Last Updated: September 15, 2022
Introduction to X-Linked Adrenoleukodystrophy
X-linked adrenoleukodystrophy (X-ALD) is an X-linked recessive disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes. This family of disorders is referred to as the peroxisome biogenesis disorders, PBD. The PBD are caused either by peroxisomal assembly defects or by deficiencies of single peroxisomal proteins. X-ALD results from the deficiency of a single peroxisomal protein. The incidence of X-ALD in males is estimated to be between 1:20,000 and 1:50,000 live births.
There are two inherited disorders that manifest with adrenoleukodystrophy (malfunction in the adrenal cortex and nervous system myelin). X-ALD is one and neonatal adrenoleukodystrophy (NALD) is the other. Both adrenoleukodystrophies are biochemically characterized by the accumulation of very long-chain fatty acids (VLCFA). NALD is an autosomal recessive disorder and belongs to the Zellweger spectrum PBD which includes Zellweger syndrome and infantile Refsum disease (IFD). Zellweger syndrome represents the extreme of the clinical manifestation of peroxisome biogenesis dysfunction with patients rarely surviving their first year of life. Zellweger syndrome is associated with either severe, moderate or mild defects in all peroxisome functions. An additional phenotypic spectrum in PBD is represented by rhizomelic chondrodysplasia punctata, RCDP. RCDP is distinguished from the Zellweger spectrum PBD by manifesting with more severe skeletal involvement as well as specific biochemical characteristics.
Molecular Biology of X-Linked Adrenoleukodystrophy
X-linked adrenoleukodystrophy is caused by mutations in the gene (ABCD1) encoding the ATP-binding cassette, subfamily D, member 1 transporter. The ABCD1 protein is involved in the import and/or anchoring of very long-chain fatty acid-CoA synthetase (VLCFA-CoA synthetase) to the peroxisomes.
The ABCD1 gene is located on the X chromosome (Xq28) spanning 21 kb and is composed of 11 exons encoding a 745 amino acid protein.
Peroxisome Biogenesis
The peroxisomes are a single membrane organelle, similar to lysosomes, present in virtually all eukaryotic cells. The peroxisome is a specialized enzyme “factory” that contains in excess of 50 different enzymes involved in a variety of metabolic processes including β-oxidation of very long chain fatty acids, α-oxidation of fatty acids and synthesis of ether-lipids. Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). At least 15 PEX genes have been identified in humans.
Enzymes that are targeted to the peroxisomes contain either of two amino acid consensus elements called peroxisome targeting sequences (PTS). The PTS1 is a C-terminal consensus sequence of –[S/A/C][K/R/H][L/M]. This sequence element is recognized by a cytosolic PTS1 receptor encoded by the PEX5 gene. There are two isoforms of PEX5 encoded proteins in humans identified as Pex5pS and Pex5pL (for short and long forms, respectively). The Pex5pL protein has an internal 37 amino acid insertion, hence the “long” designation.
The PTS2 is an N-terminal consensus sequence of –[R/K][L/V/I/Q]XX[L/V/I/H/Q][L/S/G/A/K]X[H/Q][L/A/F]–, (where X represents any amino acid). The PTS2 receptor is encoded by the PEX7 gene and the encoded protein is referred to as Pex7p. Proteins that are targeted to the membrane of the peroxisome (called peroxisome membrane proteins, PMPs) contain a consensus sequence identified as the PEX19 binding site (PEX19BS) and this site is recognized by the membrane protein receptor encoded by the PEX19 gene.
Pex5pS, Pex5L, and Pex7p interact with newly synthesized target proteins in the cytosol and direct them to the peroxisome. On the membrane of the peroxisome is a component of the protein import machinery encoded by the PEX14 gene called Pex14p. Following interaction of Pex5pS or Pex5pL, bound to a protein containing a PTS1 sequence, with Pex14p, the PTS1 containing protein is transferred into the peroxisome. The activity of Pex7p in peroxisome protein import actually requires Pex5pL as well. PTS2 containing proteins interact with Pex7p and then, in conjunction with Pex5pL, the complex interacts with Pex14p and the PTS2 containing protein is transferred into the peroxisome. Very few proteins contain a PTS2 sequence but one enzyme of note is phytanoyl-CoA hydroxylase (PhyH) which is defective in classic Refsum disease.
Clinical Features of X-ALD
X-ALD is also sometimes called Addison disease which refers to the adrenal deficit. X-ALD results from the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body, particularly hexacosanoic acid (C26:0; also known as cerotic acid). The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.
Several clinically distinct phenotypes are observed in X-ALD. About 35% of X-ALD patients have the childhood cerebral form in which afflicted boys develop normally until 4 to 8 years of age and then manifest dementia and progressive neurological decline resulting in a vegetative state. Over 90% of these patients have adrenal insufficiency.
Approximately 40% of X-ALD patients will present with symptoms in young adulthood which include slowly progressive paraparesis (weakness in the lower extremities) referred to as adrenomyeloneuropathy. Like the childhood cerebral form of X-ALD, these latter patients also manifest with adrenal insufficiency which is seen in about 70% of patients.
The remainder of X-ALD cases are rarer manifesting forms such as “Addison-only”, adult cerebral, and olivo-ponto-cerebellar. Some female heterozygotes, approximately 20%, develop overt manifestations that resemble the adrenomyeloneuropathy seen in males. Adrenal hormone replacement can alleviate the adrenal insufficiency in X-ALD but does nothing to counter the neurological deficits.