History of X-ALD

September 8th, 2014 |

Marc Engelen, M.D. and Stephan Kemp, Ph.D.

1910: In retrospect, Haberfeld and Spieler presented the first clinical description of a patient with X-linked adrenoleukodystrophy (Haberfeld and Spieler, 1910). A previously healthy 6 year old boy developed a deeply bronzed skin (hyperpigmentation), impaired visual acuity, and his school performance deteriorated. The following months, this boy became incontinent, lost his ability to speak and developed spastic tetraparesis, which eventually progressed to an inability to walk. He was hospitalized at the age of 7, and died 8 months later. An older brother had died of a similar illness at the age of 8. Postmortem histological examination of the brain revealed extensive changes in brain white matter, combined with perivascular accumulation of lymphocytes and plasma cells in the nervous system, indicating an inflammatory response.

1923: Siemerling and Creutzfeldt reported the case of a boy with a similar disease progression, including the dark skin and neuropathological findings as in the case described by Haberfeld & Spieler in 1910, except that atrophy of the adrenal cortex was documented.

1963: By now nine comparable cases had been reported. The fact that all patients were males suggested X-linked recessive inheritance (Fanconi et al., 1963).

1970: The name adrenoleukodystrophy was introduced based on the striking association of a leukodystrophy with adrenocortical insufficiency (Blaw, 1970).

1972: The key to all subsequent knowledge about the disease was the observation made by Powers, Schaumburg, and Johnson that adrenal cells of ALD patients contained characteristic lipid inclusions (fat droplets), followed by the demonstration that these fat droplets consisted of cholesterol esters that contained a striking and characteristic excess of very long-chain fatty acids (VLCFA).

Identification of this biochemical characteristic led to the development of assays capable of demonstrating more subtle increases in VLCFA levels in cultured skin cells (fibroblasts), plasma, red blood cells and amniocytes. These techniques have permitted precise postnatal and prenatal diagnosis, the facilitation of genetic studies and gene mapping and the evaluation of therapeutic approaches. Metabolic studies have demonstrated that VLCFA are metabolized (through beta-oxidation) exclusively in subcellular organelles called peroxisomes. Therefore, X-ALD is a peroxisomal disease.

1976: A more slowly progressive adult form of the disease characterized by adrenocortical insufficiency, myelopathy and peripheral neuropathy was described (Budka et al., 1976). A year later, five more cases were reported by Griffin et al. who proposed this clinical presentation of X-ALD to be named adrenomyeloneuropathy (AMN) (Griffin et al., 1977; Schaumburg et al. 1977).

1981: The X-ALD locus was mapped to the terminal segment of the long arm of the X-chromosome, Xq28 (Migeon et al., 1981).

1981: The first bone-marrow transplantation was performed in a boy with adolescent onset of cerebral demyelination. Although the effects on VLCFA were favorable, the clinical outcome was deeply discouraging. The patient died of an adenovirus (cold) infection on day 141 post-transplantation.

1986: Rizzo et al. demonstrated that the addition of oleic acid to the culture medium normalizes the levels of saturated VLCFA in cultured skin fibroblasts from X-ALD patients. These findings resulted in the development of Lorenzo’s oil. Treatment of X-ALD patients with Lorenzo’s oil normalizes plasma VLCFA levels within 4 weeks (Moser et al., 1987). The clinical efficacy of Lorenzo’s oil has never been evaluated in a proper placebo-controlled clinical trial. In 2001, Prof Hugo Moser wrote: “It is our view that Lorenzo’s oil therapy is not warranted in most patients who already have neurologic symptoms. The clinical benefit of Lorenzo’s oil is limited at best”.

1988: The team of Prof. Patrick Aubourg reported on the first successful bone-marrow transplantation (BMT). They had transplanted an 8-year old boy with mild neurological, mild neuropsychological and mild MRI abnormalities. His unaffected nonidentical twin was the donor. The patient recovered completely and the neurological, neuropsychological and MRI abnormalities disappeared. When conducted at the earliest stage of cerebral demyelination, a bone-marrow or hematopoietic stem-cell transplantation (HSCT) can stabilize or even reverse cerebral demyelination in boys or adolescents with X-ALD.

1993: The research groups of Prof. Mandel and Prof. Aubourg identified the putative gene for X-ALD (ABCD1) using positional cloning strategies (Mosser et al., 1993). The identification of the X-ALD gene enabled the detection of disease causing mutations, prenatal diagnosis and accurate carrier testing.

1997: Three laboratories reported the generation of a mouse model for X-ALD (Forss-Petter et al., 1997; Kobayashi et al., 1997; Lu et al., 1997). While the X-ALD mouse exhibits the same biochemical abnormalities as observed in patients, the mouse does not develop X-ALD (Pujol et al., 2001).

1999: The X-ALD database was created by Hugo Moser and Stephan Kemp as a registry for all the mutations identified in the ABCD1 gene.

2001: It was reported and established that X-ALD affects all ethnic groups and it is the most common peroxisomal disorder with a minimum incidence ranging from 1:42,000 for hemizygotes (males) only to 1:17,000 for hemizygotes plus heterozygotes (males and females) combined (Bezman et al., 2001). This makes X-ALD the most common inherited leukodystrophy.

2005: In X-ALD is biochemically not only characterized by a defect in the breakdown of VLCFA, but there also is an increase in the synthesis of VLCFA in patients with X-ALD (Kemp et al. 2005).

2006: The team led by Dr. Ann Moser developed a high-throughput VLCFA analysis method to be used on dried blood spots (Hubbard et al., 2006). These advancements in VLCFA screening will allow the addition of X-ALD to newborn screening programs.

2009: Drs Nathalie Cartier and Patrick Aubourg and colleagues successfully treated two 7-year old boys with early signs of cerebral-ALD using gene therapy (Cartier et al., 2009). Brain MRI scans and cognitive tests showed that progression of the cerebral disease stopped after 14-16 months. This is comparable with the clinical outcome of HSCT.

2010: The research team of Dr. Kemp established that ALDP transports VLCFA across the peroxisomal membrane. A deficiency in ALDP has two major effects: on the one hand, it impairs peroxisomal degradation of VLCFA, and on the other hand, it raises cytosolic levels of VLCFA. These VLCFA are then further elongated to even longer fatty acids by ELOVL1, the human C26 specific elongase (Ofman et al. 2010).

2014: In the United States, two states (New York and Connecticut) started newborn screening for X-ALD.

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