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 deep brown skin (hyperpigmentation), impaired visual acuity, and deteriorating school performance. Over the following months, this boy became incontinent, lost his ability to speak, and developed spastic tetraparesis, which eventually progressed to the inability to walk. He was hospitalized at age 7 and died 8 months later. An older brother had died of a similar illness at the age of 8. Postmortem histologic examination of the brain revealed extensive white matter changes, combined with perivascular accumulation of lymphocytes and plasma cells in the nervous system, indicating an inflammatory response.

1923: Siemerling and Creutzfeldt report the case of a boy with a similar course of disease, 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 this time, nine similar cases had been reported. The fact that all patients were male suggested an 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 of the disease was the observation 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 were composed of cholesterol esters containing 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 is described (Budka et al. 1976). One year later, five more cases are reported by Griffin et al. who propose that this clinical presentation of adrenoleukodystrophy be called 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 detection of elevated levels of VLCFA in cultured skin cells (fibroblasts), plasma, red blood cells and amniocytes (Moser et al. 1981). These tests allowed accurate postnatal and prenatal diagnosis. Metabolic studies have shown that VLCFA are metabolized (by beta-oxidation) exclusively in subcellular organelles called peroxisomes and that this oxidation of VLCFA is reduced in fibroblasts from adrenoleukodystrophy patients (Singh et al 1981). Thus, adrenoleukodystrophy is a peroxisomal disease.

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

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

1986: Rizzo et al. demonstrated that the addition of oleic acid (C18:1) to the tissue culture medium normalized the levels of saturated VLCFA in cultured skin fibroblasts from patients with adrenoleukodystrophy. These findings were 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 studies have shown that Lorenzo’s oil does not improve neurological or endocrine function, nor does it halt disease progression. 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 opinion that Lorenzo’s oil therapy is not warranted in most patients who already have neurological symptoms. The clinical benefit of Lorenzo’s oil is limited at best”.

1990: Prof. Patrick Aubourg’s team reports the first successful bone marrow transplant (BMT) (Aubourg et al. 1990). They 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 made a full recovery and the neurological, neuropsychological and MRI abnormalities disappeared. When performed at the earliest stage of cerebral demyelination, 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 identifies 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 has the same biochemical abnormalities as patients, the mouse does not develop cerebral ALD or adrenal dysfunction, but rather late-onset spinal cord involvement (Pujol et al. 2002).

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

2001: It was reported and established that adrenoleukodystrophy affects all ethnic groups and 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 characterized not only by a defect in the degradation of VLCFA in peroxisomes, but also by an increase in the synthesis of VLCFA (Kemp et al. 2005).

2006: Dr. Ann Moser’s team develops a high-throughput method for VLCFA analysis (using C26:0-lysoPC as the diagnostic metabolite) that can be applied to dried blood spots (Hubbard et al. 2006). These advances in VLCFA screening will allow the inclusion of adrenoleukodystrophy in newborn screening programs.

2009: The team led by Drs. Cartier and Aubourg reports 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 brain disease was halted 14-16 months after treatment. This is comparable to the clinical outcome of HSCT.

2010: Dr. Stephan Kemp’s research team shows that the ALD protein (ALDP) transports VLCFA across the peroxisomal membrane. ALDP deficiency has two major effects: it impairs the peroxisomal degradation of VLCFA, and it increases the 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 began newborn screening for adrenoleukodystrophy on December 30, 2013 (Vogel et al. 2015). Early diagnosis of adrenoleukodystrophy is key to saving lives, as newborn screening allows for prospective monitoring and early intervention.

2016: On February 16, adrenoleukodystrophy was added to the US Recommended Uniform Screening Panel (RUSP). In the US, California initiated newborn screening for adrenoleukodystrophy. Since then, other states and countries have initiated newborn screening programs for adrenoleukodystrophy or are in the process of adding adrenoleukodystrophy to their existing newborn screening programs. For detailed and up-to-date information on adrenoleukodystrophy newborn screening, please visit the “newborn screening” page.

Last modified | 2024-06-24