality
• High forehead
• Hyperreflexia(Increased reflexes)
• Low-set, posteriorly rotated ears
• Muscular hypotonia(Low or weak muscle tone)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Optic atrophy
• Primary adrenal insufficiency
• Seizure
• Sensorineural hearing impairment
• Severe global developmental delay
• Short stature(Decreased body height)
• Strabismus(Cross-eyed)
• Wide nasal bridge(Broad nasal bridge)

30%-79% of people have these symptoms

• Abnormality of neuronal migration
• Abnormality of retinal pigmentation
• Bilateral single transverse palmar creases
• Cataract(Clouding of the lens of the eye)
• Macrocephaly(Increased size of skull)
• Ptosis(Drooping upper eyelid)
• Visual impairment(Impaired vision)
• Wide anterior fontanel(Wider-than-typical soft spot of skull)

Diagnosis

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 b. 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 , 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.

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

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

NIH genetic and rare disease info

• NIH info on Neonatal adrenoleukodystrophy

Neonatal adrenoleukodystrophy is a rare disease.

Neonatal adrenoleukodystrophy Resources
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