What is Adrenoleukodystrophy (ALD)?
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene (located on the X chromosome) that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long chain fatty acids (VLCFA; C22).
A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to increasingly severe cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60. In individual patients, the course of the disease remains unpredictable.
Epidemiology
With an estimated birth incidence of 1 in 17,000 newborns (male and female), X-ALD is the most common peroxisomal disorder. It occurs in all regions of the world. Now that newborn screening has become technically feasible and can be implemented in some parts of the world, the actual prevalence may be even higher.
Genetic Transmission
The disease is linked to the X chromosome. Affected carrier mothers transmit the genetic disorder to 50% of their sons and daughters, causing them to acquire affected status. Male patients, on the other hand, transmit the mutation to all their daughters, who acquire the status of affected carriers, but never to a son. If a patient is diagnosed with X-ALD, screening and family counselling are recommended.
Genetic transmission of ALD mother carrier
Genetic transmission of ALD father carrier
[source “Genetic Transmission”: https://www.orpha.net/consor/cgi-bin/Disease_Search.php lng=EN&data_id=761]
Phenotypes – Male patients with X-ALD
ISOLATED ADDISON’S DISEASE
Adrenal insufficiency may be the first symptom of X-ALD in boys and adult males, years or even decades before the onset of neurological symptoms. X-ALD frequently causes Addison’s disease in boys and adult males. Recognising that Addison’s disease may be due to X-ALD has important implications for patient management, but also for genetic counselling. It is therefore important to consider the possible presence of X-ALD in all children or adults who manifest Addison’s disease.
CEREBRAL ALD (C-ALD)
This phenotype is the most rapidly progressing and increasing in severity. It occurs most frequently during childhood (childhood cerebral ALD; CCALD), but never before the age of 2.5 years. The onset of CCALD is insidious, with deficits in cognitive abilities involving visual and motor functions or attention and reasoning. In boys and adolescents, it initially results in a decline in school performance. These early clinical symptoms are often misdiagnosed as attention deficit disorder and may delay the diagnosis of CCALD.
As the disease progresses, major neurological deficits become evident, which include withdrawn or hyperactive behaviour, apraxia, astereognosis, hearing impairment (‘speech deafness‘ reflecting deterioration in the acoustic analysis of speech sounds), diminished visual acuity, spastic hemiparesis or tetraparesis, cerebellar ataxia and seizures. At this stage, the progression is extremely rapid with increase in severity. The rapid neurological decline of CCALD is caused by a severe process of inflammatory demyelination that mainly affects the cerebral hemispheres.
Less frequently, brain demyelination as a phenotype of X-ALD occurs in adolescence (AdolCALD) or adulthood (ACALD). The symptomatology in these patients strongly resembles CCALD, but the initial progression of symptoms is usually slower. In adults, early cognitive decline is rarely recognised by their families and friends or at work.
As the disease progresses, psychiatric disorders mimicking schizophrenia or psychosis are not uncommon. In those cases, the diagnosis of X-ALD is often delayed; particularly when there is no history of X-ALD in the family and when clinical symptoms of Addison’s disease are absent.
About 10% of children or adolescents with cerebral ALD may not develop the rapidly progressive neuroinflammatory stage of the disease. The same may occur in men with ACALD or men with AMN who develop secondary cerebral demyelination. This cerebral demyelinating form of X-ALD is often referred to as ‘chronic or arrested cerebral X-ALD‘.
The process of cerebral demyelination stops spontaneously and the patient can remain stable for a decade or more. But even after a period of stability of 10-15 years, there may be a sudden onset of rapid neurological deterioration, reflecting a complete progression to the neuroinflammatory stage of the disease.
ADRENOMYELONEUROPATHY
Almost all patients with X-ALD who reach adulthood develop AMN, usually in the third or fourth decade. Initial symptoms are limited to the spinal cord and peripheral nerves. Patients gradually develop progressive spastic paraparesis, sensory ataxia
with altered sense of vibration, sphincter dysfunction (mainly urinary), leg pain and impotence.
The clinical burden of peripheral nerve involvement is usually moderate and difficult to assess due to significant spinal cord symptoms. If polyneuropathy is studied electrophysiologically, axonopathy is found in most patients.
