Symptoms of Peroxisomal Disorders Like X-ALD Often Mistaken for Another Disease, Study Finds

Symptoms of Peroxisomal Disorders Like X-ALD Often Mistaken for Another Disease, Study Finds

Peroxisomal disorders, including adrenoleukodystrophy, are evident in a relatively high number of Chinese patients whose symptoms are similar to those caused by hereditary spastic paraplegia (HSP), highlighting the importance of a careful and involved diagnosis, a study says.

Results from the study, “Chinese patients with adrenoleukodystrophy and Zellweger spectrum disorder presenting with hereditary spastic paraplegia,” were published in the journal Parkinsonism & Related Disorders.

Adrenoleukodystrophy (ALD), also known as X-linked ALD (X-ALD), and Zellweger spectrum disorder (ZSD) are both peroxisomal diseases — disorders in which peroxisomes (small cell compartments filled with enzymes necessary for several chemical reactions) malfunction — due to the build-up of fatty molecules called very long‐chain fatty acids (VLCFA).

“Considering the wide variability of manifestation, patients with ALD and atypical ZSD are easily misdiagnosed as hereditary spastic paraplegia (HSP) [a group of neurological disorders that affect upper motor neurons, which are responsible for controlling upper body movements] on their clinical grounds,” the investigators wrote.

A team led by researchers at The First Affiliated Hospital of Fujian Medical University, in China, set out to determine the incidence of peroxisomal diseases in that country, and compare their clinical manifestations to those normally associated with HSP.

To that end, researchers used targeted DNA sequencing to examine the expression levels of a panel of 149 genes previously associated with HSP in 120 families.

Among these families, 74 were found to carry genes known to cause HSP and excluded from the study. The remaining 46 families, whose individuals had HSP-like symptoms but lacked a genetic cause for the disease, were further analyzed using whole-exome sequencing (WES) — a technique that examines the DNA sequence of all genes that code for proteins (exome).

To complement the genetic analyses, researchers also reviewed patients’ clinical and radiological data, as well as VLCFA test results.

Results revealed that in several people in seven families carried genetic mutations in the ABCD1 gene — five of these mutations were previously associated with X-ALD, while the other two variants were new (c.217C > T and c.497T > C). In one other family analyzed, several individuals carried mutations in PEX16, which is associated with ZSD.

Of note, mutation carriers only had one copy of the mutated gene, while affected individuals carried two copies of the mutated gene.

After reviewing patients’ clinical data, researchers found that besides HSP-like symptoms, four people with two copies of the mutated ABCD1 gene also had adrenal insufficiency, a condition in which the adrenal glands are unable to produce certain hormones in normal amounts. This is one of the most common symptoms of X-ALD.

They also found that two sisters carrying two copies of the mutated PEX16 gene had developed thyroid problems in addition to HSP-like symptoms.

VLCFA test results confirmed that the levels of VLCFAs were abnormally high in all affected individuals with ABCD1 mutations. Radiological data also found that three affected people with ABCD1 mutations, and one carrying PEX16 mutations, had brain and spinal cord abnormalities.

“In conclusion, our study indicated that peroxisomal diseases represent a significant portion (8/120) of the spastic paraplegia entities, and that the combination of WES and plasma VLCFA analysis can be used for differential diagnoses,” the researchers wrote.

“Likewise, as cerebral involvement is a poor prognostic indicator, brain MRI [magnetic resonance imaging] examination should be routinely performed to monitor the disease progression during follow-up,” they added.

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