Pseudoneonatal adrenoleukodystrophy

Alternate names

Peroxisomal Acyl-CoA oxidase deficiency; Straight-chain Acyl-CoA oxidase deficiency; Pseudo-neonatal adrenoleukodystrophy; Pseudoadrenoleukodystrophy

Definition

Peroxisomal acyl-CoA oxidase deficiency is a disorder that causes deterioration of nervous system functions (neurodegeneration) beginning in infancy.

Epidemiology

Peroxisomal acyl-CoA oxidase deficiency is a rare disorder. Its prevalence is unknown. Only a few dozen cases have been described in the medical literature.

Cause

• Peroxisomal acyl-CoA oxidase deficiency is caused by mutations in the ACOX1 gene, which provides instructions for making an enzyme called peroxisomal straight-chain acyl-CoA oxidase.
• This enzyme is found in sac-like cell structures (organelles) called peroxisomes, which contain a variety of enzymes that break down many different substances. The peroxisomal straight-chain acyl-CoA oxidase enzyme plays a role in the breakdown of certain fat molecules called very long-chain fatty acids (VLCFAs).
• Specifically, it is involved in the first step of a process called the peroxisomal fatty acid beta-oxidation pathway. This process shortens the VLCFA molecules by two carbon atoms at a time until the VLCFAs are converted to a molecule called acetyl-CoA, which is transported out of the peroxisomes for reuse by the cell.

Gene mutations

ACOX1 gene mutations prevent the peroxisomal straight-chain acyl-CoA oxidase enzyme from breaking down VLCFAs efficiently. As a result, these fatty acids accumulate in the body. It is unclear exactly how VLCFA accumulation leads to the specific features of peroxisomal acyl-CoA oxidase deficiency. However, researchers suggest that the abnormal fatty acid accumulation triggers inflammation in the nervous system that leads to the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. Destruction of myelin leads to a loss of myelin-containing tissue (white matter) in the brain and spinal cord; loss of white matter is described as leukodystrophy. Leukodystrophy is likely involved in the development of the neurological abnormalities that occur in peroxisomal acyl-CoA oxidase deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Newborns with peroxisomal acyl-CoA oxidase deficiency have weak muscle tone (hypotonia) and seizures. They may have unusual facial features, including widely spaced eyes (hypertelorism), a low nasal bridge, and low-set ears. Extra fingers or toes (polydactyly) or an enlarged liver (hepatomegaly) also occur in some affected individuals. Most babies with peroxisomal acyl-CoA oxidase deficiency learn to walk and begin speaking, but they experience a gradual loss of these skills (developmental regression), usually beginning between the ages of 1 and 3. As the condition gets worse, affected children develop exaggerated reflexes (hyperreflexia), increased muscle tone (hypertonia), more severe and recurrent seizures (epilepsy), and loss of vision and hearing. Most children with peroxisomal acyl-CoA oxidase deficiency do not survive past early childhood.

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 electroretinogram
• Abnormal nervous system morphology(Abnormal shape of nervous system)
• Abnormality of metabolism/homeostasis(Laboratory abnormality)
• Abnormality of visual evoked potentials
• Developmental regression(Loss of developmental milestones)
• EEG abnormality
• Gait disturbance(Abnormal gait)
• Global developmental delay
• [[Hyperreflexia](Increased reflexes)
• Hypodontia(Failure of development of between one and six teeth)
• Intellectual disability, severe(Early and severe mental retardation)
• Muscular hypotonia(Low or weak muscle tone)
• Neurological speech impairment(Speech disorder)
• Seizure
• Sensorineural hearing impairment

30%-79% of people have these symptoms

• Death in infancy(Infantile death)
• Depressed nasal bridge(Depressed bridge of nose)
• Epicanthus(Eye folds)
• Failure to thrive(Faltering weight)
• Hepatomegaly(Enlarged liver)
• Hypertelorism(Wide-set eyes)
• Low-set ears(Low set ears)
• Myopia(Close sighted)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Optic atrophy
• Respiratory insufficiency(Respiratory impairment)
• Strabismus(Cross-eyed)

5%-29% of people have these symptoms

• Hand polydactyly(Extra finger)
• Hypertonia

Diagnosis

Diagnosis is based on laboratory studies revealing increased serum very-long chain fatty acids (VLCFA) and markedly reduced acyl-CoA oxidase activity in fibroblasts. MRI examination of the brain shows abnormal white matter signals. Diagnosis can be confirmed by the presence of mutations in the ACOX1 gene.

Differential diagnosis Differential diagnoses include Usher syndrome and all causes of neonatal hypotonia. The other peroxisomal disorders should also be discarded, especially neonatal adrenoleukodystrophy , which presents similar clinical manifestations.

Antenatal diagnosis Antenatal diagnosis is possible through biochemical and/or molecular analysis of amniocytes or chorionic villus cells.

Treatment

No specific treatment is available. Multidisciplinary supportive care should be offered.

Prognosis

Prognosis is unfavorable; death usually occurs at around 5 years from respiratory issues.

NIH genetic and rare disease info

• NIH info on Pseudoneonatal adrenoleukodystrophy

Pseudoneonatal adrenoleukodystrophy is a rare disease.

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