An ABCD1 Mutation (c.253dupC) Caused Diverse Phenotypes of Adrenoleukodystrophy in an Iranian Consanguineous Pedigree

Abstract

ObjectivesCurrent study was the first to report a consanguineous Iranian pedigree with ABCD1 mutation.MethodsTargeted molecular analysis was initially performed in three affected individuals in one family suspected to have X-ALD due to chronic progressive spasticity. Upon confirmation of genetic diagnosis, further neurologic and genetic evaluation of all family members was done.ResultsA mutation in ABCD1 was identified in 35 affected individuals (out 96 pedigree members). The c. 253dup, in exon 1, leads to a frame shift and a premature stop codon at amino acid position 194 (p.Arg85Profs*110). Surprisingly, affected individuals in our cohort show some variability in phenotype, including childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes, expanding the phenotype of X-ALD with p.Arg85Profs*110.ConclusionThis report characterizes the clinical spectrum of an expanded Iranian pedigree with X-ALD due to an ABCD1 mutation. Given a high frequency of carriers in this region, we expect the prevalence of X-ALD to be higher, underscoring the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities.

Genetics and genomic medicine in Iran

“…It is higher than in the European population (Hasanzad et al., ). A high prevalence (39.3%) of subjects (respectively, 24.3% homozygous T/T CYP2D6*10 and 15% heterozygous C/T CYP2D6*10 as poor and intermediate metabolizers) among Iranians; therefore, the harmful effects of drugs are relatively common (Bagheri et al., ). An ABCD1 mutation (c.253dup leading to p.Arg85Profs*110) was identified in 35 affected individuals (out of 96 pedigree members) among an expanded pedigree among Lurs. Therefore, the prevalence of X‐ALD is expected to be higher among consanguineous Lurs ethnicity (Mehrpour et al., ). ) MSH3, MSH6, APC, and PIK3CA genes are predicted to play a bigger role in the pathogenesis of colon cancer in Iranian population (Ashktorab et al., ). In a pilot study of Persian nephropathic cystinosis population, the common 57‐kb deletion was not observed; however, at least 50% of mutations were observed in exons 6 and 7 of CTNS (Ghazi et al., ). In another pilot study, the role of kidney anion exchanger 1 gene (AE1) mutations is highlighted in Iranian children with distal renal tubular acidosis (dRTA); moreover a novel mutation pattern of AE) has been reported in patients with distal renal tubular acidosis in Iran (Hooman et al., ). Among all Iranian patients with cystic fibrosis, just 16.6% has shown a delta F508 mutation in CFTR (either homozygote or heterozygote) (Najafi et al., ), which is different from many other populations around the world.…”

“…An ABCD1 mutation (c.253dup leading to p.Arg85Profs*110) was identified in 35 affected individuals (out of 96 pedigree members) among an expanded pedigree among Lurs. Therefore, the prevalence of X-ALD is expected to be higher among consanguineous Lurs ethnicity (Mehrpour et al, 2016). 6.…”

A novel mutation in the ABCD1 gene of a Chinese patient with X-linked adrenoleukodystrophy

“…Although the same mutation is present, the patients exhibit different clinical signs and biochemical aspects. [11,12] Therefore, it is possible that the c.1502del mutation was present in the maternal grandfather.…”

X-Linked Sensorineural Hearing Loss: A Literature Review

“…This recessive X-linked syndrome is associated with mutation in the ABCD1 gene that provides instructions for producing adrenoleukodystrophy protein (ALDP), which is involved in transporting fat molecules called Very Long-Chain Fatty Acids (VLCFAs) into peroxisomes [11]. Mutations in this gene can cause different phenotypes [12]. In the literature three different forms of X-linked adrenoleukodystrophy are described: a childhood cerebral form, an adrenomyeloneuropathy type, and an adrenal gland failure form called Addison disease.…”