X-ALD has several, potentially overlapping phenotypes. The phenotypes include (1) asymptomatic status, (2) adrenal insufficiency, (3) inflammatory cerebral demyelination often called cerebral X-ALD, and (4) progressive spastic paraparesis and sphincter dysfunction often called adrenomyeloneuropathy. Each phenotype, in effect, describes a specific subset of symptoms with a distinct management strategy. All X-ALD gene carriers are asymptomatic for at least the first few years of life, after which males should undergo regular serologic surveillance for adrenal insufficiency and regular radiologic surveillance for cerebral demyelination; both phenotypes are life-threatening but treatable if identified in a timely fashion. Males with an X-ALD mutation should be screened via cortisol stimulation testing every 6–9 months for adrenal insufficiency. Women are typically spared adrenal insufficiency and cerebral demyelination. Patients who show signs of adrenal insufficiency should be started on corticosteroids and followed by an endocrinologist. All men and most women with an X-ALD mutation will eventually develop symptoms of spastic paraparesis and associated sphincter dysfunction during adulthood. Rehabilitation therapy and symptomatic treatment for spasticity, pain, and maintenance of ambulation can greatly enhance quality of life and prevent or mitigate early disability. Attentive urologic and gastroenterologic care may similarly help maintain comfort and independence and reduce the incidence of urinary tract infections.

In patients with cerebral X-ALD, Hematopoietic Stem Cell Transplantation (HSCT) has been shown to improve survival and stabilize or improve cognitive abilities, but only if treatment is initiated during the early stages of cerebral demyelination when the lesion is still relatively small [5–7], highlighting the importance of early diagnosis. Surveillance MRI studies are important for early identification of brain lesions, before clinical symptoms appear and in time for HSCT. Specific clinical and radiologic criteria have been established for triaging cerebral X-ALD patients who are candidates for HSCT and have been described in detail using established clinical and radiologic criteria that have been established for triaging candidates for HSCT [5]. Factors associated with favorable treatment outcomes include low pre-transplant Loes radiographic severity score [8], limited degree of neurologic disability and high neuropsychometric measures after HSCT intervention [5, 7]. The therapeutic benefits of HSCT in X-ALD patients are believed to arise, at least in part, through the replacement of the patient’s genetically deficient brain microglia with genetically competent microglial progenitor cells arising from the donor blood [9].

Newborn screening for X-ALD is being implemented in a growing number of US states and is performed through the measurement of 26:0-lyso-PC levels and the ratios of 26:0-lyso-PC to 20L0-lyso-PC [10]. X-ALD males, aged 3–12 years identified through newborn screening or as relatives of a proband, should undergo gadolinium-enhanced magnetic resonance imaging (MRI) of the brain every 6 months to screen for early signs of cerebral demyelination in order to establish the need for early intervention. Annual MRI studies should be considered for adolescent boys and adults, who are at slightly lower risk for developing the cerebral ALD phenotype, Many practitioners continue to screen adult males yearly, though the incidence of development of cerebral X-ALD in adults is less well known. Among X-ALD men over 50 years and X-ALD women (heterozygotes) of any age, the onset of the cerebral and/or adrenal insufficiency phenotypes are uncommon, suggesting that routine surveillance screening for these individuals is probably unnecessary.

In boys who have not yet developed cerebral ALD, daily consumption of Lorenzo’s Oil, a mixture of oleic and erucic acid, in combination with dietary restriction of very long chain fatty acids, may help mitigate the risk of developing cerebral demyelination [11]. The oil acts as a competitive inhibitor of endogenous very long chain fatty acid production [12]. Use of Lorenzo’s Oil appears to offer a modest reduction in the risk of developing cerebral X-ALD, although it has no impact on the progression of cerebral X-ALD once the disease process has begun [11]. Its consumption carries health risks [13] and it’s availability in the US is currently restricted to X-ALD boys aged 3–10 under an expanded access trial (Clinical Trials.gov, NCT02233257).

A pilot phase trial using sobetirome, a thyromimetic, synthetic structural analogs of thyroid hormone that mimic tissue-restricted thyroid hormone actions [14] is in preparatory phases (ClinicalTrials.gov, NCT01787578) based on the molecule’s ability to upregulate ABCD2, whose genetic expression can help metabolize very long chain fatty acids [15]. Sobetirome showed efficacy and safety, indicating that it has been well tolerated at all doses studied.

