Adrenoleukodystrophy (ALD) is a genetic disorder that follows X linked inheritance pattern in most cases (X-ALD). A unique neonatal form classified as one form of Zellweger syndrome has an autosomal recessive inheritance pattern (N-ALD). Although, the earlier report in the 1900s described the clinical presentations suggestive of this disease.; the terminology and pathophysiology were first reported in the 1970s. The brain, spinal cord, adrenal glands, and testes are the most commonly affected organs. Given the multiple organs, involvement multidisciplinary team approach is highly recommended in the management plan.
X-ALD disease has links with the ABCD1 gene mutation. ABCD1 gene plays a significant role in the very-long-chain fatty acids (VLCFA)s transport system in the peroxisomes, where VLCFAs can undergo further metabolism. The abnormal ABCD1 gene mutation interferes with this process and results in abnormal accumulation of VLCFA in different body organs and subsequently interferes with the organs' normal physiological function. A mutation causes the neonatal form in any of the PTS1 receptor, PXR 1, PEX1, PEX 10 or PEX 13 genes. Four main subtypes of ALD have been described based on organs affected and age of presentation:
On gross examination, affected adrenal glands appear small and atrophied. Histological findings at the microscopic level consist of nodular swelling affecting mainly the zona fasciculata and zona reticularis. Celluar vacuoles and clefts may be visible as well. The medulla is usually spared and appears normal.
Central nervous system pathological findings in ALD consist of symmetrical demyelination of the white matter. These effects commonly occur in the corpus callosum and the occipitoparietal region. In severe cases, the spinal cord may get affected. At the cellular level, swelling and vacuolization are caused by infiltrates of active inflammatory cells ( macrophages and astrocytes). These changes usually result in the loss of the myelin sheets, oligodendrocytes, and neuronal axons. Ultimately dystrophic mineralization is seen on the histological examination.
Clinical manifestations vary significantly according to the disease severity and the age at presentation.
N-ALD can manifest immediately after birth. However, some infants will be mildly affected. Hence diagnosis is usually delayed in these cases. Typical signs and symptoms in N-ALD include :
X-ALD usually has three phenotypes, classified based on the age of presentation and the organs affected:
Females who are carriers may develop milder symptoms (unbalanced gait, neuropathy, mild paresis). The adrenal glands and cerebrum are rarely involved.
Typical Clinical presentation, characteristics, symptoms and signs, and suggestive family history are considered the starting point for adrenoleukodystrophy evaluation. Several states started using newborn screening tests as a screening tool to identify newborns with a potential genetic predisposition for X-ALD. The driving principle behind adding X-ALD to the newborn screening is to identify newborns with the mutation to receive treatment before the symptoms appear.
Nonspecific laboratory workup may reveal an abnormal liver function and reduced response to ACTH administration. The more indicative test results will show :
Magnetic resonance imaging (MRI) of the brain is an essential part of the evaluation; Typical findings are:
Further genetic testing to identify the specific genetic mutation is recommended to confirm the diagnosis.
There is no effective treatment for most of the forms of N-ALD or X-ALD. Supportive care by optimizing nutrition, occupational therapy, and respiratory support can help alleviate some of these disorders' severe consequences but typically do not significantly impact survival or long-term outcomes. Coreterosteriod and mineralocorticoid replacement therapy is the recommended therapy in those with impaired adrenal gland function. Some reports have shown that allogeneic hematopoietic cell transplant (HCT) may have beneficial effects. Favorable outcomes with HCT therapy occur in asymptomatic patients at the time of diagnosis or those with mild symptoms and CNS involvement.
Recent trials to use docosahexaenoic acid (DHA) or the induction of peroxisome proliferation were not conclusive. Given the multiple organs affected and the multiple needs for the management of ALD patients, an interprofessional team approach (endocrinologist, neurologist, genetics, psychologist) is recommended.
The differential diagnosis for N-ALD is comprehensive and includes other genetic syndromes that present in the neonatal period with neurological signs and symptoms ( Angelman, RET syndrome, Prader Willi, hypoxic-ischemic encephalopathy, metabolic disorders, myotonic dystrophy, and others). For X-ALD; Other demyelination disorders (acute disseminated encephalomyelitis (ADEM), multiple sclerosis, specific central nervous system dysfunction) should be excluded as the evaluation, management, and prognosis for these conditions are different from ALD.
Two ongoing clinical trials to evaluate potential therapeutic interventions for ALD are actively recruiting. NCT03727555 clinical trial evaluates the use of lentiviral vector TYF-ABCD1 to correct the defective ABCD1 gene associated with ALD. Another trial, NCT03852498, aims to assess the effect of autologous CD34+ HCT on ALD.
Prognosis is poor with N-ALD and most of the other forms of X-ALD. Treatment is usually limited to symptomatic supportive management. Replacement therapy for patients with Addison disease and HCT for asymptomatic patients ( identified by newborn screen or incidental imaging) or have mild symptoms may be effective in selected cases. Severe disabilities and death are the expected outcomes on the majority of patients with N-ALD or X-ALD.
Adrenoleukodystrophy is a peroxisome disease that affects neonates ( N-ALD) or children and adult (X-ALD) with multiple organs involvement ( commonly; the central nervous system and the adrenal glands).
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