Adrenoleukodystrophy

Etiology

X-ALD disease is linked to ABCD1 gene mutation. The ABCD1 gene plays a significant role in the VLCFA transport system in the peroxisomes, where VLCFAs can undergo further metabolism. The ABCD1 gene mutation product interferes with this process, resulting in abnormal accumulation of VLCFA in different body organs and interference with the affected organs' normal physiological function. A mutation in the PTS1 receptor, PXR1, PEX1, PEX10, or PEX13 genes causes the neonatal form.[3] Four main subtypes of ALD have been described based on organs affected and age at presentation: neonatal, childhood cerebral form, adrenomyeloneuropathy, and adrenal insufficiency.

Epidemiology

ALD is the most common genetic disease that affects the peroxisomes. The condition has an approximated prevalence of 1 in 20,000. The disease incidence is higher in patients of Latino or African descent.[4] N-ALD has a prevalence of 1 in 50,000.[5]

Histopathology

On gross examination, affected adrenal glands appear small and atrophied. Histological findings consist of nodular swelling affecting mainly the zona fasciculata and zona reticularis. Cellular vacuoles and clefts may also be visible. The medulla is usually spared and appears normal.[6]

Central nervous system (CNS) pathological findings in ALD consist of symmetrical demyelination of the white matter. These effects commonly occur in the corpus callosum and occipitoparietal region. Severe cases may involve the spinal cord. 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 sheaths, oligodendrocytes, and neuronal axons. Dystrophic mineralization is ultimately seen on histological examination.[7]

History and Physical

Clinical manifestations vary significantly according to disease severity and the age at presentation. The cases are broadly categorized as N-ALD and X-ALD.

N-ALD can manifest immediately after birth. However, some infants only have mild manifestations, potentially delaying the diagnosis in such cases. Typical N-ALD signs and symptoms include the following:

• Seizures, hypotonia, and hearing dysfunction
• Vision loss, cataracts, and optic nerve dysplasia
• Jaundice and hepatomegaly
• Failure to thrive and facial dysmorphism (hypertelorism and flat midface) [8]

X-ALD has 3 phenotypes, classified based on the age at presentation and the organs affected. These phenotypes are childhood cerebral ALD, Addison disease, and adrenomyeloneuropathy.

Childhood cerebral ALD typically presents between ages 3 and 10 years. The hallmark feature that characterizes this form is developmental regression. Progressive sensory and severe neurological deficits are generally followed by severe disability, coma, and death. A small percentage of adults may develop symptoms similar to childhood cerebral ALD. 

Adrenal gland dysfunction characterizes the Addison disease phenotype of X-ALD. The manifestations of this subtype result from reduced aldosterone and cortisol production, which include hyponatremia, fatigue, hypotension, dehydration, hypoglycemia, and generalized weakness. Hyperpigmentation of the skin may also occur.

Adrenomyeloneuropathy comprises a milder spectrum of X-ALD. The typical age at presentation is in the 3rd decade of life. Typical manifestations include walking difficulties, unbalanced gait, and bowel or bladder sphincter dysfunction.

Female X-ALD carriers may develop subtler symptoms, such as unbalanced gait, neuropathy, and mild paresis. The adrenal glands and cerebrum are rarely involved.[9]

Evaluation

Typical clinical presentation, characteristics, symptoms, signs, and suggestive family history are considered the starting point for ALD evaluation. Several states started using newborn screening tests to identify newborns with X-ALD. Adding X-ALD to newborn screening identifies newborns with the mutation so they can receive treatment before the symptoms appear.

Laboratory workup may reveal abnormal liver function and reduced response to adrenocorticotropic hormone administration. However, results more suggestive of ALD include increased plasma VLCFA concentration, decreased plasmalogen concentration in red blood cells, and increased pipecolic and phytanic acid concentration in both plasma and fibroblasts.[10]

Brain magnetic resonance imaging (MRI) is essential to the evaluation. The typical MRI findings are white matter demyelination pattern, microgyria, and germinolytic cysts in the caudothalamic groove. Further genetic testing to identify the specific mutation causing the disorder is recommended to confirm the diagnosis.[11]

Treatment / Management

ALD has no effective cure. Supportive care, by optimizing nutrition, occupational therapy, and respiratory support, can help alleviate some of the disorder's severe consequences but typically does not significantly impact survival or long-term outcomes. Corticosteroid and mineralocorticoid replacement therapy is recommended in patients with impaired adrenal gland function. Some studies report that allogeneic hematopoietic cell transplantation (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.[12] 

Recent trials exploring docosahexaenoic acid use to induce peroxisome proliferation are inconclusive.[13][14] Given the multiple organs affected and the various needs of patients with ALD, an interprofessional team approach, involving endocrinologists, neurologists, geneticists, and psychologists at the minimum, is recommended.

Differential Diagnosis

The differential diagnosis of N-ALD is comprehensive and includes other genetic syndromes that present in the neonatal period with neurological signs and symptoms. These conditions include Angelman, Rett, and Prader-Willi syndromes, hypoxic-ischemic encephalopathy, metabolic disorders, and myotonic dystrophy. Meanwhile, X-ALD's differentials include conditions manifesting with demyelination, such as acute disseminated encephalomyelitis and multiple sclerosis.

Pertinent Studies and Ongoing Trials

Two ongoing clinical trials to evaluate potential therapeutic interventions for ALD are actively recruiting. The NCT03727555 clinical trial evaluates the use of lentiviral vector TYF-ABCD1 to correct the defective ABCD1 gene causing ALD symptoms. Another trial, NCT03852498, aims to assess the effect of autologous CD34+ HCT on ALD.

Prognosis

The prognosis for N-ALD and most forms of X-ALD is poor. Treatment is usually limited to symptomatic supportive management. Replacement therapy is effective for patients with Addison disease, while HCT may benefit asymptomatic patients identified through newborn screening or incidental imaging, as well as those with mild symptoms. Severe disabilities and a short life span are the expected outcomes for most patients with N-ALD and X-ALD.