Lentiviral-based gene therapy has shown early promise in X-ALD [16]. This technology involves the ex-vivo transduction of autologous HSCs with a human immunodeficiency virus type 1-derived vector. This retroviral vector targets microglial precursors, with no evidence of insertional mutagenesis, which can trigger leukemia and has the advantage of theoretically eliminating the risk of graft-versus host disease. Lentiviral ALD gene therapy has shown encouraging results in ALD patients where its use has resulted in polyclonal hematopoietic repopulation, stable transgene expression, and stabilization or reversal of demyelination [9] and is entering phase II/III clinical trials (ClinicalTrials.gov identifier: NCT01896102).

AGS patients share many common features with those affected by systemic lupus erythematosus (SLE), and rare cases of SLE have been found to be associated with TREX1 mutations. All AGS patients should be monitored and symptomatically treated for skin inflammation (e.g. chilblains), arthritis, inflammatory bowel disease, hematologic complications, and cardiomyopathy [22]. AGS patients with a SAMHD1 mutation are at risk high risk of developing potentially life-threatening complications from large vessel vasculitis; consideration should be given for both radiologic and serologic screening in these individuals. Many AGS patients exhibit a range of endocrine dysfunction (e.g. hypothyroidism) that may benefit from periodic screening and supplementation when indicated. Systemic immunosuppressive regimens (e.g. corticosteroids) have been employed as part of symptom management for AGS, but have not yet demonstrated definite improvement in neurologic symptoms [23].

Experiments in the murine model of AGS have demonstrated over-accumulation of endogenous retro elements [24, 25] while SAM domain and HD domain-containing protein 1 (SAMHD1) have been shown to be a dominant suppressor of Long Interspersed Element 1 (LINE-1). AGS-related mutations compromise the potency of SAMHD1 against LINE-1 retrotransposition [26]. Within the murine model of AGS, the use of reverse transcriptase inhibitors presumably targeting production of endogenous retroelements has been studied with promising results [27]. Significant work is still necessary to better understand the mechanisms of this disorder but efforts are underway to test the use of antiretroviral therapy in AGS patients.

Most individuals with Krabbe disease typically experience severe neurological disturbances. Krabbe Disease results from pathogenic mutations in the GALC gene which encodes the lysosomal enzyme galactosylceramidase. Most Krabbe-causing mutations result in severely diminished function of the enzyme. The classical presentation of Krabbe occurs in infancy where affected individuals manifest spasticity and irritability. Less commonly, some GALC mutations appear to result in a less severe attenuation of enzyme function which may lead to a milder phenotype. Unfortunately, genotype-phenotype correlations in Krabbe disease are generally inconsistent which poses a significant hurdle for treatment selection and clinical trial design.

Early studies suggest that in carefully selected cases (e.g. “presymptomatic” infants or older patients with low neurologic morbidity) HSCT may help attenuate the usually rapid neurologic deterioration [37–39]. The presymptomatic treatment paradigm constitutes the argument for newborn screening for Krabbe disease, which is currently available in a small number of US states. Among patients with later disease onset, HSCT may also prove beneficial, although the rarity of these phenotypes has limited its study [37, 39]. As in MLD, these treatment recommendations are tempered by a lack of long-term outcome data and poor genotype-phenotype correlations [40–42]. Clinical staging criteria have been proposed for Krabbe disease [43] and may be useful in evaluating patients for HSCT [44].

Missense mutations, occurring in >60% of Krabbe patients, are predicted to generate misfolded proteins [45]. Misfolded proteins can be prematurely degraded, aggregate within the cell, or trigger an unfolded protein response [46–48]. It is estimated that just 10% of normal galactosylceramidase (GALC) function is necessary to avoid the neurological symptoms associated with Krabbe disease [49]. Thus, an intervention that restores 10% of missense-causing GALC function would have the potential for impacting this disease. Pharmacological chaperones, synthetic low molecular weight molecules that can be administered orally with broad body-wide distribution (including the CNS), can rescue function of mutant proteins by directing them into a proper conformation or cellular location, or protecting them from degradation [50–52]. Pharmacological chaperones that improve the activity of misfolded GALC are currently being screened, with α-lobeline and 3′,4′,7-trihydroxyisoflavone recently identified candidates [53, 54].

MLD results from a pathogenic mutation in the gene encoding either arylsulfatase A or saposin B, either of which results in the accumulation of toxic metabolites (i.e. sulfatides) within the nervous system as well as some visceral organs. As with Krabbe disease, enzymatic activity levels tend to correlate with age of onset and severity of symptoms with age of onset ranging from infancy (most common) to adulthood (rare). Although motor symptoms dominate early life presentation of MLD, adults often manifest with increasingly severe psychiatric disturbances. The gallbladder accumulates particularly high levels of sulfatides which may result in potentially life-threatening, but treatable gall bladder pathologies (e.g. gallstones, papillomatosis, cholecystitis). In rare cases, identification of gallbladder dysfunction prior to the onset of neurologic symptoms could provide a theoretic window for early intervention to mitigate neurologic sequelae of MLD [55].

