X-Linked Adrenoleukodystrophy via the ABCD1 Gene

X-linked adrenoleukodystrophy (X-ALD) is a congenital neurodegenerative disorder due to deficient beta-oxidation of very long-chain fatty acids (VLCFAs) in peroxisomes. It is the most common inherited peroxisomal disorder and affects 1 in 18,000 individuals (Steinberg et al. 2012; Kemp et al. 2012).

In affected male hemizygotes, the two main clinical phenotypes are cerebral X-ALD (CALD) and adrenomyeloneuropathy (AMN). CALD is the most severe form of X-ALD associated with rapid progression of inflammatory cerebral demyelization. The first symptoms of CALD usually appear between the age of 4 and 12 years as behavioral problems, such as attention deficit and hyperactivity. Then the patients rapidly develop severe neurologic and cognitive deterioration, including blindness, deafness, cerebella ataxia, seizures, dementia, hemiplegia or quadriparesis, and often die within two to five years after diagnosis. AMN is the milder, adult form of X-ALD with the age of onset between 20 and 30 years. Unlike CALD, AMN is a slowly progressive distal axonopathy disorder which affects sensory ascending and motor descending spinal cord tracts. The clinical presentation includes stiffness or weakness of legs, impaired sphincter control, sexual dysfunction, alopecia, and spastic paraplegia. Up to 20% of AMN male patients may develop CALD symptoms later. Adrenocortical insufficiency (Addison disease) is found in most boys with CALD and in about 70% of males with AMN. About 10% of affected males present with adrenocortical insufficiency only, but may develop AMN phenotype later in life (Steinberg et al. 2012; Kemp et al. 2012; Berger et al. 2014).

Approximately 20- 65% of heterozygous female carriers develop milder AMN symptoms with an average onset later than in males (age > 40 years). Cerebral X-ALD has been reported in a few female cases, but is extremely rare. Adrenal function usually is normal in female carriers, and less than 5% of female AMN patients have adrenocortical insufficiency (Steinberg et al. 2012; Kemp et al. 2012).

X-linked adrenoleukodystrophy is inherited in an X-linked recessive manner, and the ABCD1 gene is the only known genetic cause of X-ALD. ABCD1 contains 10 exons and encodes a transmembrane protein that transports VLCFAs (C24:0, C26:0 and others) into the peroxisomes for beta-oxidation. The penetrance is 100% in male hemizygotes. Approximately 20- 65% of heterozygous female carriers develop the disorder due to skewed X-inactivation. Gonadal or gonosomal mosaicism has been observed. About 4-12% of reported patients have a de novo ABCD1 mutation (Wang et al. 2011; Shimozawa et al; 2011; Kemp et al. 2001). Of over 1,500 reported mutations, ~60% are missense substitutions, ~22% frame shifts, ~10% nonsense mutations, ~3% amino acid deletions/insertions and 3-6% gross deletions/duplications (http://www.x-ald.nl; Steinberg et al. 2012; Kemp et al. 2001; Shimozawa et al. 2011). Reported missense mutations are commonly found in the transmembrane domain or in the ATP binding domain, and rarely in the C-terminal 52 amino acids (693-745) (Kemp et al. 2012). There is no phenotype-genotype correlation established. The same mutations can result in all different X-ALD phenotypes (Kemp et al. 2001).

Over 93% of patients with X-ALD are caused by ABCD1 mutations which can be detected by Sanger sequencing. Gross deletions/duplications account for the remaining ~7% of causative mutations (http://www.x-ald.nl; Steinberg et al. 2012).

This test provides full coverage of all coding exons of the ABCD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.