The cases were reported in “Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy,” a study published in the Journal of Pediatric Endocrinology and Metabolism.
A rare genetic disorder that mainly affects men, ALD is characterized by neurodegeneration due to the loss of myelin — the protective sheath around nerve cells — and progressive dysfunction of the adrenal glands, which are small hormone-producing glands located above the kidneys.
ALD is caused by mutations in the ABCD1 gene, which contains the instructions for producing the adrenoleukodystrophy protein (ALDP). These mutations result in a deficient ALDP protein, leading to the toxic build-up of very-long-chain fatty acids (VLCFAs) in several tissues and organs.
Missense mutations lead to a switch of an amino-acid — the building blocks of proteins — in the resulting protein, while frameshift mutations change the way the gene sequence is read. Nonsense mutations result in a premature stop in protein production, leading to a shorter and likely nonfunctional protein.
Now, researchers have reported the identification of three new ABCD1 mutations associated with ALD in three Iranian families. This is in addition to the detection of one previously reported mutation in a fourth family.
Among these four Iranian families, the team characterized the clinical and genetic data of nine males with ALD, ranging in age from 7 to 37 years. In three of these families, two of three siblings had ALD. In the remaining family, three out of four siblings were affected.
Early ALD symptoms included hyperpigmentation, walking difficulties, weakness in the legs, visual impairment, and mental deterioration. Symptom onset occurred between ages 6 and 31.
All nine patients with the disease showed cognitive deficits. At least one patient from each family had evidence of brain lesions, while lesions in the spinal cord were detected in two males from different families. One of these two males also had brain lesions. All patients had higher-than-normal levels of VLCFA in the blood.
Their cognitive impairment prevented them from completing any schooling beyond high school, and most of them were unemployed. Affected males in one of the families were given Lorenzo’s oil, which did not show a significant therapeutic effect.
Genetic analysis identified one previously reported disease-causing missense mutation (c.1978C>T), and three new mutations (c.1797dupT, c.879delC, and c.1218C>G) in the ABCD1 gene, each specific of one family.
Further analyses showed that all three new mutations — two missense and one frameshift — classified as nonsense mutations, leading to a premature stop in protein production and significantly changing ALDP’s structure. These changes were determined to affect protein function and cause ALD.
“We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for [ALD],” the researchers said.
There was no link between the different mutations and specific symptoms or age of symptom onset. That is in accord with the lack of a significant association between genetic and clinical data in ALD to date.
The team noted that the age of onset differed between patients of the same family and with the same mutation. Thus, early diagnosis and subsequent early treatment may be relevant in siblings of affected patients, they said.
“Our results may be useful in future functional analysis, genetic counseling, and prenatal diagnosis,” the researchers said.
“The reported mutations are good candidates for more experimental analyses in order to reach a better understanding of the ABCD1 function, and effects of its mutations in adrenoleukodystrophy,” they added.