MLD patients have been treated with HSCT [39, 42, 56, 57], although its use has been widely debated due to phenotypic variability, transplant-refractory peripheral neuropathy, high treatment-related morbidity and mortality, and limited long-term outcome data. The most substantial disagreement centers on the use of HSCT among very young patients with early disease onset (i.e. late-infantile MLD); in addition to variable neurocognitive outcomes, these patients typically manifest transplant-refractory neuropathy which results in progressive flaccid paralysis [5]. Experts do agree, however, that symptomatic children with the late-infantile form of MLD are poor candidates for these therapies, as are individuals with later onset forms of the disease who have already accrued cognitive morbidity [5, 39, 58, 59]. Bone marrow transplantation has been shown to halt demyelination in minimally symptomatic patients with juvenile or adult MLD [60]. Since the initial publication of transplant outcomes in MLD [5], the treatment regimens have improved and there are indications that morbidity rates have fallen. In addition, the use of umbilical cord blood decreases the time between diagnosis and transplantation, improving outcomes of minimally symptomatic patients with late-infantile and juvenile MLD. Outcomes vary according to clinical status, Loes score, peripheral nerve disease and neurologic examination, with the best results for those with minimally symptomatic juvenile disease [40, 61–63]. Treatment recommendations are based on the limited long-term longitudinal outcome data currently available, as is the case of allogeneic HSCT for Krabbe disease patients [40–42]. The decision to pursue transplant among patients with these disorders can be complex and as a result, must be evaluated on an individual basis by a specialized and experienced center, prepared to provide the most up to date information and support patients with complex neurologic and systemic manifestations.

As therapy with HSCT has resulted in variable outcomes, Enzyme Replacement Therapy (ERT) is being studied under clinical trial in Europe, South America and Australia. ERT replaces the deficient or missing enzyme with an active enzyme, which is a recombinant human protein produced by gene activation technology. Therapeutic efficacy of ERT is thought to depend on the enzyme dose, frequency, and the disease stage at which treatment is initiated. Prior studies using a regular repeated intravenous delivery of recombinant human arylsulfatase A (rhASA) failed to show efficiency in permeating the blood-brain barrier [64]. Current Phase I/II studies, using an intrathecal delivery mechanism and a different enzyme are underway although no formal data will be available until late 2015 (ClinicalTrials.gov Identifier NCT01510028).

Lentiviral-based gene therapy for MLD have produced above-normal enzyme activity in the central nervous system and halted disease progression in the first three patients, who were presymptomatic when treated (ClinicalTrials.gov identifier: NCT01560182)[16]. Phase I/II post-therapy monitoring is underway with Phase II/III studies expected to start in 2015.

Almost all leukodystrophies may manifest acute neurologic deterioration in periods of acute stress, often without full recovery to premorbid baseline, however in certain disorders this is a classic presentation. Patients with Vanishing White Matter Disease (VWM) may present following febrile illness, head trauma and severe fright.[75]. Some mitochondrial disorders may manifest white matter abnormalities and episodic decline. Step-wise decline may also occur following infection in Pol III-related leukodystrophies [74] or in AGS [22], and after head trauma in X-ALD [76]. Therapeutic strategies for these disorders include aggressive infection prevention and treatment measures including frequent hand-washing, annual vaccinations for influenza and pneumococcus, and liberal antibiotic use. In the case of mitochondrial disorders, avoiding metabolic catabolism (i.e. nutritional fasting physiology) during periods of stress may also be appropriate [77]. Finally, greater than usual attention to avoid mild traumatic brain injury may also be warranted.

Pol III-related leukodystrophies, Cockayne syndrome, and Oculodentodigital Dysplasia (ODD) are three hypomyelinating leukodystrophies typically manifesting dental anomalies. For patients with these three hypomyelinating leukodystrophies, dental care is of utmost importance and regular visits to the dentist are recommended. In the Peroxisome Biogenesis Disorders, absence of enamel on the secondary teeth is a recurrent finding [78]. However, regular dental care and hygiene is important for all leukodystrophy patients as cavities and abscesses may go unnoticed in routine medical care and can result in severe medical morbidity. Thus, regular dental visits are recommended for all leukodystrophy patients.