History of ALD

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 primary adrenocortical (adrenal) 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 adrenoleukodystrophy 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).

1976: A more slowly progressive adult form of the disease characterized by adrenal 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 adrenoleukodystrophy to be named adrenomyeloneuropathy (AMN) (Griffin et al. 1977; Schaumburg et al.1977).

1981: The identification of VLCFA as a biomarker for adrenoleukodystrophy led to the development of a diagnostic test for adrenoleukodystrophy based on the demonstration of elevated levels of VLCFA in cultured skin cells (fibroblasts), plasma, red blood cells and amniocytes (Moser et al. 1981). These tests have permitted precise postnatal and prenatal diagnosis. Metabolic studies demonstrated that VLCFA are metabolized (through beta-oxidation) exclusively in subcellular organelles called peroxisomes and this oxidation of VLCFA is reduced in fibroblasts from adrenoleukodystrophy patients (Singh et al 1981). Therefore, adrenoleukodystrophy is a peroxisomal disease.

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

1982: The first bone-marrow transplantation (BMT) was performed in a boy with cerebral ALD. An allogeneic BMT from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy. Engraftment and complete hematologic recovery occurred within 4 weeks. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal. But neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT.

1986: Rizzo et al. demonstrated that the addition of oleic acid (C18:1) to the tissue culture medium normalizes the levels of saturated VLCFA in cultured skin fibroblasts from adrenoleukodystrophy patients. These findings formed the basis for the development of Lorenzo’s oil. Treatment of adrenoleukodystrophy patients with Lorenzo’s oil normalizes plasma VLCFA levels within 4 weeks (Moser et al. 1987). Several open-label trials have shown that Lorenzo’s oil failed to improve neurological or endocrine function nor did it arrest the progression of the disease. Unfortunately, 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”.

1990: The team of Prof. Patrick Aubourg reported on the first successful bone-marrow transplantation (BMT) (Aubourg et al. 1990). They had transplanted an 8-year old boy with mild neurological, mild neuropsychological and mild MRI abnormalities. His unaffected non-identical 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 adrenoleukodystrophy.

1993: A team led by Drs. Mandel and Aubourg identified the putative gene for adrenoleukodystrophy (ABCD1) using positional cloning strategies (Mosser et al. 1993). The identification of the adrenoleukodystrophy 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 adrenoleukodystrophy (Forss-Petter et al. 1997; Kobayashi et al. 1997; Lu et al. 1997). While the adrenoleukodystrophy mouse exhibits the same biochemical abnormalities as observed in patients, the mouse does not develop ALD (Pujol et al. 2002).

1999: The ALD database was created by Hugo Moser and Stephan Kemp. Initially it served only as a registry for mutations identified in the ABCD1 gene, but soon thereafter it was expanded to provide information on many aspects of adrenoleukodystrophy.

2001: It was reported and established that adrenoleukodystrophy affects all ethnic groups and it is the most common peroxisomal disorder with an estimated incidence of 1:17,000 (males and females combined) (Bezman et al. 2001). This makes adrenoleukodystrophy the most common inherited leukodystrophy.

2005: Biochemically, adrenoleukodystrophy is not only characterized by a defect in the breakdown of VLCFA in peroxisomes, but there is also an increase in the subsequent chain-elongation of VLCFA (Kemp et al. 2005).

2006: The team led by Dr. Ann Moser developed a high-throughput VLCFA analysis method (with C26:0-lysoPC as the diagnostic metabolite) to be used on dried blood spots (Hubbard et al. 2006). These advancements in VLCFA screening will allow the addition of adrenoleukodystrophy to newborn screening programs.

2009: The team led by Drs. Cartier and Aubourg reported on the successful treatment of 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 14-16 months post-treatment. This is comparable with the clinical outcome of HSCT.

2010: The research team of Dr. Stephan Kemp established that the ALD protein (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).

2013: In the United States, New York State started newborn screening for adrenoleukodystrophy (Vogel et al. 2015) on December 30th of 2013. Early diagnosis of adrenoleukodystrophy is the key to saving lives, because newborn screening allows prospective monitoring and early intervention.

2015: In the US, Connecticut initiated adrenoleukodystrophy newborn screening. In Europe, the Netherlands expanded its national newborn screening program from 17 to 31 conditions, including adrenoleukodystrophy (a pilot – The SCAN: Screening for ALD in the Netherlands study will start January 2021 (scanstudie.nl)).

2016: On February 16, adrenoleukodystrophy was added to the United States Recommended Uniform Screening Panel (RUSP). In the US, California initiated adrenoleukodystrophy newborn screening. Since then other states and countries have started newborn screening programs, or have initiated processes intended to add adrenoleukodystrophy to their existing newborn screening program. Detailed and up-to-date information on adrenoleukodystrophy newborn screening can be found at the “newborn screening” page.

Last modified | 2021-06-03