Rarely, the initial symptomatology may be that of a peripheral, demyelinating or axonal neuropathy. The pathological basis of AMN is a non-inflammatory distal axonopathy involving long stretches of the spinal cord and, to a lesser extent, peripheral nerves.
This phenotype is in most cases slowly progressive, causing severe motor disability in the lower limbs within one or two decades, but slight or no significant deficits in the arms and hands.
A retrospective study revealed that over a 10-year period, approximately 20 per cent of patients with AMN developed additional cerebral demyelination. After an initial progression, demyelinating lesions may stabilise spontaneously leading to moderate cognitive deficits. However, once demyelinating brain lesions have entered the active phase of neuroinflammation, the prognosis is as poor as in CCALD.
The neurological symptoms of patients with AMN who develop cerebral ALD are identical to those observed in adults with CALD, with additional symptoms of the pre-existing myelopathy.
Approximately 70% of patients with AMN suffer from adrenocortical insufficiency. An equal percentage of affected males show subclinical signs of testicular failure. Clinical symptoms of testicular failure are rare. The hair of patients with AMN is often thin and sparse; these patients often show baldness at an early age.
Phenotypes – Female patients with X-ALD
Women develop AMN-like symptoms, although, as in many X-linked diseases, female carriers are assumed to remain asymptomatic. Physical examination of a large group of female carriers attending family conferences in the US revealed that more than 50 per cent had some kind of abnormality on neurological examination.
An increasing number of symptomatic heterozygous women have been identified as the first member of their family to be affected by X-ALD and the true incidence of AMN in heterozygous women is likely to be close to 65% by the age of 60.
The onset of neurological symptoms mainly occurs between the fourth and fifth decade and are very similar to those observed in adult males with AMN.
Sensory ataxia, faecal incontinence and pain in the legs are, however, often more prominent in symptomatic women with AMN. Brain involvement and adrenocortical insufficiency are rare, 2% and 1%, respectively.
Evolution of the disease
X-ALD phenotypes are not standardisable. Pre-symptomatic males are almost all at risk of developing neurological (cerebral ALD, AMN) or endocrinological (Addison’s disease) symptoms.
Males with Isolated Addison’s disease may develop AMN and males with C-ALD and AMN may develop cerebral demyelination.
It is estimated that over a period of 10 years about 20 per cent of patients with AMN will progress to a brain phenotype.
Pre-symptomatic women with X-ALD are at risk of developing AMN. The progression of X-ALD in a specific individual cannot be predicted.
Role of VLCFAs (very long chain fatty acids)
X-ALD is caused by variants in the ABCD1 (Xq28) gene, with approximately 900 different mutations reported. There is no genotype-phenotype correlation. The encoded peroxisomal transmembrane protein plays a central role in the transport of very long chain fatty acids (VLCFA) from the cytosol into the peroxisome, where they should undergo beta-oxidation and their subsequent catabolism.
Although the exact pathophysiology is poorly understood, the disrupted homeostasis of VLCFAs in glial cells may contribute to myelin sheath destabilisation and impaired axonal function.
[source: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=761]
Furthermore, the excessive accumulation of VLCFA in the ALD-affected brain initiates a cytokine-mediated cascade that eventually causes demyelination. Excess VLCFA has been shown to stimulate an overproduction of free radicals leading to high oxidative damage of proteins.
[Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ADRENOLEUKODYSTROPHY implications for potential therapies A.S.Paintlia, A.G. Gilg, M.Khan, A.K.Singh, E.Barbosa and I.Singh]
The importance of nutritional therapy
‘In general, dietary support therapy is an important aid for all types of adrenoleukodystrophy.’
First of all, substances are prescribed to help lower plasma VLCFA levels. A low VLCFA diet, developed by a nutritionist, is then drawn up and prescribed.
‘This type of combination therapy should be started as early as possible, even in marrow transplant candidates,’ the expert emphasises.
‘This is crucial in order to reduce the accumulation of long-chain fatty acids early on, even before the symptoms of the disease begin to appear.’
Adrenoleukodystrophy, dietary support therapy is a key aid
https://www.osservatoriomalattierare.it/malattie-rare/adrenoleucodistrofia/16693-adrenoleucodistrofia-la-terapia-di-supporto-dietetico-e-un-ausilio-fondamentale
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